Microbiology & Immunology Exam Flashcards
what are the main components of a TCR?
1 antigen binding site • variable regions • constant regions • transmembrane region • α chain • β chain
what is the difference between a BCR and a TCR’s CD molecules?
on a B cell IgM and IgD are associated with CD79 • TCR is associated with CD3
what are the 2 classes of TCR?
α:β • γ:δ
how are gene rearrangements in a TCR similar to gene rearrangements in a BCR?
VDJ segments for beta and gamma chains • VJ segments for alpha and delta chains
unlike a B cell where a B cell carries IgM and IgD as antigen receptors, a T cell carries what?
either alpha beta receptor or gamma-delta receptor
which has more variation, V region of alpha and beta chain or V region of gamma and delta chains
V region of alpha and beta chains
generation of the variable region of TCR is generated the same way like in BCR, except what?
that TCR does not undergo somatic mutation
which enzymes are involved in TCR development?
RAG1 and RAG2 • the same enzymes involved in TCR development
generation of antigen-binding diversity for TCR depends on what?
the same somatic recombination and junctional mechanisms used for BCR diversity
How is diversity created in TCR?
- joining of VDJ segments for beta and gamma chains • 2. joining of VJ segments for alpha and delta chains • 3. RAG-1 and RAG-2 encoded recombinase and TdT are required for somatic recombination • 4. junctional diversity
is there somatic hypermutation in TCR?
NO
T cell progenitors originate from and develop where?
they originate from bone marrow and develop in the thymus
to what is the TCR’s source of diversity in antigen recognition similar?
BCR because of random rearrangements of gene fragments VDJ and VJ
what is the structure of TCR?
has 2 peptides • α and β
how many epitope receptors does a TCR have?
1
how many CD3’s is each TCR associated with?
2
what is the function of ζ peptides in TCR?
signal transduction
what are the co-receptor molecules of CDR’s?
CD4 • CD8
when is Pre-TCR found?
on immature T cells; expressed early in development
when is TCR found?
on mature T cells
what is the major difference between pre-TCR and TCR?
pre-TCR has an incomplete α peptide: • pTα
how do T cell receptors recognize processed epitope?
in association with MHC
TCR require which co-receptors?
CD4 • CD8
which T cell type has co-receptor CD4?
Helper T cell
which T-cell type has the co-receptor CD8?
cytotoxic T cell
what is the MHC restriction of Helper T cells?
MHC II
what is the MHC restriction of cytotoxic T cells?
MHC I
what is the function of helper T cells?
B cells help macrophage activation • help for CD8 T cell cytokine secretion
what is the function of cytotoxic T cells?
killing virus infected cells • killing tumor cells
what are the parts of a CD4 co-receptor?
D1 • D2 • D3 • D4
what are the parts of the CD8 co-receptor?
α • β
what is the immune consequence of DiGeorge Syndrome?
thymic hypoplasia
What CD is expressed on a lymphoid precursor that just entered the thymus?
CD34
in the subcapsular zone of the thymus the cell becomes committed to develop to T cells by expressing what?
CD2
what are the two lines of development of committed CD2+ cells in the subcapsular zone?
beta-alpha expressing TCR • gamma-delta expressing TCR
in the beta-alpha line of development, the genes for beta gene segments are rearranged first and if it is productive, what happens next?
it is transcribe and translated to a beta chain that gets associated with a pTα.
what does a preT cell of the beta-alpha line express?
β • PTα
what happens if the pre T cell expressing β and PTα is functional?
the cell is signaled to rearrange the gene segments for α chain.
what is expressed on double positive T cells and where are they found?
double positive CD4+, CD8+ express TCR (βα) and are found in the cortex
What is positive selection in T cell development of the αβ line?
the TCR is checked if it can interact with MHC alleles of the person. • thymic epithelial cells present self antigen on MHC to the TCR. T cells expressing TCR that can interact with the MHC of the individual survive, if not they die
what is MHC restriction also known as?
positive selection
where and by what cells is negative selection in T cell development carried out?
by dendritic cells in the corticomedullary junction
what happens in negative selection during T cell development?
dendritic cells present self antigens on MHC I and II to the double positive cells. T cells with high affinity die, T cell with weak or intermediate affinity live. T cells that survive either become CD4 or CD8 depending on their affinity to either MHC I or MHC II
what happens in terms of CD during T cell development, to T cells with affinity to MHC I molecules?
CD8 marker retained • CD4 will be lost
what happens in terms of CD during T cell development to T cells with affinity to MHC II molecules?
CD4 will be retained • CD8 will be lost
what are single positive T cells?
CD4+ or CD8+ and self tolerant
which type of T cells leave the thymus after T cell development?
single positive
what is AIRE?
autoimmune regulator gene that plays a role in negative selection to T lymphocytes specific to self antigens not found in the thymus
what is the purpose for AIRE’s existence?
not all self antigens are present in the thymus to cause deletion of self reacting lymphocytes • -AIRE gene induces the expression of such self antigens in the thymus-m so that they can be used in negative selection
what % of the T cell pool is CD4-, CD8-, γδ+?
2-10% of total T cell pool
where are CD4-, CD8-, γδ+ cells found?
in tissue just before the dermis
do CD4-, CD8-, γδ+ T cells undergo selection?
no
how do CD4-, CD8-, γδ+ T cells emigrate?
Emigrate as CD4CD8 to epithelial tissues in skin, intestines and lungs
what is the function of CD4-, CD8-, γδ+ T cells ?
immunosurveillance of transformed, damaged, or stressed epithelial cells
what do CD4-, CD8-, γδ+ T cells recognize?
non-peptides • lipids • not completely identified (microbes or stressed host cells
do CD4-, CD8-, γδ+ T cells require APC?
no
what is the level of diversity of CD4-, CD8-, γδ+ T cells ?
limited diversity
what do naive T CD4 cells do upon exposure to antigens presented by APC?
differentiate into effector T CD4 cells
what are the effector T CD4 cells?
Th1 • Th2 • Th17 • Treg
the development of effector T CD4 cells depends on what?
cytokines in the environment, produced by the APC
what happens in naive T CD4 cells when they are exposed to the cytokines in the surroundings?
different transcription factors are activated
what do the effector T CD4 cells do?
produce a variety of cytokines that mediate different immunological activities
does clonal selection theory apply to T cell post antigen exposure development?
yes
What happens in development of Th1?
naive T CD4, under the influence of IL-12 and IFN-γ, induces T-bet, producing Th1
what are the cytokines produced by Th1?
IL-2 • IFNγ
what is the major effector function of Th1?
Cell mediated immunity, • intracellular pathogens • Activate macrophages • Activate B cells and CD8
what happens in development of The2?
Naive T CD4, under the influence of IL-4, induces GATA-3, producing Th2
what are the cytokines produced by Th2?
IL-4 • IL-5 • IL-13 • IL-10
what are the major effector functions of Th2?
Humoral immunity, • B cell activation • extracellular pathogens • parasites and allergy
what happens in the development of Th17?
Naive T CD4, under the influence of IL-23, IL-6, IL-1 induces RORyt, producing Th17
what cytokines are produced by Th17?
Proinflammatory: • inflamamtion • autoimmunity • response to fungi and extracellular bacteria
what happens in the development of Treg?
Naive T CD4, under the influence of TGF-β, induces FoxP3, producing Treg
what cytokines are produced by Treg?
TGF-β, IL-10
what are the major effector functions of Treg?
Down regulation: • Suppress other T cell subsets- anti-inflammatory activity
cytokines produced by Th1 act on what?
macrophages • NK cells • CD8 cells • B cells to switch to IgG1
cytokines produced by Th2 act on what?
eosinophils • B cells to switch to other class of IgG and IgE
cytokines produced by Th17 act on what?
neutrophils and epithelial cells
Treg acts on what cells?
other lymphocytes to prevent T cell proliferation
how many peptides in BCR?
4
how many peptides in TCR?
2
how many antigen binding regions in BCR?
2
how many antigen binding regions in TCR?
1
do TCR or BCR have variable and constant regions?
both have both
do TCR or BCR have gene segments and gene rearrangement?
both have both
what is the signal transducer molecule on BCR?
CD79
what is the signal transducer molecule on TCR?
CD3
Can BCR recognize free unprocessed antigen without MHC?
YES
can TCR recognize free unprocessed antigen without MHC?
NO
how does TCR recognize antigen?
recognize processed antigen in association with MHC on antigen presenting cells
what are the co-receptor molecules on TCR?
CD4 or CD8
from where does Tcell progenitor cell originate?
bone marrow
once a T cell progenitor migrates to the thymus, what can it develop into?
- γδ (CD4-, CD8-); • 2. αβ cells (CD4+ or CD8+) carrying TCR
how does the source of antigenic diversity of TCR relate to BCR?
source of antigenic diversity of TCR is similar to BCR
what is the difference between αβ and γδ T cell development?
α:β T lymphocytes undergo through positive and negative selection in the thymus while γδ cells do not
AIRE gene has a role in what type of disease?
autoimmune
CD3 and zeta associated with TCR serves as what?
signal transducer
CD4 and CD8 are coreceptors of what?
TCR
TCR recognizes epitopes associated with what?
MHC
Which CD interacts with which MHC in TCR?
CD4 interacts with MHC II and CD8 interacts with MHCI
under the influence of cytokines in the environment, naive CD4 (helper cells differentiate into what?
into Th1 • Th2 • Th17 • Treg
what is the function of Th1, Th2, Th17, and Treg?
these subsets of cells produce different set of cytokines with different roles in the immune system
what are the pre-antigen exposure B cell stages?
Pro B cell–> • Pre B cell –> • Immature B cell–> • mature B cell
what are the post antigen exposure B cell stages?
mature B cells become either Plasma cells or Memory cells
pre antigen b cell development involves what?
generation of antigen specific receptors which are immunoglobulin molecules of IgM and IgD isotypes
what is the specificity of BCR?
is antigen (epitope) specific
what type of immunoglobulin is BCR?
membrane immunoglobulin (mIg)
BCR is associated with which CD?
CD79 (Igα,β)
what is the function of CD79 (Igα,β)?
it’s a signal transducer
BCR belong to which two isotypes?
IgM • IgD
what is the similarity of the IgM and IgD on a single B cell clone?
both belong to the same idiotype (specific to a particular antigen)
the maturation stages of the B cell can be identified by what?
- changes in enzyme activity • 2. CD marker expression • 3. synthesis of BCR (IgM and IgD)
CD10, CD19, and CD20 are markers of what?
B cells
is CD 20 found on plasma cells?
no
what cells is CD 20 found on?
early to late B cell • lymphoma cells
how many B cell clones and repertoires can a person generate?
in any given individual it is possible to generate 10^9-10^10 different B cell clones, each with different epitope binding regions
construction of a unique variable region is possible by the process known as what?
somatic recombination
what factors contribute to somatic recombination?
- existence of multiple copies of gene segments that code for the variable regions • 2. combinatorial diversity generated by random selection and combination of gene segments • 3. junctional diversity generated by addition of deletion of bases • 4. random assortment of light and heavy chains
on which chromosome is the λ light chain locus?
chromosome 22
on which chromosome is the κ light chain locus?
chromosome 2
on which chromosome is the heavy chain locus?
chromosome 14
immunoglobulins are encoded by how many gene complexes?
3 gene complexes located on separate chromosomes
what are the functions of the 3 gene complexes located on separate chromosomes?
one for all heavy chains • one for κ chains • one for λ chains
how continuous are the gene complexes that code for immunoglobulins?
these genes are discontinuous and require translocations to be activated
what are the segments that encode the variable region of the light chain?
V • J
what are the segments that encode the variable region of the heavy chain?
V • D • J
what post-transcriptional processing do the gene complexes that encode immunoglobulin chains require?
DNA rearrangement • RNA splicing
what is the term for the process of gene rearrangement that occurs in generating BCR?
Cut and Paste process
RAG1 and RAG2 are what and what do they code for?
Recombination activating genes code for RAG1 and RAG2
what is an example of alternative splicing in gene selection for BCR?
the rearranged VDJ segment recombines first with Cμ segment creating the heavy chain μ for IgM, followed by Cδ segment creating the heavy chain δ for IgD
what is the reason for the alternative splicing seen in gene selection during synthesis of BCR?
in this way, both the IgM and IgD expressed on a B cell have the same VDJ
what are the 6 sources of BCR diversity?
- multiple copies of germline VDJ • 2. Random recombination of gene segments • 3. imprecision during cut and paste • 4. junctional diversity • 5. random reassortment of any light chain with any heavy chain • 6. somatic hypermutation
what is junctional diversity?
addition of sequence at the splice junction between V_D or D_J gene segments
what is somatic hypermutation?
fine tuning change after mutation
what is the cause of imprecise recombination in BCR formation?
the precise positions at which the genes for the V and J or VDJ segments are joined are not constant
imprecise DNA recombination can lead to what?
changes in the amino acid at the junctions
where does insertion of a new piece of DNA at the junctions take place?
at the junction of new segments
what is TdT?
terminal deoxynucleotidyl transferase
what is affinity maturation?
when somatic hypermutation improves the affinity of the antibody to the epitope
what is somatic hypermutation?
change in nucleotide in the rearranged variable gene segment of the light and heavy chain mainly in the CDR regions
the maturation stages of B cell development can be identified by what?
changes in enzyme activitiy • CD marker expression • synthesis of the BCR
what is allelic exclusion?
in a single B cell only one set of genes is expressed either maternal or paternal
what is Heavy chain rearrangement in the Pro B Cell?
DJ joined in both the chromosomes. Then VDJ is formed in one of the chromosomes
where do B cells develop?
in the fetal liver and adult bone marrow
when does heavy chain rearrangement take place?
in the pro B cell
what happens durring Ig Gene expression in the Pre B Cell?
VDJ get joined to the HCμ. μ chain together with surrogate chain is expressed
what is the μ chain together with the surrogate chain in the pre-Bcell called?
pre-B cell receptor
at the pro B cell level in the bone marrow, gene rearrangement of the H chain start with what?
a union of the D and J genes in both chromosomes (maternal and paternal)
what are the genes need to complete IgM?
VDJCμ
what happens if VDJCμ is productive- capable of being properly transcribed and translated?
further rearrangement of VDJ gene from the other chromosome is shut down, if not, the cell is given a second chance to use the other chromosome. if this fails, the cell dies by apoptosis
what is a surrogate light chain?
a false light chain
do the genes for VpreB and λ5 undergo rearrangement?
no
what do Igα and Igβ do in the pre-B cell?
singal the cell that has successfully rearranged its Ig H chain and has made functional μ chain to shut down further H chain rearragement
what is Bruton’s tyrosine Kinase?
one of the enzymes involved in intracellular signalling by Igα/β
mutation in the Btk gene results in what?
lack of differentiation to proB cell level
what is the condition caused by deficiency or defect in Btk?
X-linked agammaglobinemia
what happens if in the maturation of a B cell the cell is not self reactive?
alternative mRNA splicing of heavy chain gene transcripts then produces the δ and μ expressing both IgD and IgM
what happens once a functional pro-B cell receptor is produced?
rearrangement of the light chain genes start
which light chain genes rearrange first?
κ chain
what is central tolerance?
negative selection of self reacting immature B cells
what is receptor editing?
alteration of speecificity: • further round of light chain (V and J) gene rearrangement
what happens when an immature B cell recognizes a multivalent self molecule?
DELETION: • clonal deletion or receptor editing –> apoptosis
what happens when an immature B cell recognizes soluble self molecules?
ANERGY: • migrates to the periphery
what happens when an immature B cell recognizes low affinity non cross linking self molecule?
IGNORANT: • migrates to periphery • Mature B cell is clonally ignorant
what happens to an immature be cell with no self reaction?
FUNCTIONAL: • it migrates to the periphery and becomes mature
do anergic B cells express IgD?
yes
do clonally ignorant B cells express Ig?
yes, IgM and IgD
what is a clonally ignorant cell?
ligand is present but is not able to activate the cell
what are the cell stages of B cell maturation?
- Stem Cell • 2. Early Pro-B cell • 3. Late pro-B cell • 4. Large Pre-B cell • 5. small pre-B cell • 6. immature B cell • 7. Mature B cell
what is the status of the H-chain genes in a stem cell?
germ line
what is the state of the L chain genes in a stem cell?
germline
what is the state of surface Ig in a stem cell?
Absent
what is the state of H chain genes in an early pro-B cell
D-J rearranging
what is the state of L chain genes in an early pro-B cell?
Germline
what is the state of surface Ig in an early pro-B cell?
absent
what is the state of the H chain genes in a late pro B cell?
V-DJ rearranging
what is the state of the L chain genes in a late pro-B cell?
germline
what is the state of the surface Ig in a late pro-B cell?
absent
what is the state of the H chain genes in a large pre-B cell?
VDJ rearranged
what is the state of the L chain genes in a large pre-B cell?
germline
what is the state of surface Ig in a large pre-B cell?
μ chain transiently at surface as part of pre-B cell receptor. mainly intracellular
when does the μ + surrogate arrive in B cell maturation?
at the large pre-B cell stage
what is the state of the H chain genes in a small pre-B cell?
VDJ rearranged
what is the state of the L-chain genes in a small pre-B cell?
V-J rearranging
what is the state of the surface Ig in a small pre-B cell?
intracellular μ chain
at what stage in B cell maturation is the check to see if they recognize self antigens?
immature B cell stage
what is the state of the H chain genes in an immature B cell?
VDJ rearranged
what is the state of the L chain genes in an immature B cell?
VJ rearranged
what is the state of surface Ig in an immature B cell?
IgM expressed on cell surface
what is the state of the H chain genes in a mature B cell?
VDJ rearranged
what is the state of the L chain genes in a mature B cell?
VJ rearranged
what is the state of surface Ig in a mature B cell?
IgD and IgM made from alternatively spliced H-chain transcripts
what do naive B cells express on their surface?
IgM and IgD
what do plasma cells express on their surface?
plasma cells do not express surface Ig, but secrete Ig
what do memory cells express on their surface?
other Ig: • either IgG, IgA, or IgE
what is the clonal selection theory?
upon exposure to an antigen, a B cell with a BCR specific to that particular antigen proliferates to give rise to a clone of B cells expressing BCR of the same specificity
what happens in Ig class/isotype switch?
change of C domain, but not the VDJ because of alternative mRNA splicing
what does DNA recombination in isotype switch permit a cell to do?
enables the rearranged VDJ to be used with other heavy chain C chains
what is the first Ig produced after a B cell encounters an antigen?
IgM, followed by IgG or IgA with the same VDJ
what is affinity maturation?
mutation that takes place in the rearranged VDJ segment gives rise to antibodies with better affinity to epitopes
do antibodies produced in primary infection have more or less affinity for the epitope than Ab produced in subsequent infections?
less
what is detection of CD10/19/20 used for?
determine the developmental stage of leukemias and lymphomas of B cell origin
what does B cell coreceptor do?
increaes the sensitivity of B cell response to an antigen in the presence of complement activation and deposition of C3d
what is C3d?
a fragment of C3b of complement component
what are the 2 important subsets of B cells?
B2 • B1 (CD5+)
when do B2 cells develop?
after birth
when are B1 cells produced?
in fetal life
which type of B cell has a poorly understood developmental pathway?
B1
which type of B cell comprises the majority of B cells?
B2
What percentage of B cells are B1 cells?
5%
where are B2 cells found?
in secondary lymphoid organs
where are B1 cells found?
in body cavities
which surface Ig do B2 cells express?
both sIgM and sIgD
which surface Ig do B1 cells express?
sIgM but little sIgD
what type of antigens do B2 cells respond to?
protein antigens
which type of antigens do B1 cells respond to?
carbohydrate antigens • T independent antigens
which B cells require T cell help?
B2 cells
which B cells do not require T cell help?
B1 cells
which B cells secrete mainly IgM?
B 1 cells
which B cells give rise to plasma cells that secrete IgM, IgG, and IgA?
B2
which B cells leave memory?
B2 cells
which B cells leave little to no memory?
B1
B cells develop where in the body?
fetal liver • adult bone marrow
stages of B cell differentiation are defined by what?
Ig gene rearrangement ‘status’ and expression of certain CD 10, 19, 20
what is essential to the clonal nature of immunity?
allelic exclusion
how many opportunities do B cells have to rearrange their antigen receptors?
several
what are the possible fates of self reacting immature B cells expressing only IgM?
- allowed for receptor editing • 2. deleted, made anergic or ignorant
why are IgM and IgD expressed simultaneously on mature B cells?
due to differential RNA splicing
what is the function of CD79?
signal transducer
what does a B cell do upon an exposure to an antigen?
proliferates and differentiates into plasma cells and memory cells
what is class switch and what does it refer to?
class switching is isotype switching and refers to changes in CH gene selection but with no change in other genes (V domains or antigen specificity) by alternative RNA splicing
what makes up B cell co-receptor?
CD19 • CD21 • CD81
what are the two subsets of B cell types?
B1 • B2
What are immunoglobulins/antibodies?
glycoprotein molecules produced by plasma cells in response to an immunogen that can recognize the immunogen/antigen
what is myeloma?
a cancer that affects B cells, the immune cells responsible for the production of antibodies
from where do immunoglobulins derive their name?
the finding that when antibody-containing serum is placed in an electrical field the antibodies migrated with the globular proteins
the Ig molecule is made up of how many proteins?
4 peptide chains
what is the composition of the 4 peptide chains in an Ig?
2 heavy identical chains • 2 light identical chains
what are the regions present in Ig molecules?
the chains have variable region and constant region
what are VL and CL?
variable and constant region of the light chain
what are VH and CH?
variable and constant region of the heavy chain
what are responsible for the folding in the domains of an Ig?
sulfide bonds
what makes up an Ig?
- 4 peptide chains with heavy and light chains with variable and constant regions • 2. hinge region • 3. domains folded by sulfide bonds • 4. oligosaccharides
what are Ig classes/isotypes?
5 different classes based on the differences in the amino acid sequences in the constant region of the heavy chain
what are the 5 different heavy chains that determine the Ig classes?
- γ • 2. μ • 3. α • 4. δ • 5. ε
What Ig is associated with the γ chain?
heavy chain of IgG
what Ig is associated with the μ chain?
heavy chain of IgM
what Ig is associated with the α chain?
heavy chain of IgA
what Ig is associated with the δ chain?
heavy chain of IgD
what Ig is associated with the ε chain?
heavy chain of IgE
what is the difference between the IgG subclasses?
differ in amino acid sequence in their constant region of H chain: • 1. IgG1- gamma 1 heavy chains • 2. IgG2- Gamma 2 heavy chains • 3. IgG3- Gamma 3 heavy chains • 4. IgG4- Gamma 4 heavy chains
what is the difference between IgA Subclasses?
differ in aa sequence in their H constant region: • 1. IgA1 • 2. IgA2
what are the 2 types of L chains of Ig?
Kappa- κ • Lambda- λ
what is the difference between κ and λ L chains of Ig?
they differ in amino acid sequences in their constant region
what is the prevalence of κ and λ chains in Ig?
both types occur in all classes of Ig, but any one Ig molecule contains only one of them, either λ or κ
how many subclasses of IgG?
4
how many classes of IgA?
2
What is the organization of H2L2 structures?
2 identical L chains • 2 identical H chains • the H chain defines the class (and subclass) of the Ig produced
what is the functional organization of H2L2 structures?
- variable N terminal regions define the antigen binding site • 2. constant regions of the heavy chains define the functions of the immunoglobulin
in humans, what is the ratio of immunoglobulins containing two kappa vs two lambda chains?
2:01
how can the distinct fragments of the heavy chains be isolated into distinct fragments?
proteolysis
what happens when you reduce and acidify immunoglobulin?
you get isolated chains separated at the sulfide bonds
what happens when you treat an immunoglobulin with papain?
you get papain fragments
what does the Fc region do?
determines the biological function of Ig
what does the Fc region of Ig bind to?
Fc receptors on: • 1. phagocytic cells • 2. NK cells • 3. eosinophils • 4. Mast cells • 5. complement C1q • 6. placental cells
what are the different kinds of Fc receptors on cells?
different Fc receptors on these cells for the different Ig classes: • FcγR- IgG • FcμR- IgM • FcαR- IgA • FcεR- IgE
why is an antibody able to bind a particular antigenic determinant?
because it has a particular combination of VH and VL
specificity of antigen binding is determined by what?
hypervariability regions within the variable region domain
how many hyper-variable regions per variable region?
3
each variable region has 3 hyper-variable regions also called what?
complementary determining regions (CDR)
how many CDR’s per antigen binding site?
an antigen binding site is composed of three light chain CDR’s and 3 heavy chain CDRs
different combinations of a VH and VL result in what?
antibodies that can bind a different epitope
what is the antigen binding region called?
Fab Region
how is variability distributed in V domains?
there are discrete regions of hypervariability in V domains
what are the positions of CDR in the 2-D and 3-D models of the light chain and heavy chain?
-CDRs are separated in the linear 2D model of the peptide chains • - the hypervariable regions of the light chain and heavy chain are brought together in the folded 3D form of the intact antibody molecule
together the CDRs constitute what?
the combining site, which is complementary to the epitope
the variability in CDRs provides what?
the diversity required for the function of antibodies of different specificities
what is affinity in an Ab/Ag interaction?
strength of interaction between one epitope and one epitope binding site (the region between the variable region of heavy chain and light chain)
what is avidity in Ag/Ab interaction?
strength of interaction of multiple epitopes on a multivalent antigen molecule such as a big protein and several epitope binding site
what are hinge options?
the ability of an antibody to bind more than one protein with variable spacing on the surface of a bacterium
what is the structure of IgG?
monomer (7S)
how do the subclasses of IgG differ?
number of disulfide bonds and length of the hinge region
which is the most versatile Ig molecule?
IgG isotype
why is IgG isotype the most versatile immunoglobulin?
because it is capable of carrying out all of the functions of immunoglobulin molecules
what is the major Ig in serum?
IgG
how much of serum Ig is IgG?
75%
which is the major Ig in the extravascular spaces?
IgG
what are the capabilities of IgG?
- neutralization • 2. fixes complement • 3. binding to cells • 4. opsonization
what is neutralization by IgG?
inhibit binding of toxins or pathogens on target cells
do all subclasses of IgG fix complement?
not all subclasses fix complement equally well; IgG4 does not fix complement
which IgG does not fix complement?
IgG4
which cells have Fc receptors for the Fc region of IgG?
- macrophages • 2. monocytes • 3. PMNs • 4. NK cells
do all subclasses of IgG bind to cells?
not all subclasses bind equally well; • IgG2 and IgG4 do not bind Fc receptors
describe opsonization by IgG
IgG is a good opsonin. • a consequence of binding to the Fc receptors on PMN’s, monocytes and macrophages is that the cell can now internalize the antigen better
what is the name for adaptive immune defense mediated by antibodies?
humoral immunity
which is the only Ig that crosses the placental barrier?
IgG
what is transfer of IgG across the placental barrier mediated by?
receptor on placental cells for the Fc region of IgG
do all IgG subclasses cross the placental barrier?
not all subclasses cross equally • IgG2 does not cross well
which IgG does not cross the placental barrier well?
IgG2
what is ADCC?
antibody dependent cell-mediated cytotoxicity
NK cells have Fc receptors for which IgG?
IgG1 and IgG3
binding of NK cells to human cells coated with IgG1 an IgG3 results in what?
killing
ADCC targets what kind of cells?
tumor cells and virally infected human cells
why are tumor cells and virally infected human cells targeted by NK cells in ADCC?
they express antigens that are not found in normal cells
what are the steps of ADCC by NK cells?
- antibody binds antigens on the surface of target cells • 2. Fc receptors on NK cell recognize bound antibody • 3. cross-linking of Fc receptors signals the NK cell to kill the target cell • 4. target cell dies by apoptosis
what are the features of the structure of IgM?
Pentamer (19s) • extra domain (CH4) • J chain
in what 2 configurations can IgM exist?
- IgM normally exists as a pentamer (19S) in serum • 2. can exist as a monomer as antigen receptor on B lymphocytes
which is the third most common Ig in serum?
IgM
what is the valence of an Ig?
it’s epitope binding capacity
what is the similarity between chains in IgM when it is in its pentameric form?
all heavy chains are identical • all light chains are identical
what is the valence of IgM in its pentameric form?
10
what are the extra peptide features of IgM?
- extra domain on the μ chain (CH4) • 2. another protein covalently bound via S-S bond called the J chain
what is the J chain on IgM?
another protein covalently bound to IgM via S-S bonds
which chain functions in polymerization of the IgM molecule into a pentamer?
J chain
what is the first Ig to be synthesized by B cells during infection in adults?
IgM
what is the first Ig produced in fetal life?
IgM
in the newborn, an increased level of IgM is an indication of what?
in utero stimulation of the immune system by pathogens such as rubella virus, CMV, syphilis, toxoplasmosis
what are the pathogens that cause increased IgM in a newborn?
- rubella virus • 2. cytomegalovirus • 3. syphilis • 4. toxoplasmosis
which is the first type of antibody to appear in the primary response, between IgG and IgM?
IgM
what happens to IgG levels in the secondary response (compared to the primary response)?
IgG: • 1. appears earlier • 2. shows a more rapid rise • 3. has higher final concentration
what would happen if at the time of the second exposure to Ag1, a second, non-cross reacting Ag2 was injected?
a primary response to Ag2 would occur while a secondary response to Ag1 was occuring
how can the IgM Fc region affect complement?
the IgM Fc region can bind and activate complement
how many antigen binding sites does IgM pentamer have?
10
how many Fc regions for complement binding does an IgM pentamer have?
10
which Ig has the most efficient complement fixation?
IgM
which Ig is most efficient at agglutinating antigens?
IgM
how is the response of IgM to T cell independent (carbohydrate) antigens?
good
how is the structure of surface IgM different than serum IgM?
- exists as monomer • 2. lacks J chain • 3. extra 20 amino acids at the C terminal end to anchor it to the membrane
what is the function of cell surface IgM?
receptor for antigen on B cells
what is the structure of serum IgA?
monomr
what are the structural features of secreted IgA (sIgA)?
Dimer (11s) • J chain • secretory component
when IgA exists as a dimer, what is associated with it?
J chain
when IgA is found in secretions it also has, in addition to the J chain, what associated with it?
another protein called the secretory piece
what is IgA in secretions called?
sIgA
where is most of IgA made?
in the plasma cell
unlike the remainder of the IgA which is made in the plasma cell, the secretory piece is made where? and when?
in the epithelial cells and is added to the IgA as it passes into the secretions
what is the function of the secretory piece?
the secretory piece helps IgA to be transported across mucosa and also protects it from degradation by enzymes in the mucosal secretions
during which part of secretion of sIgA is the secretory component added?
during trancytosis between the extracellular space and the lumen
for transcytosis and association with the secretory component to take place, the IgA dimer must bind what?
a membrane bound Fc receptor (poly-Ig receptor)
what is the second most common serum Ig?
IgA
IgA is the major class of Ig in what?
secretions: • 1. tears • 2. saliva • 3. colostrum • 4. mucus
how is IgA transferred from mother to child?
breast feeding
what type of immunity transfer is breast feeding?
passive transfer of immunity
since it is found in secretions, sIgA is important in what type of immunity?
local (mucosal) immunity
does IgA fix complement?
normally IgA does not fix complement unless aggregated
how does IgA function in mucosal immunity?
IgA inhibit by neutralizing adhesion of pathogens/toxins to epithelial cell on mucosal surface
what are the structural components of IgD?
monomer • tail piece
how does IgD exist?
IgD exists only as a monomer
is IgD found in serum?
IgD is found in low levels in serum
what is the role of serum IgD?
role in serum is uncertain
where is IgD primarily found?
on B cell surfaces
what is the function of B cell bound IgD?
receptor for antigen
which Ig’s are found on the B cell surface?
IgD • IgM
IgD on the surface of B cells has what for anchoring to the membrane?
extra amino acids at C-terminal end
does IgD bind complement?
no
what are the structural components of IgE?
monomer • extra domain Cε4
which is the least common serum Ig?
IgE
why is IgE the least common serum Ig?
it binds very tightly to FcεR receptors on basophils and mast cells
IgE is primarily involved in what?
allergic reactions
why is IgE involved in allergic reactions?
as a consequence of its binding to basophils and mast cells
does IgE fix complement?
IgE does not fix complement
Binding of IgE to mast cell surface receptors does what?
primes the cell to respond to allergen
introduction of allergen and its subsequent binding to IgE on a mast cell induces what?
crosslinking of IgE and clustering of Fc receptors
clustering of Fc receptors on a mast cell post introduction of allergen does what?
initiates a signal transduction event that stimulates the mast cell to degranulate
besides allergic reactions, what does IgE play a role in?
parasitic helminth infections
what are the functions of IgE?
allergic reactions • parasitic helminth infections
why is measuring IgE levels helpful in diagnosing parasitic infections?
because serum IgE levels rise in parasitic diseases
how does IgE help kill parasites?
eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminthes results in release of granular contents which kill the parasite
which Ig’s predominate in the blood?
IgM, IgG and monomeric IgA predominate in the blood
which are the major Ig’s in the extracellular fluid?
IgG and monomeric IgA
which Ig predominates in the secretions?
dimeric IgA
where is IgE found?
IgE is associated with mast cells and is therefore found in the connective tissue beneath epithelial surfaces, particularly of the skin, respiratory tract and the GI tract
which Ig’s are in the brain?
THE BRAIN IS DEVOID OF IMMUNOGLOBULIN
isotypes of Ig have variations in what?
the Fc region, constant heavy chain
what are allotypes of Ig?
alleles: • variations in the Fc region found in members of the same species
when is the allotype of Ig important?
tissue typing for transplantation
what are idiotypes of Ig?
variation in the variable region
what does the idiotype of an Ig determine?
antigen specificity
what differentiating class of an Ig is present in all individuals of a species?
isotype
which differentiating class of an Ig is different alleles within a species?
allotypic determinants
which differentiating Ig class determines the antigen binding site?
idiotypic determinants
What is the degree of neutralization functionality of IgM?
+
what is the degree of neutralization function of IgD?
-
what is the degree of neutralization function of IgG1?
+++
what is the degree of neutralization function of IgG2?
+++
what is the degree of neutralization function of IgG3?
+++
what is the degree of neutralization function of IgG4?
+++
what is the degree of neutralization function of IgA?
+++
what is the degree of neutralization function of IgE?
-
which Ig’s have + degree of neutralization function?
IgM
which Ig’s have - degree of neutralization function?
IgD • IgE
which Ig’s have +++ degree of neutralization function?
IgG1 • IgG2 • IgG3 • IgG4 • IgA
what is the degree of opsonization function of IgM?
-
what is the degree of opsonization function of IgD?
-
what is the degree of opsonization function of IgG1?
+++
what is the degree of opsonization function of IgG2?
* req complement
what is the degree of opsonization function of IgG3?
++
what is the degree of opsonization function of IgG4?
+
what is the degree of opsonization function of IgA?
+
what is the degree of opsonization function of IgE?
-
which Ig’s have - degree of opsonization function?
IgM • IgD • IgE
which Ig’s have + degree of opsonization function?
IgG4 • IgA
which Ig’s have ++ degree of opsonization function?
IgG3
which Ig’s have +++ degree of opsonization function?
IgG1
what is the degree of sensitization for killing by NK cells function of IgM?
-
what is the degree of sensitization for killing by NK cells function of IgD?
-
what is the degree of sensitization for killing by NK cells function of IgG1?
++
what is the degree of sensitization for killing by NK cells function of IgG2?
-
what is the degree of sensitization for killing by NK cells function of IgG3?
++
what is the degree of sensitization for killing by NK cells function of IgG4?
-
what is the degree of sensitization for killing by NK cells function of IgA?
-
what is the degree of sensitization for killing by NK cells function of IgE?
-
which Ig’s have - degree of sensitization for killing by NK cells function?
IgM • IgD • IgG2 • IgG4 • IgA • IgE
what is the degree of sensitization of mast cells function of IgM?
-
what is the degree of sensitization of mast cells function of IgD?
-
what is the degree of sensitization of mast cells function of IgG1?
+
what is the degree of sensitization of mast cells function of IgG2?
-
what is the degree of sensitization of mast cells function of IgG3?
+
what is the degree of sensitization of mast cells function of IgG4?
-
what is the degree of sensitization of mast cells function of IgA
-
what is the degree of sensitization of mast cells function of IgE?
+++
which Ig’s have - degree of sensitization of mast cells function?
IgM • IgD • IgG2 • IgG4 • IgA
which Ig’s have + degree of sensitization of mast cells function?
IgG1 • IgG3
which Ig’s have +++ degree of sensitization of mast cells function?
IgE
what is the degree of activation of complement system function of IgM?
+++
what is the degree of activation of complement system function of IgD?
-
what is the degree of activation of complement system function of IgG1?
++
what is the degree of activation of complement system function of IgG2?
+
what is the degree of activation of complement system function of IgG3?
+++
what is the degree of activation of complement system function of IgG4?
-
what is the degree of activation of complement system function of IgA?
+
what is the degree of activation of complement system function of IgE?
-
which Ig’s have - degree of activation of complement system function?
IgD • IgG4 • IgE
which Ig’s have + degree of activation of complement system function?
IgG2 • IgA
which Ig’s have ++ degree of activation of complement system function?
IgG1
which Ig’s have +++ degree of activation of complement system function?
IgM • IgG3
what is the degree of transport across epithelium of IgM?
+
what is the degree of transport across epithelium of IgD?
-
what is the degree of transport across epithelium of IgG1?
-
what is the degree of transport across epithelium of IgG2?
-
what is the degree of transport across epithelium of IgG3?
-
what is the degree of transport across epithelium of IgG4?
-
what is the degree of transport across epithelium of IgA?
NAME?
what is the degree of transport across epithelium of IgE?
-
which Ig’s are not transported across epithelium?
IgD • IgG1 • IgG2 • IgG3 • IgG4 • IgE
which Ig’s are transported across epithelium to some degree?
IgM
which Ig’s are transported across epithelium A LOT?
sIgA
what is the degree of transport across placenta of IgM?
-
what is the degree of transport across placenta of IgD?
-
what is the degree of transport across placenta of IgG1?
+++
what is the degree of transport across placenta of IgG2?
+
what is the degree of transport across placenta of IgG3?
++
what is the degree of transport across placenta of IgG4?
++
what is the degree of transport across placenta of IgA?
-
what is the degree of transport across placenta of IgE?
-
what Ig’s are not transported across placenta?
IgM • IgD • IgA • IgE
which Ig’s are transported across placenta to some degree?
IgG2 (+)
which Ig’s are transported across placenta to a moderate degree?
IgG3 • IgG4 • (++)
which Ig’s are transported across placenta A LOT?
IgG1 (+++)
what is the mean serum level (mg/mL) of IgM?
1.5
what is the mean serum level (mg/mL) of IgD?
0.03
what is the mean serum level (mg/mL) of IgG1?
9
what is the mean serum level (mg/mL) of IgG2?
3
what is the mean serum level (mg/mL) of IgG3?
1
what is the mean serum level (mg/mL) of IgG4?
0.5
what is the mean serum level (mg/mL) of IgA
2.5
what is the mean serum level (mg/mL) of IgE?
5 x 10^-5
what is an immunogen?
substance capable of inducing adaptive immune response
what is an antigen?
substance capable of being recognized by the adaptive immunity.
what is the relationship between antigens and immunogens?
All immunogens are antigens, but not all antigens are immunogens
what is an epitope?
the region(s) of the antigen in direct contact with the antibody, B-Cell Receptor, or T-Cell Receptor
what is a synonym for epitope?
antigenic determinant
how many epitopes are there per antigen?
there may be one or more epitopes per antigen
what is a hapten?
a small molecule which can function as an antigen, but by itself is incapable of inducing an immune response
is a hapten an immunogen?
no
what are the 3 types of antigen/immunogen receptor molecules?
- BCR (b cell receptor) • 2. TCR (t cell receptor) • 3. MHC
of the 3 types of antigen/immunogen receptor molecules, which are surface immunoglobulins?
B-Cell Receptors
how many antigen recognition sites are there on a BCR?
two identical antigen recognition sites
how many antigen recognition sites are there on a TCR?
one antigen recognition site
where are MHC-I molecules expressed?
on all nucleated cells
where are MHC-II molecules expressed?
macrophages • dendritic cells • lymphocytes
which of the 3 types of antigen/immunogen receptor molecules is expressed on antigen presenting molecules?
MHC
which various antigens or sources of antigens are immunogens?
- parasites • 2. foreign proteins • 3. bacteria • 4. viruses • 5. fungi
antigens are big molecules- however, the area that triggers the specific immunity is a small part, known as what?
epitope
how big is an epitope?
an epitope in a protein antigen could be as few as 20 amino acids long
what is the shape of an epitope?
could be linear, conformational
what type of cells recognize a conformational epitope?
BCR only, not TCR
what is the difference between a linear and conformational epitope?
in a conformational epitope, the sequence of amino acids is discontinuous, but they are brought into proximity by the protein’s 3-D structure
what is a synonym for conformational epitope?
discontinuous epitope
when is there cross-reaction between different antigens?
when a different antigen has one identical determinant or a similar determinant
when is there no reaction between different antigens?
when there is no structural similarity
what is the receptor/binding activity of a BCR?
BCR–> Ag
what is the receptor/binding activity of a TCR?
TCR –> Ag/MHC
is MHC required for BCR?
no
is MHC required for TCR?
yes
does a BCR bind soluble antigen?
yes
does a TCR bind soluble antigen?
No
what is the chemical nature of BCR antigens?
protein • polysaccharides • lipids • nucleic acids
what is the chemical nature of TCR antigens?
proteins • some lipids, glycolipids
what type of epitope is recognized by BCR?
accessible, either linear or conformational
what type of epitope is recognized by TCR?
linear peptides (short)
what makes a good antigen/immunogen?
- physical size : > –> better • 2. complexity: chemical composition and structural complexity • 3. solubility or degradability by antigen processing cells, macrophages, dendritic cells and B cells • 4. foreignness to the individual
what size are the best immunogens?
>=100kD
what is the minimum size for active immunogens (proteins)
>30kD
how immunogenic is an immunogen that is <5-10kD?
minimally immunogenic, usually require carrier
what is an example of a <5-50kD immunogen that is minimally active and requires a carrier?
hapten
How do the categories of chemical compounds rank in terms of their immunogenicity based on complexity in descending order?
HIGH IMMUNOGENICITY: • 1. proteins and glycoproteins • 2. Polysaccharides • 3. nucleic acids, phospholipids • 4. haptens • LOW IMMUNOGENICITY:
are proteins and glycoproteins good immunogens?
yes
how complex are proteins and glycoproteins in terms of their immunogenicity?
complex in composition and structure
can proteins and glycoproteins induce immunity?
can induce humoral and cell-mediated immunity
how complex are polysaccharides in terms of their immunogenicity?
repeating structures, generally low affinity
what type of response do polysaccharide immunogens elicit?
IgM response
do polysaccharides stimulate a cell-mediated immune response?
cannot be processed and presented as linear epitopes for T cells, thus do not induce cell-mediated response
how foreign are nucleic acids and phospholipids in terms of their immunogenicity?
evolutionarily conserved; less foreign
how do nucleic acids and phospholipids become better immunogens?
conjugation with proteins or polysaccharides
how immunogenic are haptens?
insufficient in size to be immunogenic. need carrier
what examples of natural haptens?
hormones, lipids, simple sugars
what are examples of synthetic haptens?
chemicals, drugs (penicillin)
what types of drugs can act like haptens and be associated with severe, life threatening anaphylactic reactions?
antibiotics, particularly penicillins
how do penicillins act as haptens?
they form covalent bonds with proteins to produce protein-drug adducts that elicit an immune response (hypersensitivities) in some individuals
what are the 3 types of epitopes in a hapten-conjugate complex?
- the pure hapten • 2. the pure antigen • 3. the hapten-antigen complex
how can a hapten be made immunogenic?
immunizing with a hapten-carrier conjugate
do identical twins recognize each other’s proteins as foreign?
no. • they have the same genetic makeup and their immune systems would recognize eachother as self
what are examples of immunologically privileged anatomical sites (sequestration)?
corneal, spermatic, CNS cell antigens
What are the types of antigens?
- mitogens • 2. superantigens • 3. T cell independent • 4. T cell dependent
mitogens are characterized by what?
the same epitope repeated many times
how many types of B cells can mitogens activate?
more than one B cell type/clone
are mitogens B cell monoclonal or polyclonal activators?
B cell polyclonal activators
what are superantigens?
antigens that can activate more than one type of T cell
are superantigens polyclonal/monoclonal B/T cell activators?
polyclonal T cell activators
what effect do superantigens have on the immune system?
cause hyper activation of the immune system
what is an example of excessive T cell activation having drastic effects?
toxic shock syndrome
what does an antigen being T cell independent vs. T cell dependent depend on?
whether an anigen can stimulate B lymphocytes with or without the help from T lymphocytes
How do superantigens induce activation of multiple types of T cells?
they are polyclonal stimulators of T cells, binding to the MHC-TCRβ (on the outside of the polypeptide of TCR) complex, without regard for antigen specificity
How much of CD4 T cells are activated by super antigens?
up to 20%
what is the result of a superantigen activating up to 20% of circulating CD4 T cells?
massive production of cytokines such as IL1, IL2, and TNFα which causes systemic shock
what are examples of conditions that are caused by superantigens?
food poisoning • toxic shock syndrome
what microbes cause food poisoning and/or toxic shock syndrome?
bacterial exotoxins: • staphylococcal • enterotoxins • staphylococcal toxic shock toxin • staphylococcal exfoliating toxin • streptococcal pyrogenic exotoxins
what forms a bridge between CD4 T cell’s receptor and the MHC II molecule?
superantigens
what do T cells do in response to a superantigen?
divide and differentiate into effector cells
what are T-independent antigens?
antigens which can directly stimulate B cells to produce antibody without the requirement for T cell help
do T independent antigens require to be presented by APC?
no
usually, T independent antigens are what?
mitogen and are resistant to degradation by antigen presenting cell
what are examples of T independent antigens?
pneumococcal polysaccharide • lipopolysaccharide • flagellar antigen
what are T dependent antigens?
antigens that require the help of T lymphocytes to activate be cells to produce antibody
are T dependent antigens degradable by antigen presenting cell?
yes
what type of compounds are T dependent antigens?
protein
in addition to size, molecular complexity and foreignness, immunogenicity of an antigen depends on what?
- physical form • 2. degradability • 3. route • 4. dose • 5. adjuvant
which physical form of an antigen is more immunogenic, particulate or soluble?
particulate > soluble
why are particulate antigens more immunogenic than soluble ones?
particulate form are more easily taken up by antigen presenting cells
which physical form is more immunogenic, denatured or native?
denatured > native
what speed of release is important for immune response?
slow release
what are the relative immunogenicities of routes of administration?
subcutaneous > intraperitoneal > intravenous > intragastric
what is the limitation of the oral route of administration’s immunogenicity?
oral route induces local mucosal immunity but not systemic immunity
what is low zone tolerance?
low doses appear to inhibit the specific antibody production
what is high zone tolerance?
very high doses of antigen inhibit immune responsiveness to a subsequent challenge
what is the effect of an adjuvant on immunogenicity?
substances mixed together with an antigen and enhance an immune response to an antigen
what is the difference between an adjuvant and a carrier molecule?
unlike carrier molecule an adjuvant does not form stable linkage with the antigen
what is an example of an adjuvant?
- complete Freund’s adjuvant • 2. aluminum hydroxide/aluminum phosphate
what is Complete Freund’s Adjuvant?
water in oil emulsion containing killed mycobacteria
how does an adjuvant increase immunogenicity of an antigen?
- insolubilize antigen for better phagocyte uptake • 2. insolubilize antigen for gradual release over time in lipid emulsions called liposomes with delayed time release of antigen • 3. stimulating the influx of phagocytic cells or other immune cells to the site
some adjuvants contain mycobacterial components capable of stimulating what?
the innate immunity- acitvation of macrophages
what can inflammation be thought of as?
a regulatory event aimed at mobilizing various innate immune effectors and trafficking them to the anatomic location where they can be most effective
what is the etymology of inflammation?
latin: inflammare- to set on fire
inflammation is initiated by the presence of what?
infectious agents • tissue damage • self (auto) antigens (autoimmunity)
in inflammation an innate or adaptive immune action?
combined action of several immune responses of both innate and specific immunity
inflammation leads to what?
- vascular dilation/ increased vascular permeability • 2. accumulation of inflammatory cells • 3. destruction of initiating agent • 4. tissue repair • 5. tissue damage/scarring
what are the symptoms of inflammation?
rubor • tumor • calor • dolor • functio laesa
what are the cellular players in acute inflammation?
tissues mast cell • neutrophil • macrophage
what cells, in addition to the cellular players in acute inflammation, may also be found at site of inflammation?
eosinophils • basophils
what are the functions of tissue mast cells in acute inflammation?
release of histamine and other mediators
what are the functions of neutrophils in acute inflammation?
phagocytosis and killing
what are the functions of macrophages in acute inflammation?
phagocytosis and killing • antigen presentation
what are the functions of eosinophils in acute inflammation?
killing of parasites
inflammatory stimuli do what?
- activate the complement system • 2. degranulate mast cells • 3. acitvate macrophages • 4. activate coagulation system
inflammatory stimulia activate the complement system, degranulate mast cells, activate macrophages and coagulation system leading to the production of what?
bradykinin, which increases vasodilation
in response to inflammatory stimuli, platelts are a mojor component of clotting, releasing what?
prostaglandins • hydrolytic enzymes • growth factors • other mediators that stimulate various cell types to contribute to antimicrobial defense, wound healing, and inflammation
microbes and/or their products that enter through a breach in the dermis induce what?
phagocytes to secrete pro-inflammatory cytokines (IL1, TNFα), also activate complement leading to the expression of adhesion molecules by vascular endothelium
the net movement of WBC’s from circulation into tissue is called what?
extravasation
what are the steps of extravasation?
- Rolling Adhesion • 2. Firm Adhesion (tethering and tight binding, margination) • 3. diapedesis (transendothelial migration) • 4. Migration toward the site of infection
Extravasation is driven by what compounds?
TNFα • IL1 • IL8 • C3a • C5a
how does rolling in extravasation work?
- rolling uses selectins • 2. rolling is a low affinity adhesion • 3. E-selectin on endothelium bind to mucin like adhesion molecule on the phagocytic membrane briefly. • 4. force of blood moves rolling on
what are the proteins that bind in rolling during extravasation?
E-selectins on endothelium bind to mucin-like adhesion molecules (selectins/Sialyl Lewis sugars) on the phagocytic membrane briefly
what force causes rolling during extravasation to move on?
blood flow
describe activation by chemoattractants during extravasation
chemokines released during inflammation stimulate conformational change in integrin molecules in phagocytic membrane that incresae their affinity for ICAM adhesion molecules on the endothelium
what are the chemokines released during inflammation that stimulate conformational change in integrin molecules in phagocytic membrane that increase their affinity for ICAM adhesion molecules on the endothelium?
IL-8 • C5a
to what family of compounds does ICAM belong?
immunoglobulin superfamily
what proteins are associated with tethering and tight binding during extravasation?
integrins (LFA)
what is LFA?
lymphocyte function-associated antigen 1
what types of adhesions are formed in tethering and tight binding during extravasation?
firm adhesion to ICAMS
what is diapedesis?
transendothelial migration
diapedesis is mediated by what?
PECAM, now renamed CD31
what is PECAM?
platelet endothelial cellular adhesion molecule
where is CD31 expressed?
on endothelial cells and neutrophils
what happens to endothelial expression of E and P selectins under the influence of inflammatory stimuli?
endothelial expression of E and P selectins increases
to what family of compounds does LFA-1 belong?
part of the integrin family of leukocyte adhesin molecules
What is CD18?
common β chain of the leukocyte integrins
what does absence of CD18 cause?
leukocyte adhesion deficiency disease
what cytokine released by macrophages upregulate the expression of P selectin on endothelial cells?
TNFα
what do P and E selectin do?
together E and P selectin slow the motion of leukocytes through the bloodstream by causing them to roll along the endothelial surface, allowing other molecules to interact with the slowed leukocytes to stop them and promote their movement into the tissues.
what compounds stimulate E and P selectin expression?
IL-1 • LPS • TNFα
what is LPS a component of?
the membranes of many gram negative bacteria
what do LPS binding proteins on macrophages do when they come into contact with their ligand?
stimulate macrophages to release inflammatory cytokines
Both E and P selectins are known to bind with what?
Sialyl-Lewis x like glycans
where are Sialyl-Lewis x-like glycans expressed?
in relatively high numbers by circulating leukocytes
in addition to Sialyl Lewis glycans, what else does P selectin bind?
P-selectin glycoprotein ligand-1 (PSGL-1)
where is PGSL-1 expressed?
modestly expressed on human leukocytes
leukocyte recruitment by E and P selectin is analogous to what?
throwing a tennis ball at a velcro surface
tight adhesion to the rolling leukocyte is performed by what?
ICAM-1
what does ICAM-1 bind to?
integrins LFA-1 and CR3 on the leukocyte surface
what does ICAM-1 do?
binds to the Integrins LFA-1 and CR3 on the leukocyte surface and arrests the motion of the rolling leukocyte.
why does ICAM-1 stop the rolling leukocyte?
stopping the leukocyte allows it to enter the tissues by secreting proteases to breach the endothelial basement membrane
what is the acute phase response?
physiological processes that occur during inflammation or tissue damage, triggered by IL-1, IL-6, TNFα
which cytokines trigger the acute phase response?
IL-1 • IL-6 • TNF-α
on what systems do IL-1, IL-6, and TNFα act during the acute phase response?
hypothalamus • bone marrow • liver
what does the acute phase response cause by acting on the hypothalamus?
fever
what does the acute phase response cause by acting on the bone marrow?
stem cell differentiation and proliferation
what does the acute phase response cause by acting on the liver?
increase production of acute phase proteins
what are the purposes of the acute phase response?
- provides replenishment of cells and acute phase proteins used during an inflammation response • - increase metabolic activity
what are acute phase proteins?
heterogenous group of serum proteins that increase during inflammation
what do acute phase proteins do?
replace exhausted components and reinforce innate defenses against infection
what are the important acute phase proteins?
- C-reactive protein • 2. mannose-binding lectin • 3. complement • 4. fibrinogen
what is CRP?
a protein found in the blood, the levels of which rise in response to inflammation
what does CRP do?
- acts as an opsonin AND • 2. it binds to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1q complex (classical pathway in the absence of antibody)
what are the relative levels of CRP and MBL in the plasma?
the levels of CRP and MBL are low in the plasma, but levels can increase by up to 1000 fold during the peak of the acute phase response
when is the peak of the acute phase response?
about 2 days after its start
CRP and MBL both bind to what?
distinct structures that are common features of pathogens and not features of human cells
what is the clinical application of CRP?
levels of CRP are routinely measured in clinical diagnostic laboratories to indicate an acute inflammation
what does MBL do?
acts as opsonin and triggers complement activation via lectin pathway
what does fibrinogen do?
plays a role in blood clotting, which limits the spread of pathogens
IL1/IL6/TNFα elicit what acute phase response in the liver?
acute phase proteins (CRP, MBL)–> activation of complement/opsonization
IL1/IL6/TNFα elicit what acute phase response in the bone marrow endothelium?
neutrophil mobilization –> phagocytosis
IL1/IL6/TNFα elicit what acute phase response in hypothalamus?
increased body temperature –> decreased viral and bacterial replication
IL1/IL6/TNFα elicit what acute phase response from fat, muscle?
protein and energy mobilization to generate increased body temperature–> decreased viral and bacterial replication
what do pyrogens do?
increase body temperature
what is the purpose of fever?
- increase metabolic activity • 2. inhibit multiplication of certain bacterial and viral agents • 3. human cells become more resistant to TNF-α
what does the acute phase reponse do to the supply of the recognition molecules of innate immunity?
increases the supply of the recognition molecules of innate immunity
what do bacteria do to induce synthesis of acute-phase proteins?
bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins
what does the liver do in response to IL-6?
synthesize CRP, MBL, fibrinogen
what does CRP synthesized by the liver do to bacteria?
CRP binds phosphocholine on bacterial surfaces, acting as an opsonin and as a complement activator
what does MBL do to bacteria?
MBL binds to carbohydrates on bacterial surfaces, acting as an opsonin and as a complement activator
when does adaptive immunity play a role in inflammation?
in chronic inflammation: • non-digestible foreign material • chronic damage
what are the causes of chronic inflammation?
- persistent infections and/or infections with resistant microorganisms such as mycobacterium • 2. autoimmune disease or malignancies (first response, acute followed by chronic) • 3. response to ‘un-digestible’ foreign material
does chronic inflammation involve innate or adaptive immunity?
both
what are the major cellular actors in chronic inflammation?
macrophages • Th1 (CD4) lymphocytes
what do macrophages do in chronic inflammation?
continue to produce pro-inflammatory cytokines (TNFα, IL-1, IL-8) and seek help from Th1
what do Th1 (CD4) lymphocytes do in chronic inflammation?
secrete several cytokines
what do IFNγ and CD40 ligand do in chronic inflammation?
regulate and strengthen the intracellular killing by macrophages and neutrophils
what does the secretion of TNFα, IL1, and IL8 by activated macrophages do in chronic inflammation?
promote recruitment of inflammatory cells to the area
how do Th1 and macrophages interact during chronic inflammation?
- Th1 cell and infected macrophage come together • 2. T cell binds to and activates macrophage • 3. killing of intravesicular bacteria
when do granuloma form?
when an intracellular pathogen resists elimination even after receiving help from CD4 Th1
what do Th1 cells do when a pathogen resists intracellular killing?
play an important role in fighting such infections by producing different sorts of cytokines which bring more help to the macrophages
what are conditions in which granuloma form?
MTB • Leishmania
what cells make up and surround a granuloma?
macrophages make up the bulk of a granuloma and lymphocytes surround it
which type of inflammation is pyogenic, acute or chronic?
acute
which type of inflammation is granulomatous, acute or chronic?
chronic
what are the typical triggers for acute inflammation?
staphylococci
what are the typical triggers for chronic inflammation?
mycobacterial infecton • hepatitis B
what are the initiating cells in acute inflammation?
mast cells • macrophages
what are the initiating cells in chronic inflammation?
macrophages
what are the effector cells in innate system during acute inflammation?
neutrophil
what are the effector cells in the innate system during chronic inflammation?
macrophage • NK cell
what are the effector cells in the adaptive system during acute inflammation?
none involved
what are the effector cells in the adaptive system during chronic inflammation?
Th1
what are the mediators of acute inflammation?
complement, • GM-CSF, • TNF, • chemokines
what are the mediators of chronic immunity?
TNF • IL-12 • IL-18 • IFNγ • chemokines
what are the systemic effects of acute inflammation?
pus formation, abscesses
what are the systemic effects of chronic inflammation?
granuloma may be present
What happens in local infection with gram-negative bacteria?
- macrophages activated to secrete TNF-α in the tissue • 2. Increased release of plasma proteins into tissue. Increased phagocyte and lymphocyte migration into tissue. Increased platelet adhesion to blood vessel wall • 3. phagocytosis of bacteria. local vessel occlusion. containment of infection. Antigens drain or are carried to local lymph node. • 5. survival. stimulation of adaptive immune system.
what happens in systemic infection with gram-negative bacteria?
- macrophages activated in the liver and spleen secrete TNF-α into the bloodstream • 2. systemic edema causes decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia. decreased blood volume causes collapse of vessels. • 3. disseminated intravascular coagulation leads to wasting and multiple organ failure: septic shock. • 4. death
what do vascular endothelial cells make in response to TNF-α and what does it do to blood?
platelet activating factor, which triggers blood clotting and blockage of the local blood vessels.
what is the benefit of PAF released in response to TNFα by vascular endothelial cells?
restricts the leakage of pathogens into the circulation and prevents disseminated infection.
infection of the blood is known as what?
sepsis, septicemia
mutation of what has been linked to development of septic shock in patients?
mutation of TLR4 (a receptor for LPS on phagocytic cells)
What are the 3 classes of cellular effectors?
- Degranulating Cells • 2. NK Cells • 3. Phagocytic Cells
What cells make up the degranulating cellular effectors of the innate immune system?
Mast Cells • Eosinophils
What cell line gives rise to NK Cells?
Lymphoid Line
with what degree of specificity do NK cells kill?
nonspecific killing
do NK cells participate in innate or adaptive immunity?
lymphoid line, but part of innate immune system
what do NK cells target?
intracellular pathogens • tumor cells
what do phagocytic cells target?
extracellular pathogens
what cells make up the phagocytic cellular effectors of the innate immune system?
neutrophils (PMNs) • monocytes/macrophages
part of the inflammatory response is the recruitment of what type of cells (the main line of defense in the non-specific immune system) to site of infection?
polymorphonuclear • eosinophils • macrophages
what are LAK cells?
Lymphokine Activated Killer Cells
what do NK and LAK cells do?
NK and LAK cells can nonspecifically kill virus infected and tumor cells
what do PMN cells do once they are recruited to the site of infection?
- they phagocytose invading organisms and kill them intracellularly • 2. they contribute to collateral tissue damage that occurs during inflammation
what is the function of tissue macrophages and newly recruited monocytes which differentiate into macrophages in innate immunty?
- phagocytosis and intracellular killing of microorganisms • 2. macrophages- contribute to tissue repair and act as antigen-presenting cells, which are required for the induction of specific immune responses
how do mast cells and eosinophils function in the innate immune response?
- have proteins in granules that are effective at helping to recruit and enhance ann immune response • 2. eosinophils- killing certain parasites
where are mast cells found?
found posted throughout the body tissue
Mast cells can be stimulated to degranulate by what?
- direct injury/ trauma • a. physical • b. chemical • 2. cross linking of IgE receptors • 3. activated complement proteins • a. C3a • b. C5a
what are the forms of chemical direct injury that cause mast cells to degranulate?
- opioids • 2. alcohols • 3. certain antibiotics (polymyxins)
what are the inflammatory mediators released by the degranulation of mast cells?
- histamine • 2. platelet activating factor • 3. prostaglandins • 4. leukotrienes
the degranulation of mast cells results in what?
- recruitment of immune cells • 2. increase in vasopermeability
where are eosinophils found?
found circulating or in tissue
how are eosinophils recruited to the site of infection?
get recruited to the site of infection by cytokines
Eosinophils have receptors for which complement product?
C3b
what does C3b do to eosinophils?
stimulates degranulation
what types of cells are targeted by eosinophils?
big parasites
how do eosinophils kill big parasites?
- producing oxygen radicals • 2. forming pores on target cells
are eosinophils phagocytic?
may be phagocytic and assist in clearing of foreign material at the site of injury or infection
how do eosinophils stain?
stain with acid dyes
chemotaxis of eosinophils to sites of infection is in response to what?
cytokines: • - IL8 • - Others belonging to chemokine family CXC and CC
NK cells participate in the recognition and killing of what target cells?
damaged or altered self cells • virally infected cells
what is the activation state of circulating NK cells?
circulate in partially activated state
what are the 2 mechanisms by which killing by NK is mediated?
- secretion of perforins and granzymes lead to apoptosis of target cells • 2. FAS ligand mediated ‘apoptosis’
what is the most important cytokine produced by NK cells?
IFN-γ
what are the CD markers present on NK cells?
CD16 • CD56
why do NK cells respond quickly to infection?
because they circulate in partly activated state, as seen from their large size and their cytoplasmic granules loaded with toxic effector molecules
what does stimulation of NK cells with IFN-α and IFN-β favor?
the development of the cell’s killer functions
what does stimulation of NK cells with IL-12 favor?
the production of cytokines
what is the principal cytokine released by NK cells?
IFN-γ/ type II interferon
what is a major function of IFN-γ?
to activate macrophages
what are the receptors on NK Cells?
- KAR- Killer activating receptor • 2. KIR- killer inhibiting receptor
what ligands on target cells are recognized by NK cells?
KAL- Killer activating ligand
what are some examples of KAL?
viral antigens • tumor antigens (stress protein) • MICA, MICB
killing by NK cells is regulated by binding of what to what?
KAR to KAL • KIR to MHC I
if a target cell expresses MHC I, will it be killed by NK or LAK cells?
no • MHC I binds Killer Inhibiting Receptor
what types of cells express MHC-I?
normal cells constitutively express MHC-I molecules on their surface
how do viruses and tumor affect MHC-I?
virus infected and malignant cells down regulate expression of class I MHC
Infection of cells may lead to the surface expression of what?
stress molecules
in response to viral infection, host cells may express what?
stress molecules: • MICA and MICB • and reduce surface expression of MHC-I
what are MICA and MICB?
MHC class I chain-related Genes
expression of MICA and MICB can be detected by what?
NK cells that seek to eliminate virally infected cells
what happens if both KIR and KAR on the NK cell are bound?
if insufficient KIR-MHC-I binding occurs, the NK cell will proceed to kill the target host cell. • sufficient binding by KIRs will override the KAR kill signal, sparing the life of the host cell
where are the MICA and MICB genes located?
within the HLA class I region of chromosome 6
are MICA and MICB similar to HLA class I genes?
their organization, expression and products differ considerably from classical HLA class I genes.
MICA and MICB are considered to be markers of what?
stress in the epithelia
what do MICA and MICB act as?
ligands for cells expressing a common activatory natural killer cell receptor • —KALs—
is the FasL on the NK cell or the target cell?
the NK cell
is the Fas Receptor on the NK cell or the target cell?
target cell
what are the 2 NK cell killing mechanisms?
- Granzymes • 2. FasL/FasR
what is the mechanism of cell death induced by NK cells?
apoptosis
what cell is responsible for phagocytosis of debris generated by NK cell killing?
macrophage
Absent NK activity is a component of what disease?
immunodeficiency disease Chediak-Higashi syndrome
what are the professional phagocytic cells?
polymorphonuclear neutrophils • mononuclear monocytes/macrophages
which class of professional phagocytic cell are granulocytes?
polymorphonuclear neutrophils
which class of professional phagocytic cells are agranulocytes?
mononuclear monocytes/macrophages
do professional phagocytic cells circulate in blood?
PMN- circulate in blood • monocytes- circulate in blood • macrophages-reside in tissues
which of the professional phagocytic cells is more committed to phagocytic activity?
PMNs- mainly phagocytic • Mononuclear monocytes- have function other than phagocytosis
what are the functions of mononuclear monocytes/macrophages other than phagocytosis?
- produce inflammatory cytokines • 2. clear debris and damaged tissue • 3. link innate to adaptive immunity
what is the lifespan of the professional phagocytic cells?
PMN’s live <2days • MM/M’s live months-years
what are the inflammatory cytokines produced by MM/M’s
IL8 • IL1 • IL6 • TNFα
what is the morphology of PMN’s?
variable and irregular shape of nucleus, contain granules
when are PMN’s found in the tissues?
not found in healthy tissue, but when there is infection they enter tissue
what calls the PMN’s to enter the tissues?
cytokines produced by the macrophages
which professional phagocytic cells set the stage for tissue repair?
macrophages
which professional phagocytic cells clear tissue of products of inflammation and of remaining microbes?
macrophages
What are the 2 major mechanisms by which immune cells recognize pathogens in innate immunity?
- Pattern Recognition Receptors (PRR) • 2. Pathogen Associated Molecular Patterns (PAMP)
where are PRR’s found?
on the surface of immune cells and soluble molecules
what are some examples of cellular PRR’s?
- Toll Like Receptors (TLR’s) • 2. Complement Receptors (CR3 and CR4) • 3. Mannose Receptor • 4. Glucan Receptor • 5. CD14, LPS Receptor • 6. Receptor/Scavenger Protein
what is an example of a soluble PRR?
complement
where are PAMP’s found?
on the surfaces of microbes or microbial products
what are examples of PAMP’s?
- LPS of gram negatives • 2. Lipoteichoic acid of gram positives • 3. Lipoarabinoman of acid fast bacteria • 4. Mannose in glycolipids and glycopeptides (surface antigens) • 5. N-Formyl methionine peptides (soluble factor) • 6. dsRNA, ssDNA of viruses • 7. bacterial and viral unmethylated CpG DNA • 8. Bacterial Flagellin • 9. Glucans from fungal cell walls
which PAMP is associated with gram negative bacteria?
LPS
which PAMP is associated with gram positive bacteria?
Lipoteichoic acid • peptidoglycan
which PAMP is associated with acid fast bacteria?
Lipoarabinomannan
which PAMP’s are assciated with surface antigens?
mannose in glycolipids and glycopeptides (surface antigens)
which PAMP is evidence of prokaryotic proteins?
N-formyl methionine
what is innate immunity designed to recognize?
molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells.
what are PAMP’s?
unique molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells
what molecules on human cells can act as PAMP’s?
DAMP’s (Damage Associated Molecular Pattern)
how do toll like receptors sense infections?
with a horseshoe shaped structure- transmembrane polypeptides with pathogen recognition domain and a signalling domain
where might TLR’s be expressed?
- cell surface • 2. endosomes in the cytoplasm
what are the structural variations possible in TLR’s?
- single polypeptide • 2. homodimer • 3. heterodimer
which TLR is typically found as homodimer?
TLR4-TLR4
which TLR is typically found as heterodimer?
TLR1-TLR2
what are the ligands of the TLR1:TLR2 heterodimer?
Lipopeptides • GPI
what are the microorganisms recognized by TLR1:TLR2 heterodimer?
Bacteria • Parasites like trypanosomes
what cells carry the TLR1:TLR2 heterodimer?
monocytes • dendritic cells • eosinophils • basophils • mast cells
what are the ligands of the TLR2:TLR6 heterodimer?
lipoteichoic acid • zymosan
what are the microorganisms recognized by the TLR2:TLR6 heterodimer?
gram-positive bacteria • yeasts (fungi)
what are the cells carrying the TLR2:TLR6 heterodimer?
monocytes • dendritic cells • eosinophils • basophils • mast cells
what is the ligand of TLR3?
viral dsRNA
what microorganisms are recognized by TLR3?
viruses (west nile)
what cells carry TLR3?
NK cells
what is the ligand of the TLR4:TLR4 homodimer?
lipopolysaccharide
what microorganisms are recognized by the TLR4:TLR4 homodimer?
gram-negative bacteria
what cells carry the TLR4:TLR4 homodimer?
macrophages • dendritic cells • mast cells • eosinophils
what is the ligand of TLR5?
Flagellin
what microorganisms are recognized by TLR5?/
motile bacteria havign a flagellum
what cells carry TLR5?
intestinal epithelia
what is the ligand of TLR7?
viral ssRNA
what microorganisms are recognized by TLR7?
viruses like HIV
what cells carry TLR7?
plasmacytoid dendritic cells • NK cells • eosinophils • B cells
what is the ligand of TLR8?
viral ssRNA
what microorganisms are recognized by TLR8?
viruses like influenza
what cells carry TLR8?
NK cells
what is the ligand of TLR9?
unmethylated CpG-rich DNA
what microorganisms are recognized by TLR9?
Bacteria • viruses like herpes
what cells carry TLR9?
plasmacytoid dendritic cells • B cells • eosinophils • basophils
what is the ligand and microorganism of TLR10 homodimer and heterodimers with TLR1 and TLR2?
unknown
which cells carry TLR10?
plasmacytoid dendritic cells • basophils • eosinophils • B cells
what TLRs are carried by NK cells?
TLR3 • TLR7 • TLR8
what TLRs are carried by monocytes?
TLR1:TLR2 • TLR2:TLR6
what TLRs are carried by dendritic cells?
TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4
what TLRs are carried by eosinophils?
TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4 • TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2
what TLRs are carried by basophils?
TLR1:TLR2 • TLR2:TLR6 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2
what TLRs are carried by mast cells?
TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4
what TLRs are carried by macrophages?
TLR4:TLR4
what TLRs are carried by plasmacytoid dendritic cells?
TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2
what TLRs are carried by intestinal epithelia?
TLR5
what TLRs are carried by B cells?
TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2
which TLRs are found on cell surfaces?
TLR1:TLR2 • TLR2:TLR6 • TLR5 • TLR4
which TLRs are found inside the cytoplasm in endosome?
TLR7 • TLR8 • all the TLRs that recognize viral nucleic acids
What are the 2 possible fates of PRR+PAMP (danger signal)?
- phagocytosis and killing • 2. cytokine production (inflammatory cytokines)
what do SOS signals include?
PAMP containing peptides released by bacteria • clotting system peptides • complement products • cytokines released from tissue macrophages that have encountered bacteria
phagocytic cells have what receptors on their cell membranes through which infectious agents bind to the cells?
- complement receptors • 2. scavenger receptors • 3. toll like receptors
which component of complement do phagocytic cells have a receptor for?
C3b
binding of C3b coated bacteria to the receptor on phagocytic cells results in what?
enhanced phagocytosis and stimulation of the respiratory burst
what do scavenger receptors on phagocytic cells bind to?
a wide variety of polyanions on bacterial surfaces, resulting in phagocytosis of the bacteria
binding of infectious agents via toll like receptors on phagocytic cells results in what?
phagocytosis and the release of inflammatory cytokines by the phagocytes
what are the inflammatory cytokines released by phagocytic cells in response to TLR binding?
IL1 • TNFα • IL6
how does the Fc receptor work in adaptive initiation?
bacteria with IgG antibody on their surface have the Fc region exposed and this part of the Ig molecule can bind to the receptor on phagocytes
binding of IgG coated bacteria to Fc receptors on phago cytic cells results in what?
enhanced phagocytosis and activation of the metabolic activity of phagocytes (respiratory burst)
what does PAMP-PRR engagement do to phagocytes?
activates phagocytes to ingest and degrade the microbes
what happens in phagocytosis of a bacterium?
- attachment of bacterium • 2. phagocyte begins to extend pseudopods around the bacterium • 3. pseudopods surround and engulf the bacterium • 4. bacterium is enclosed in a phagosome • 5. granules or lysosomes of the phagocyte fuse with the phagosome and empty their contents • 6. result is beacterium engulfed in phagolysosome which contains the contents of the granules or lysosomes
sensing of LPS by TLR4 on macrophages leads to what?
activation of the transcription factor NFκB and the synthesis of inflammatory cytokines
what does NFκΒ do in the nucleus of a macrophage?
activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted via the ER
PRR+PAMP sends signaling –> what?
cytokine production
what are the steps in phagocytosis by PMN’s?
- bacterium is phagocytosed by neutrophil • 2. phagosome fuses with azurophilic and specific granules • 3. pH of phagosome rises, antimicrobial response is activated, bacterium is killed • 4. pH of phagosome decreases, fusion with lysosome allows acid hydrolases to degrade the bacterium completely • 5. neutrophil dies by apoptosis and is phagocytosed by macrophage
why do neutrophils die?
the mature neutrophil cannot replenish its granule content, so once they are used up the neutrophils die by apoptosis and are cleared by macrophages
what do the contents of neutrophils’ granules kill?
- microbes intracellularly during phagocytosis • - released extracellularly where they kill not only microbes but also surrounding cells and tissue
what are the 2 major types of neutrophil granules?
- primary (azurophil) • 2. secondary (specific)
what are the contents of a primary granule in a neutrophil?
- proteases • a. elastase • b. cathepsin G • 2. hydrolases • 3. myeloperoxidase • 4. defensins • 5. lysozyme • 6. BPI (bactericidal permeability increasing protein)
what keeps the contents of a primary granule inactive in a resting neutrophil ?
low pH
what are the contents of a secondary granule in a neutrophil?
- lactoferrin • 2. lysozyme • 3. collagenase • 4. components of the NADPH oxidase system
what does BPI do?
binds to LPS and kills gram negative bacteria
what 2 mechanisms make up intracellular killing in neutrophils?
- preformed compounds • 2. production of antimicrobial compounds
do preformed compounds in intracellular killing by neutrophils require oxygen?
no they are oxygen independent
where are preformed compounds in intracellular killing in neutrophils stored?
they are stored in cytoplasmic granules
do the antimicrobial compounds produced in intracellular killing in neutrophils require oxygen?
they are oxygen dependent • RESPIRATORY BURST
what is bystander damage?
when compounds involved in intracellular killing by neutrophils are released to the surrounding tissue and cause damage
what are the oxygen independent preformed microcidal compounds found in neutrophils that damage microbial membranes?
- Cathepsin G • 2. Low molecular weight defensins • 3. high molecular weight cationic proteins • 4. bactericidal permeability • 5. BPI
what are the oxygen independent microcidal compounds in neutrophils that split mucopeptide in bacterial cell walls?
lysozyme
what oxygen independent microcidal compounds in neutrophils complex with iron?
lactoferrin
what oxygen independent microcidal compounds in neutrophils digest killed organisms?
proteolytic enzymes • other hydrolytic enzymes
how does lactoferrin exert its microcidal effect?
it chelates iron, which deprives bacteria of this required nutrient
which intracellular killing mechanism is more efficient, oxygen dependent or independent?
oxygen dependent
can patients with defects in oxygen dependent mechanism of itnracellular killing still kill bacteria?
yes
patients with defects in oxygen dependent microcidal pathways have what problem?
they are more susceptible and get more serious infections
What are three reactions involving superoxide and hydrogen peroxide in the oxygen dependent respiratory burst?
-
how is glucose metabolized during phagocytosis?
via the Pentose phosphate pathway and NADPH is formed
what is the respiratory burst
the increase in glucose and oxygen consumption during phagocytosis
what is the consequence of the respiratory burst?
a number of oxygen containing compounds are produced which kill the bacteria being phagocytosed
what are the 2 types of oxygen dependent intracellular killing?
- oxygen dependent myeloperoxidase-independent intracellular killing • 2. oxygen-dependent myeloperoxidase-dependent intracellular killing
what is the role of cytochrome B in oxygen-dependent myeloperoxidase-independent intracellular killing?
cytochrome B, which was part of the specific granule, combines with the plasma membrane NADPH oxidase and activates it
what does NADPH oxidase do?
the activated NADPH oxidase uses oxygen to oxidize the NADPH, resulting in the production of a superoxide ion, some of which is converted to H2O2 and singlet oxygen by superoxide dismutase
what is the product of the reaction between H2O2 and superoxide?
hydroxyl radical and singlet oxygen
what are the toxic oxygen species produced in oxygen dependent myeloperoxidase independent intracellular killing?
O2- (superoxide ion) • H2O2 • OH* (hydroxyl radical)
when is myeloperoxidase released into the phagolysosome in oxygen dependent myeloperoxidase dependent intracellular killing?
as the azurophilic granules fuse with the phagosome
what does myeloperoxidase do?
utilized H2O2 and halide ions (Cl-) to produce hypochlorite, a highly toxic substance
what happens when some of the hypochlorite produced in oxygen dependent myeloperoxidase dependent intracellular killing breaks down spontaneously?
yields singlet oxygen
what are the toxic species produced in oxygen dependent myeloperoxidase dependent intracellular killing?
OCl- • singlet oxygen
activated macrophages (via PRR or INFγ) express high levels of what enzyme?
nitric oxide synthase
is NO+O2- more or less toxic?
NAME?
which TNF is associated with increased expression of iNOS by macrophages?
TNFα
how does TNFα affect production of Nitric Oxide?
TNF acts in an autocrine manner to induce the expression of the iNOS gene, resulting in the production of NO
what is the toxicity of NO in macrophages?
nitric oxide released is toxic and can kill microorganisms in the vicinity of the macrophage
what are the pro-inflammatory cytokines released by macrophages?
IL6 • TNF α • IL1β • CXCL8 • IL12
what are the systemic effects of IL6 released by macrophages?
- fever • 2. induces acute phase protein production by hepatocytes
what are the local effects of TNFα released by macrophages?
activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage into lymph nodes
what are the systemic effects of TNFα released by macrophages?
- Fever • 2. Mobilization of metabolites • 3. Shock
what are the local effects of IL1β released by macrophages?
- activates vascular endothelium • 2. activates lymphocytes • 3. local tissue destruction • 4. increases access of effector cells
what are the systemic effects of IL1β released by macrophages?
- fever • 2. production of IL6
what are the local effects of CXCL8 released by macrophages?
chemotactic factor recruits neutrophils and basophils to site of infection
what are the local effects of IL12 released by macrophages?
activates NK cells
what was CXCL8 previously known as?
IL8
where does oxygen independent and dependent intracellular killing take place?
inside phagolysosome
where does nitric-oxide dependent killing take place?
inside phagolysosome and cytosol
what does a defect in NADPH oxidase cause?
chronic granulomatous disease
what are the 8 steps of phagocytosis of a bacterium by a phagocyte?
- chemotaxis • 2. adherence through PAMP recognition • 3. membrane activation through danger signal • 4. initiation of phagocytosis • 5. phagosome formation • 6. fusion • 7. killing and digestion • 8. release of degradation products
at what step of phagocytosis does tissue damage known as bystander damage take place?
release of degradation products
what does the complement system consist of?
several proteins, about 30, circulating in blood plasma, lymph and extracellular fluids
how are complement proteins designated?
C#…C1, C2, C3 • factor ALPHA… factor B, factor H
what produces complement proteins?
liver cells • monocytes • macrophages • gut epithelial cells
are complement proteins heat stable or heat labile?
heat-labile
how are complement proteins activated?
most of these are proenzymes, inactive until they are cleaved (complement activation)
what triggers complement activation?
microbial substances • immune complex (antigen + antibody)
how are cleavage products of complement activation designated?
split products are distinguished from the parent pro-enzyme by suffix lower case letters: • C3–> C3a + C3b
what happens to complement proteins when they are cleaved?
they become active enzymes, proteases, “convertase” that act on other complement components
In what fashion does complement activation take place?
in a sequential fashion
describe the cascade fashion in which complement activation takes place
many components of the system serve as the substrate of a prior component and then as an enzyme to activate a subsequent component
what does C’-fixation mean?
utilization of C’ by antigen-antibody complexes
what are the 3 activation pathways of the complement system?
- classic • 2. alternative • 3. lectin/mannan pathway
in which type of immunity are the 3 activation pathways of the complement system involved?
innate and adaptive immunity
what are the major functions of the 3 activation pathways of the complement system?
- inflammation- vasodilation • 2. chemotaxis- attraction of cells of the immune system • 3. killing of pathogen cells by lysis • 4. opsonization- enhancing phagocytosis
what is an opsonin?
any molecule that targets an antigen for an immune response
what happens in the alternative pathway of complement activation?
pathogen surface creates local environment conducive to complement activation
which of the pathways of complement activation is first to act?
alternative pathway
what happens in the lectin pathway of complement activation?
mannose binding lectin binds to pathogen surface
which of the pathways of complement activation is second to act?
lectin pathway
what happens in the classical pathway of complement activation?
C-reactive protein or antibody binds to specific antigen on pathogen surface
which of the pathways of complement activation is the 3rd to act?
Classical Pathway
what happens in complement activation as a result of all 3 pathways of complement activation?
cleavage of C3 to C3a and C3b • C3b covalently bound to surface components of pathogen
what 3 things happens as a result of C3 cleavage and C3b binding to surface components of pathogen?
- recruitment of inflammatory cells • 2. opsonization of pathogens, facilitating uptake and killing by phagocytes • 3. perforation of pathogen cell membranes • …which collectively cause the death of the pathogen
what are the key steps in all pathways of complement activation?
- initiation • 2. formation of the C3 convertase • 3. formation of the C5 convertase • 4. all pathways feed into terminal or membrane attack complex formation
is the alternative pathway part of the innate or adaptive immune response?
part of the innate immune response
what happens in the initiation of the alternative pathway of complement activation?
spontaneous cleavage of C3 at low rate in plasma: • - C3b gets inactivated in plasma, but: • –if it binds human cells, it is inactivated by complement regulator proteins produced by host cells. • – if it binds to the surface of foreign microorganisms, it gets stabilized
what are examples of specific molecules on the surface of microorganism required for the alternative pathway of complement activation?
- peptidoglycan • 2. teichoic acids • 3. lipolysaccharides
what triggers the alternative pathway of complement activation?
C3 hydrolysis directly on the surface of a pathogen
what does the alternative pathway of complement activation not rely on, that the other pathways do rely on?
pathogen-binding protein
where is C3 produced and cleaved in the alternative pathway of complement activation?
protein C3 is produced in the liver and is then cleaved into C3a and C3b by enzymes in the blood
what happens to C3a and C3b if there is no pathogen in the blood?
the C3a and C3b protein fragments will be deactivated
what happens in the alternative pathway if there is a nearby pathogen?
- some of the C3b is bound to the plasma membrane of the pathogen. • 2. it will bind factor B • 3. this complex will be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb
what does C3bBb do?
The C3bBb complex, which is ‘hooked’ onto the surface of the pathogen, will act like a chain saw, catalyzing the hydrolysis of C3 in the blood to C3a and C3b, which positively affects the number of C3bBb hooked onto a pathogen.
what happens after hydrolysis of C3 in the alternative pathway of complement activation/
C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b.
C5a and C3a are known to trigger what?
mast cell degranulation
what is a membrane attack complex and how is it formed?
C5b, with C6, C7, C8, C9 (C5b6789) complex to form the MAC, which is inserted into the cell membrane, punches a hole, and initiates cell lysis.
which pathway provides another means of protection against certain pathogens before an antibody response is mounted?
the alternative pathway of C activation
what does a deficiency of C3 cause?
increased susceptibility to the organisms that activate the alternative pathway
which is the most primitive of the complement activation pathways?
alternative pathway
what are the benefits of the alternative pathway of complement activation?
provides a means of non-specific resistance against infection without the participation of antibodies and hence provides a first line of defense against a number of infectious agents.
which protein has been extensively studied for its ability to activate the alternative pathway ?
cobra venom factor (CVF)
what happens when C3b associates with C3bBb?
C3BbCBb is formed
what is C3bBbCBb?
a C5 convertase
what kind of organisms activate the alternative pathway?
- many Gram-negative bacteria (most significantly, Neisseria meningitidis and N. gonorrhoea) • 2. some Gram-positive • 3. certain viruses and parasites
In serum there is a low level of spontaneous hydrolysis of C3 to produce what?
iC3
Factor B binds to iC3 and becomes what?
susceptible to Factor D
what does factor D cleave factor B into?
Bb
what does the iC3Bb complex do?
acts as a convertase and cleaves C3 into C3a and C3b
What does factor B do once Cb is formed by cleavage of C3?
Factor B will bind to C3b and becomes susceptible to cleavage by factor D, resulting in a C3bBb complex.
what does the C3bBb complex generate?
more C3b, thus amplifying C3b production
what happens if C3 activation continues unchecked?
consumption of all C3 in the serum
what role does properdin play in alternative pathway control?
properdin stabilizes C3 convertase C3bBb
what are the roles of factors H and I in the control of the alternative pathway?
destabilization/destruction: • inactivation of C3b by factor H and I to give fragment iC3b
what does deficiency of factor H and I lead to?
depletion of C • fail to control infections
what role does DAF, MCP play in control of the alternative pathway
destabilization/destruction: • DAF and MCP disrupt C3 convertase C3bBb on a human cell surface
what does deficiency of DAF, MCP lead to?
destruction of self cells
What is DAF?
decay accelerating factor
What is MCP?
membrane co-factor protein
how do factor H and I avoid excessive usage and depletion of C3 from the plasma?
by inactivating C3b and preventing further cleavage of C3
when faced with bacterial infection, patients with factor H/I deficiency run out of C3 and fail to control infections, especially with WHICH TYPE of bacteria?
capsulated bacteria which require opsonization for elimination by phagocytic cells
what is the role of i3Cb?
deposited on surface of pathogens • serves as opsonin • facilitate phagocytosis by binding to CR3 and CR4 (complement receptors) on phagocytic cells.
what are the 2 main features of membrane attack complex formation (pathway)?
- initiated by the formation of C5 convertase • 2. requires the presence of an accessible phospholipid membrane on the target cell on which to build the pore complex
what does formation of the c5 convertase trigger in the MAC formation (pathway)?
the association of a group of complement proteins which do not undergo cleavage but are active as intact proteins which build a transmembrane pore (MAC) in the target cell, resulting in leakage of cytoplasmic contents
what are examples of microbes resistant to MAC?
- encapsulated bacteria • 2. gram positive bacteria • 3. un-enveloped viruses
what happens in the Membrane Attack (lytic) Pathway?
- C5 convertase from the alternative (C3bBb3b) pathway cleaves C5 into C5a and C5b. • 2. C5a remains in the fluid phase and the C5b rapidly associates with C6 and C7 and inserts into the membrane. • 3. C8 binds, followed by several molecules of C9. • 4. The C9 molecules form a pore in the membrane through which the cellular contents leak and lysis occurs.
is membrane attack pathway lysis an enzymatic process?
no: • it is thought to be due to physical damage to the membrane
what is the complex consisting of C5bC6C7C8C9 referred to as?
the membrane attack complex
what are some of the potent biological activities of C5 generated in the lytic pathway?
- it is the most potent anaphylotoxin • 2. it is a chemotactic factor for neutrophils and stimulates the respiratory burst in them • 3. it stimulates inflammatory cytokine production by macrophages
the activities of C5 generated in the lytic pathway are controlled by what?
carboxypeptidase B (C3-INA)
what intermediate of the lytic pathway can dissociate from the membrane and enter the fluid phase?
C5b67, the dissociation of which could cause damage to bystander cells
damage to bystander cells by C5b67 from the lytic pathway which has dissociated from the membrane is prevented by what?
Protein S (vitronectin): • Protein S binds to soluble C5b67 and prevents it from binding other cells
what binds to the C5b678 complex on human cells and prevents recruitment of C9 to form the pore?
CD59
what are the main features of the lectin (mannan) pathway?
- part of the innate immune response • 2. nonspecific • 3. initiated when MBL binds to mannose or GlcNAc residues on microorganisms
what does initiation of the lectin (mannan) pathway activate?
MBL-associated serine proteases (MASPs) which split C4 and C2 to form C3 convertase
what happens after the initiation of the lectin (mannan) pathway creates the C3 convertase?
- C3b is produced • 2. the C5 convertase (C4b, C2a, C3b) is formed and the MAC complex begins
To which other complement activation pathway is the Lectin pathway most similar?
the classical pathway
how is the Lectin pathway initiated?
by the binding of MBL to bacterial surfaces with mannose containing polysaccharides.
what are mannans?
mannose containing polysaccharides
binding of MBL to a pathogen results in what?
association of 2 serine proteases: • 1. MASP-1 • 2. MASP-2
what other proteins are MASP-1 and MASP-2 similar to?
C1r and C1s
what protein is MBL similar to?
C1q
formation of the MBL/MASP-1/MASP-2 trimolecular complex results in what?
the activation of the MASP’s and subsequent cleavage of C4 into C4a and C4b
what happens to the C4a/b fragments formed by cleavage of C4 in the Lectin pathway?
- the C4b fragment binds to the membrane • 2. C4a fragment is released into the microenvironment
in addition to cleaving C4 in the Lectin pathway, MASP’s also cleave what?
C2 into C2a and C2b
what do C2a and C2b cleaved by the MASP’s in the Lectin pathway do?
- C2a binds to the membrane in association with C4b. • 2. C2b is released into the microenvironment
what is the function of the C4bC2a complex in the Lectin pathway?
it is a C3 convertase which cleaves C3 into C3a and C3b
what happens to C3a and C3b formed from cleavage by C4bC2a in the Lectin pathway?
- C3b binds to the membrane in association with C4b and C2a. • 2. C3a is released into the microenvironment
what is the function of C4bC2aC3b complex in the Lectin pathway?
C5 convertase
what is the end of the Lectin pathway?
generation of the C5 convertase
What are Ficolins?
a group of oligomeric lectins with subunits consisting of both collagen (Col)-like long thin stretches and fibrinogen (Fi)-like globular domains with lectin (Lin) activity usually specific for N-acetylglucosamine (GlcNAc)
what are Ficolins similar to?
ficolins are homologous to MBL and function via MASP in a similar way
what do ficolins do in non-vertebrates without an adaptive immune system?
ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules
the biological activities and the regulatory proteins of the Lectin pathway are the same as those of what pathway?
the classical pathway
Is the classical pathway part of innate or adaptive immunity?
both
why is the classical pathway ‘specific’?
due to the requirement of antibodies bound to the surface of particulate antigen
the classical pathway is activated by what?
Antigen-Antibody
the ‘innate’ classical pathway is activated by what?
C-reactive protein bound to pathogens
what complement protein does the classical pathway require?
C1
what is C1 composed of?
C1q • C1r • C1s
what is the best activator of the classical pathway?
IgM
what are the weaker activators of the classical pathway?
some classes of bound IgG: • IgG3,1,2
What does the C1-complex consist of?
one molecule of C1q and two molecules of C1r and C1s
how is the classical pathway triggered?
by activation of the C1 complex
how is the C1-complex activated?
- C1q’a binding to antibodies from classes M and G complexed with antigens • or • 2. binding of C1q to the surface of the pathogen
the binding of C1q to the antibodies or the surface of the pathogen leads to what?
- conformational changes in C1q molecule, which leads to the activation of two C1r molecules. • 2. then C1r cleaves C1s
what does the C1-complex do after 2 C1r’s cleave 2 C1s’s in the classical pathway?
the complex now binds to and splits C2 and C4, producing C2a and C4b
the inhibition of C1r and C1s is controlled by what?
C1-inhibitor
in the classical pathway, what molecules bind to form the C3 convertase?
C4b and C2a
which protein is larger, C2a or C2b?
C2a
what signals the end of the classical pathway?
production of the C3 convertase, but cleavage of C3 by this enzyme brings us to the start of the Alternative pathway
to what 2 things does C1 bind in the same way?
IgM and C-reactive protein
what are the 2 types of C3 convertase?
- Lectin and Classical- C4bC2a • 2. Alternative- C3bBb
what are the types of C5 convertase?
- Lectin and Classical- C2a4b3b • 2. Alternative- C3bBb3b
what does C4-BP inhibit?
C4b
What are the components of the Alternative pathway?
C3 • Factor B • Factor D • Properdin
what are the components of the Classical Pathway?
C1 • C4 • C2 • C3
what are the components of the Lectin pathway?
MBL • MASP-1 • MASP-2 • C4 • C2 • C3
is the Alternative pathway antibody initiated?
NO
is the Classical Pathway Antibody initiated?
YES
is the Lectin Pathway Antibody Initiated?
NO
is the alternative pathway initiated by pathogen surfaces?
yes
is the classical pathway initiated by pathogen surfaces?
Yes via antibody attachment or CRP
is the Lectin pathway initiated by pathogen surfaces?
yes
is there anaphylotoxin generation in the alternative pathway?
yes
is there anaphylotoxin generation in the classical pathway?
yes
is there anaphylotoxin generation in the lectin pathway?
yes
what is anaphylotoxin?
C3a • C5a
does the alternative pathway feed into the MAC?
yes
does the classical pathway feed into the MAC?
yes
does the Lectin pathway feed into the MAC?
yes
what are the regulatory components of the alternative pathway?
Factor H • Factor I • DAF • CR1
what are the regulatory factors of the classical pathway?
C1-INH • C4-BP • Factor I
what are the regulatory components of the Lectin pathway?
C1-INH • C4-BP • Factor I
what type of pathogens do opsonization and MAC lysis target?
extracellular pathogens
what are anaphylotoxins?
inflammatory mediators
what type of anaphylotoxin is C4a?
a weak anaphylotoxin
what do anaphylotoxins do?
- mediate degranulation of mast cells, basophils, eosinophils- release of biologically active mediator (eg histamine) • 2. promote smooth muscle contraction- increase vasodilation and vascular permeability (edema, low BP) • 3. mediate chemotaxis of leukocytes to sites of infection- activate macrophages and neutrophils • 4. promote platelet aggregation
what does C5a do to C’ receptors?
increases expression of CR’s on inflammatory cells (neutrophils, monocytes, macrophages, B cells)
describe the dose dependent action of anaphylotoxins
beneficial in low doses, cause anaphylaxis at high doses
What types of cells have C3a and C5a receptors?
- smooth muscle cells • 2. Mast cells • 3. basophils • 4. eosinophils • 5. endothelial cells • 6. phagocytic cells • 7. platelets
what is the effect of anaphylotoxins increasing vascular permeability?
- increased permeability allows increased fluid leakage from blood vessels and extravasation of complement and other plasma proteins at the site of infection • 2. Migration of monocytes and neutrophils from blood into tissue is increased
what is the binding action of the complement receptors on phagocytic cells?
CR1 binds to C3b • CR3 and CR4 binds to iC3b
what are the steps of opsonization and phagocytosis of bacteria?
- complement activation leads to deposition of C3b on the bacterial cell surface • 2. CR1 on macrophage binds C3b on bacterium • 3. endocytosis of the bacterium by the macrophage • 4. macrophage membranes fuse, creating a membrane-bounded vesicle, the phagosome • 5. Lysosomes fuse with the phagosomes forming the phagolysosome
Describe step-wise the role of complement in clearing immune complexes from the circulation
- circulating immune complexes become substrates for the activation of the classical pathway • 2. complement fragment C3b attaches to these immune complexes, mediating attachment of the complexes to RBCs via CR1. • 3. The RBC circulates the liver where CR1 acts as a cofactor for Factor I mediated cleavage of fragment C3b, forming the 2 products iC3b and C3f. • 4. iC3b is not bound by CR1, and so the RBC releases the immune complex, which is immediately bound by macrophages via CR3 or CR4. • 5. The macrophage ingests the immune complex
in the liver, CR1 acts as a cofactor for what cleavage reaction?
Factor I mediated cleavage of C3b
what are the products of factor I mediated cleavage of C3b in the liver?
iC3b • C3f
what happens to the complement level in the blood of patients with immune complex diseases?
patients with immune complex diseases will deplete their complement level in the blood
what is used in diagnosis of immune complex disease?
measurement of C2 and C4
What is the activity of C2b?
prokinin, accumulation of fluids
what is the effect of C2b?
edema
what are the control factors for C2b?
C1-INH
what is the activity of C3a?
- basophil and mast cell degranulation • 2. ennhanced vascular permeability • 3. enhanced smooth muscle contraction
what is the effect of C3a?
anaphylaxis
what are the control factors of C3a?
C3a-INA
what is the activity of C3b?
opsonin, phagocyte activation
what is the effect of C3b?
phagocytosis
what are the control factors of C3b?
Factors H and I
what is the activity of C4a?
- Basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction
what is the effect of C4a?
anaphylaxis (least potent)
what are the control factors of C4a?
C4-BP and Factor I
what is the activity of C5a?
- basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction • 4. chemotaxis • 5. stimulation of respiratory burst • 6. activation of phagocytes • 7. stimulation of inflammatory cytokines
what are the effects of C5a?
anaphylaxis (most potent) • inflammation
what are the anaphylactic activities of C5a?
- basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction
what are the inflammatory activities of C5a?
- chemotaxis • 5. stimulation of respiratory burst • 6. activation of phagocytes • 7. stimulation of inflammatory cytokines
what are the control factors of C5a?
C3a-INA
what happens to prokinin?
cleaved by plasmin to yield kinin, which results in edema
Which has a higher plasma concentration, complement control proteins or complement proteins?
complement control proteins
what is an example of a control protein present on the membrane of self-cells preventing them from being targeted by complement?
CD59, which inhibits C9 polymerization during formation of the MAC
What syndromes/disease states are caused by deficiency of Factors B or D in the alternative pathway?
susceptibility to pyogenic bacterial infections
what is the mechanism of disease developing in deficiency of Factors B or D in the alternative pathway?
Lack of sufficient opsonization of bacteria
what is caused by deficiency of C3 in the alternative pathway?
susceptibility to bacterial infections • glomerulonephritis • SLE
what is the mechanism of disease development in deficiency of C3 in the alternative pathway?
lack of opsonization and inability to utilize the membrane attack pathway
what is the most severe complement deficiency in the alternative pathway?
C3
what is caused by deficiency of C5, C6, C7, C8, C9 in the alternative pathway?
susceptibility to gram-negative bacterial infections
what is the mechanism of disease development in deficiency of C5,6,7,8,9 in the alternative pathway?
inability to attack the outer membrane of gram-negative bacteria
what is caused by deficiency of properdin in the alternative pathway?
susceptibility to meningococcal meningitis
what is the mechanism of disease development in deficiency of properdin in the alternatie pathway?
lack of opsonization of bacteria
what is caused by deficiency of factors H and I in the alternative pathway?
C3 deficiency and susceptibility to bacterial infections
what is the mechanism of disease development in deficiency of factors H and I in the alternative pathway?
uncontrolled activation of C3 via alternative pathway resulting in depletion of C3
what is caused by deficiency of C1-INH in the classical pathway?
Hereditary Angioedema
what is the mechanism of disease development in deficiency of C1-INH in the classical pathway?
overproduction of C2b (prokinin)
what is caused by deficiency of C1, C2, C4 in the classical pathway?
predisposition to SLE
what is the mechanism of disease development in the deficiency of C1,2,4 in the classical pathway?
opsonization of immune complexes helps keep them soluble, deficiency results in increased precipitation in tissues and inflammation
what is caused by deficiency of MBL in the Lectin pathway?
susceptibility to bacterial infections in infants or immunosuppressed
what is the mechanism of disease development in deficiency of MBL in the Lectin pathway?
inability to initiate the Lectin pathway
It is though that the complement system might play a role in what diseases with an immune component?
- Barraquer-Simons Syndrome • 2. Alzheimer’s disease • 3. asthma • 4. SLE • 5. various forms of arthritis • 6. autimmune heart disease • 7. multiple sclerosis
deficiencies in the terminal pathway predispose to what?
both autoimmune disease and infections (particularly meningitis)
what does host protective factor C1-INH do?
down-regulates the activity of the classical pathway of complement, the coagulation and kinin cascade
what is another name for C1-INH and how does it work?
AKA: Serpin • Serpin displaces C1rs from the C1qrs complex
how is Hereditary Angioneurotic Edema treated?
Danazol- promotes C1-INH production • ε-amino caproic acid- decreases plasmin activity
Does innate immunity refer to nonspecific or specific defense mechanisms?
nonspecific
does innate immunity have a limited or unlimited repertoire of recognition molecules?
limited
what is the timeframe for action of innate immunity?
acts immediately or within several hours
which is the immunity one is born with?
innate immunity
which immunity is the initial response by the body to eliminate microbes and prevent infection?
innate immunity
does innate immunity leave memory?
no
what are the 4 steps of the major function of innate immunity?
- recognition of the presence of a pathogen (foreign) • 2. recruitment of destructive effectors- mechanisms that kill and eliminate pathogens • 3. create communication mechanisms between the different parts of immune system- via cytokines • 4. activation of the specific immunity
what is included in the destructive effectors recruited in the 2nd step of the major function of innate immunity?
cells of different types • a battery of serum proteins
what are the general terms for the 3 layers of immunity?
- innate • 2. NK cells, eosinophils • 3. Adaptive
what makes up the nonspecific defenses, in general terms?
- Innate immunity • 2. NK cells, eosinophils
What makes up the specific defenses, in general terms?
adaptive immunity
which lines of defense make up the nonspecific defenses?
- First line • 2. Second line
what lines of defense make up the specific defenses?
- Third Line
what makes up the 1st line of defense in the layers of immunity?
- skin • 2. mucous membranes • 3. chemicals
what makes up the second line of defense in the layers of immunity?
- phagocytosis • 2. complement • 3. interferon • 4. inflammation • 5. fever
what makes up the 3rd line of defense in the layers of immunity?
- lymphocytes • 2. antibodies
What are the 4 classes of components of innate immunity?
- External Barriers • 2. Chemical Factors (soluble factors) • 3. Cellular Components • 4. Inflammation
what types of barriers make up the external barriers component of innate immunity?
- physical • 2. mechanical • 3. chemical • 4. microbiological (normal flora)
what makes up the chemical (soluble) factors component of innate immunity?
- interferons • 2. cytokines • 3. complement system • 4. acute phase proteins
what makes up the cellular component of innate immunity?
- degranulating cells • 2. non-phagocytic killing cells • 3. professional phagocytic cells
what types of cells make up the degranulating cells in innate immunity?
- mast cells • 2. eosinophils • 3. basophils
what do the degranulating cells of innate immunity do?
release biologically active mediators
what are the non-phagocytic killing cells of innate immunity?
- natural killer cells • 2. eosinophils
what are the professional phagocytic cells of innate immunity?
- neutrophils • 2. monocytes/macrophages • 3. dendritic cells
what does the inflammation component of innate immunity do?
brings the “actors to the stage” (site of infection or damaged tissue)
what structures and tracts make up the external barriers of innate immunity?
- hair • 2. skin • 3. nails • 4. eyes • 5. mammary glands • 6. respiratory tract • 7. gastrointestinal tract • 8. urogenital tract
what structures that make up the respiratory tract contribute to the external barrier component of innate immunity?
- sinuses • 2. trachea • 3. lungs
what structures of the urogenital tract contribute to the external barrier component of innate immunity?
- kidneys • 2. bladder • 3. vagina
what structures of the gastrointestinal tract contribute to the external barrier component of innate immunity?
- oral cavity • 2. esophagus • 3. stomach • 4. intestines
what makes up the mechanical component of the skin’s function as an external barrier?
- epithelial cells joined by tight junctions • 2. flow of fluid • 3. perspiration • 4. sloughing off of skin
what makes up the chemical component of the skin’s function as an external barrier?
- Sebum • 2. Defensins • 3. Lactoferrin • 4. Transferrin
What makes up Sebum?
- fatty acids • 2. lactic acid • 3. lysozyme
what makes up the microbiological component of the skin’s function as an external barrier?
normal flora of the skin
what are the mechanical components of the GI tract’s function as an external barrier?
- epithelial cells joined by tight junctions • 2. flow of fluid, mucus, food, saliva
what are the chemical components of the GI tract’s function as an external barrier?
- acidity • 2. enzymes (proteases) • 3. defensins • 4. Lactoferrin • 5. Transferrin
what are the microbiological components of the GI tract’s function as an external barrier?
normal flora of the GI tract
what involuntary actions contribute to the GI tact’s function as an external barrier?
- vomiting • 2. diarrhea
what are the mechanical components of the respiratory tract’s function as an external barrier?
- epithelial cells joined by tight junctions • 2. flow of fluid and mucus (by cilia) • 3. Air flow
what are the chemical components of the respiratory tract’s function as an external barrier?
- lysozyme in nasal secretions • 2. defensins • 3. lactoferrin • 4. transferrin
what are the microbiological components of the repiratory tract’s function as an external barrier?
Normal Flora of the respiratory tract
what are the involuntary actions that contribute to the respiratory tract’s function as an external barrier?
- coughing • 2. sneezing • 3. surfactants
what are the mechanical components of the urogenital tract’s function as an external barrier?
- epithelial cells joined by tight junctions • 2. flow of fluid, urine, mucus, sperm
what makes up the chemicall component of the urogenital tract’s function as an external barrier?
- acidity in vaginal secretions • 2. spermine and zinc in semen • 3. defensins • 4. lactoferrin • 5. transferrin
what makes up the microbiological component of the urogenital tract’s function as an external barrier?
normal flora of the urogenital tract
what makes up the mechanical component of the eyes’ function as an external barrier?
- epithelial cells joined by tight junctions • 2. flow of fluid, tears
what makes up the chemical component of the eyes’ function as an external barrier?
- lysozyme in tears • 2. defensins • 3. lactoferrin • 4. transferrin
what makes up the microbiological component of the eyes’ function as an external barrier?
normal flora of the eyes
what mechanical component is common to the function as an external barrier of the skin, GI tract, respiratory tract, GU tract, eyes?
epithelial cells joined by tight junctions
what chemical component is common to the function as an external barrier of the skin, GI tract, respiratory tract, GU tract, Eyes?
- defensins • 2. lactoferrin • 3. transferrin
What are the mechanisms by which normal flora contribute to immunity?
- competitive exclusion • 2. space and nutrition • 3. pH • 4. bacteriocins • 5. stimulation of the immune system (physiological inflammation in the gut)
describe cytokines in terms of their size and solubility
cytokines are small soluble proteins
what is the specificity with which cytokines are produced and secreted?
cytokines are produced then secreted by many cell types: cells of the immune system and other cells
what is the function of cytokines in the immune system?
serve as messengers (hormones) of the immune system- • means of communication
how are cytokines generally synthesized and released?
most are synthesized and released upon cellular activation (induced) but a few are stored in a preformed state
what is the half life of cytokines like?
have a brief and limited half life
what do cytokines bind to?
specific receptors expressed on the membrane of a target cell or cells
what does the binding of cytokines to membrane receptors trigger?
triggers intracellular signaling cascades leading to changes in the target cell
what do cytokines do to the innate and adaptive immune responses?
induce, regulate and coordinate the innate and adaptive immune responses
cytokines can be divided into what 3 types of molecules?
- interleukins • 2. interferons • 3. chemokines
what are interleukins?
cytokines produced by leukocytes which act to regulate other leukocytes
what are interferons?
cytokines made by leukocytes and virally infected cells
what do interferons do?
contribute to cellular immunity to viral infection
what are chemokines?
cytokines that direct the flow of leukocytes movement (chemotactic activities)
what is the significance of the chemotaxis controlled by chemokines?
movement to site of infection, during development, and recirculation through lymphoid organs
how are interleukins that were named recently designated?
IL#
what are some examples of recently named interleukins?
IL1, IL6
how are interleukins that were named less recently designated?
they carry their original name
what are some examples of interleukins that carry their original name?
Tumor Necrosis Factor-α (TNF-α), Transforming Growth Factor-ß (TGF-ß)
how are interferons named?
Carry interferon designation plus α, β, γ, ..etc
what is an example of an interferon?
IFN-γ
how are chemokines named?
different groups based on the arrangement of pairs of cysteine residues
how are cysteines arranged in chemokines?
chemokines are small peptides with pairs of cysteine residues which are either adjacent (CC) or separated by another amino acid (CXC)
what are some examples of chemokines?
CC, CXC, CX3C
what is autocrine target activity?
bind to a receptor on the same cell that secreted it
what is paracrine target activity?
bind to a receptor on a target cell in close proximity to the cell that secreted it
what is endocrine target activity?
cytokine binds to target cells at distant sites from the cell that secreted it
what is the most common type of cytokine target activity?
paracrine
what is pleiotropy as it relates to cytokines?
one cytokine has different biological effects on different target cells
what is redundancy as it relates to cytokines?
two or more cytokines mediate similar or identical functions by binding to receptors on the same target cell
what is synergy as it relates to cytokines?
the combined effects of two or more cytokines on a target cell is greater than the additive effects of the individual cytokines
what is antagonism as it relates to cytokines?
the effects of one cytokine decrease or totally inhibit the effects of another cytokine
what does IL-4 do to a B cell?
Alter the form of the antibody molecule produced by an activated B cell to alter its biological properties
which interleukins show redundancy in that they all stimulate the proliferation of B cells?
IL-2 • IL-4 • IL-5
what is the effect of the synergistic action of IFN-gamma and TNF?
increased expression of class I MHC molecules on many cell types
what is the relationship between IFN-gamma and IL-10 in the way that they afffect macrophages?
IFN-gamma stimulates macrophage activation • IL-10 inhibits the activation of macrophages • —they are antagonists
how are cytokine receptors classified?
as families of receptors on the basis of structural composition
what are some examples of chemokine receptors?
CCR • CXCR
what family do interleukin receptors bind?
immunoglobulin superfamily
what is the signaling mechanism stimulated by binding to chemokine receptors?
signaling via G proteins/MAPK pathway
what is the signaling pathway stimulated by binding of interleukins?
JAK/STAT pathway
why are the receptor components of interleukin receptors members of the immunoglobulin family
due to the presence of an immunoglobulin fold
what are the steps of intracellular signaling using the jak-stat pathway?
- cytokine receptors consist of at least two chains, the cytoplasmic domains of which bind JAKs • 2. cytokine binding dimerizes the receptor, bringing together the cytoplasmic JAKs, which activate each other and phosphoylate the receptor • 3. STATs bind to the phosphorylated receptors and are in turn phosphorylated by the activated JAKs • 4. phosphorylated STATs form dimers and move into the nucleus to initiate gene transcription
type I interferon comprises what?
IFN α • IFN ß
what triggers type I interferon?
triggered by viral infection or signaling via a receptor
what is an example of something that triggers Type I interferon?
Ds RNA
what produces Type I interferon?
produced by cells infected by viruses
what does Type I interferon target?
targets intracellular pathogens such as viruses
what type I interferon interfere with ?
viral replication in an infected cell
what does type I interferon do to non infected neighboring cells?
warn non infected neighboring cells to get prepared
what does type I interferon do to infected cells?
makes infected cells more vulnerable for elimination by natural killer cells as well as cytotoxic T lymphocytes (CD8)
How does type I interferon stop viral replication by both infected and uninfected cells?
by inducing the production of proteins that: • 1. destroy viral mRNA • 2. inhibit protein synthesis by inactivating eIF-2
How does Type I interferon increase sensitivity to CD8?
increased expression of MHC I
What are the important classes of cytokines?
I. Growth Factors • II. Interleukins • III. Tumor Necrosis Factors • IV. Interferons • V. Chemokines
What are the Growth Factors relevant to the study of immunology?
- Granulocyte Colony-Stimulating Factor (G-CSF) • 2. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) • 3. Transforming Growth Factor -β (TGF-β)
what are the interleukins relevant to the study of immunology?
- IL-1 • 2. IL-2 • 3. IL-3 • 4. IL-4 • 5. IL-5 • 6. IL-6 • 7. IL-7 • 8. IL-10 • 9. IL-12 • 10. IL-13 • 11. IL-17 • 12. IL-23
What are the Tumor Necrosis Factors relevant to the study of immunology?
- TNF- α • 2. TNF- β
What are the type I interferons relevant to the study of immunology?
- IFN-α • 2. IFN-β • 3. IFN-κ
what are the type II interferons relevant to the study of immunology?
IFN-γ
what are the chemokines relevant to the study of immunology?
- RANTES • 2. MIP-1α, MIP-1β • 3. CXCL8 (IL-8)
What are the other names for G-CSF?
- Colony Stimulating Factor β • 2. Pluripoietin- β
What secretes G-CSF?
- bone marrow stromal cells • 2. macrophages • 3. endothelial cells
what are the functions of G-CSF?
- stimulates the development of neutrophils and other granulocytes • 2. stimulates the proliferation and migration of endothelial cells
what are the other names of GM-CSF?
- Colony Stimulating Factor α • 2. Pluripoietin-α
what secretes GM-CSF?
- T cells • 2. macrophages • 3. endothelial cells • 4. fibroblasts
what are the functions of GM-CSF?
- stimulates the differentiation of granulocyte and monocyte progenitors • 2. stimulates the growth of endothelial cells
what secretes TGF-β?
- platelets • 2. macrophages • 3. lymphocytes • 4. mast cells
what are the functions of TGF-β?
- stimulate epithelial and mesenchymal cell growth • 2. down-regulates pro-inflammatory activities • 3. induce class switch to IgA by plasma cells
What secretes IL-1?
- monocytes • 2. macrophages • 3. dendritic cells • 4. endothelial cells • 5. B-cells • 6. fibroblasts • 7. keratinocytes • 8. chondrocytes
does IL-1 play a role in innate or adaptive immunity?
both
What the role played by IL-1 in innate immunity?
- Enhances NK cell activity • 2. increases expression of ICAMS on vascular endothelial cells • 3. chemotactically attracts macrophages and neutrophils • 4. induces synthesis of acute-phase proteins by hepatocytes • 5. induces fever by acting on the hypothalamus (endogenous pyrogen)
what role does IL-1 play in adaptive immune response?
- costimulates the activation of T helper cells • 2. promotes maturation and clonal expansion of B cells • 3. additional roles: • a. stimulation of the secretion of IL-6 and IL-8 • b. induction of the expression of IL-2R
what secretes IL-2?
activated T cells
what is another name for IL-2?
often referred to as the T Cell growth factor
does IL-2 play a role in innate immunity of adaptive immunity?
both
what is the role of IL-2 in the innate immune response?
- stimulates growth of monocytes and macrophages • 2. enhances proliferation and activation of NK cells
what is the role of IL-2 in the adaptive immune response?
- induces the proliferation and activation of antigen primed T cells • 2. Acts on B cells to stimulate proliferation and antibody production
what secretes IL-3?
- T cells • 2. NK cells • 3. eosinophils • 4. mast cells
does IL-3 play a role in the innate or adaptive immune response?
both
what role does IL-3 play in the innate immune response?
- supports growth and differentiation of hematopoietic cells (myeloid) • 2. stimulates growth and histamine production by mast cells
what is the role of IL-3 in the adaptive immune response?
promotes growth of monocytes and B cells
What secretes IL-4?
- T cells • 2. NK Cells • 3. Mast Cells
does IL-4 play a role in the innate or adaptive immune system?
both
what role does IL-4 play in the innate immune response?
- regulates some stages of hematopoiesis • 2. acts with other cytokines to stimulate mast cell proliferation (innate and adaptive)
what is the role of IL-4 in the adaptive immune response?
- role in the regulation of Th1-Th2 axis, pushes terminal differentiation of Th cells to Th2 (humoral arm) • 2. upregulates MHCII expression, antigen presentation and phagocytosis by macrophages • 3. stimulates proliferation, differentiation and activation of antigen activated B cells • 4. induces antibody class switching to IgE and IgG4 • 5. Acts to increase expression of MHC II on resting B cells • 6. Induces proliferation of thymocytes and T cells
What secretes IL-5?
- T-Cells • 2. Mast Cells • 3. Eosinophils
does IL-5 play a role in innate or adaptive immunity?
adaptive
what is the role of IL-5 in adaptive immunity?
- promotes growth and differentiation of eosinophils (also helps innate) • 2. costimulates the proliferation and differentiation of activated B cells • 3. induces antibody class switching to IgA
what secretes IL-6?
- monocytes • 2. macrophages • 3. T cells • 4. B cells • 5. keratinocytes • 6. fibroblasts • 7. endothelial cells • 8. bone marrow stromal cells
does IL-6 play a role in innate or adaptive immunity?
plays a major role in innate immune response
what role does IL-6 play in the innate immune response?
- induces synthesis of acute phase proteins by hepatocytes • 2. act on hypothalamus to induce fever (endogenous pyrogen) • 3. promotes differentiation of myeloid cells • 4. promotes terminal differentiation of proliferating B cells into plasma cells (antibody secreting cells) • 5. Stimulates antibody secretion by plasma cells
what is the other name for IL-7?
Lymphopoietin
what secretes lymphopoietin?
- bone marrow stromal cells • 2. thymus stromal cells
does IL-7 play a role in adaptive or innate immunity?
adaptive immune response
what role does IL-7 play in the adaptive immune response?
- induces differentiation of lymphoid stem cells into progenitor progenitor B and T cells • 2. increases expression of IL-2 and it’s receptor on resting T cells
what secretes IL-10?
secreted by monocytes, macrophages, keratinocytes and T cells
does IL-10 play a role in the innate or adaptive immune system?
adaptive
what is the role of IL-10 in the adaptive immune response?
- blocks production of cytokines by macrophage (downregulates cell mediated response) • 2. Shuts down transcription of TNF-α (downregulates inflammatory response) • 3. downregulates MHCII expression on antigen presenting cells
What secretes IL-12?
- monocytes • 2. macrophages • 3. dendritic cells and B cells
does IL-12 play a role in adaptive or innate immunity?
both
what role does IL-12 play in the adaptive immune response?
- Regulation of the Th1:Th2 axis (promotes Th1 production) • 2. costimulates differentiation of active CD8+ cells into CTL’s
what roles does IL-12 play in both innate and adaptive immunity?
- stimulates proliferation of NK and LAK cells and antigen activated Th1 cells • 2. stimulates the production of IFN-γ by NK cells and CTL’s
what produces IL-13?
T cells
what are the functions of IL-13?
- anti-inflammatory • 2. enhances B cell activation
what produces IL-17?
T cells; particularly the CD4 T cells in the peripheral blood
does IL-17 play a role in the innate or adaptive immune system?
innate
what role does IL-17 play in the innate immune response?
- induces production of IL-6 and IL-8 • 2. Enhances surface expression of ICAM-1 on human fibroblasts • 3. regulates expression of complement proteins • 4. chemotactic for neutrophils
What produces IL-23
dendritic cells
what is the function of IL-23?
activation of memory T cells
what secretes TNF-α?
- monocytes • 2. macrophages • 3. fibroblasts • 4. B cells • 5. T cells • 6. NK cells
does TNF-α play a role in innate or adaptive immunity?
innate response
what is the role of TNF-α in innate immune response?
- induces cytokine secretion by inflammatory cell • 2. increases expression of CAMS on vascular endothelial cells • 3. Increases expression of ligands on circulating neutrophils • 4. causes smooth muscle contraction • 5. induces production of acute phase proteins (C-reactive Protein and mannose binding protein) • 6. cytotoxic effect on tumor cells
what is the other name for TNF-β?
lymphotoxin (LT)
does TNF-β play a role in innate or adaptive immunity?
both
what role does TNF-β play in the innate immune response?
- has cytotoxic effects on tumor cells • 2. enhances phagocytic activity of macrophages and neutrophils • 3. inhibits proliferation of lymphoid and hematopoietic cells
what role does TNF-β play in the adaptive immune response?
- secreted by Th1 and CTL cells
what secretes TNF-β?
- Th1 • 2. CTL
what secretes IFN-α?
- macrophages • 2. monocytes • 3. lymphocytes
what secretes IFN-β?
- fibroblasts • 2. epithelial cells
what secretes IFN-κ?
keratinocytes
how do type I interferons promote the production of antiviral agents by uninfected cells?
induce production of the Double Stranded Activated Inhibitor of Translation (aka: DAI or RNA-dependent protein kinase)
what do type I interferons do to MHC I on virally infected cells?
increase expression of MHC I on virally infected cells
What secretes IFN-γ?
- Th1 cells • 2. CTL’s • 3. NK cells
what are the functions of IFN-γ?
- enhances intracellular killing by macrophages • 2. increases expression of MHC I and II on many cells • 3. regulates Th1-Th2 terminal differentiation • 4. excess amounts inhibit proliferation of Th2 cells • 5. Excess amounts down regulate humoral immune response: • 6. mediates effects important in a Th1 driven DTH • 7. promote the production of antiviral agents by uninfected cells by enhancing and inducing production of 2’,5’ adenylate synthetase, ribonucleases, Mx protein (also blocks capsid assembly
What are RANTES?
Regulated upon Activation, Normal T-cell Expressed and Secreted
what are the functions of RANTES?
enhances extravasation by promoting chemotaxis of monocytes, basophils, and eosinophils
what are MIP-1α, MIP-1β?
Monocyte/Macrophage Inflammatory Proteins
what are the functions of MIP-1α/β?
enhances extravasation by promoting chemotaxis of monocytes and macrophages
what secretes CXCL8?
- monocytes • 2. Macrophages • 3. fibroblasts • 4. endothelial cells • 5. epithelial cells • 6. keratinocytes • 7. B cells • 8. T cells
what is the role of CXCL8 in innate immune response?
- acts as a chemokine to promote extravasation • 2. stimulates angiogenesis
how does CXCL8 act as a chemokine to promote extravasation?
- recruits neutrophils to site of injury • 2. Induces neutrophil adherence to endothelium
how does IFN-γ in excess amounts decrease humoral immune response?
- induces class switch to IgA2a (ADCC via Th1 axis) • 2. Blocks IL-4 induced class switch to IgE and IgG1
what does G-CSF do to the development of neutrophils and other granulocytes?
stimulates
what does G-CSF do to the proliferation and migration of endothelial cells?
stimulates
what does GM-CSF do to granulocyte and monocyte progenitors?
stimulates the differentiation of granulocyte and monocyte progenitors
what does GM-CSF do to endothelial cells?
stimulates the growth of endothelial cells
what does TGF-β do to epithelial and mesenchymal cells?
stimulates epithelial and mesenchymal cell growth
what does TGF-β do to pro-inflammatory activities?
down-regulates pro-inflammatory activities
what does TGF-β do to plasma cells?
induce class switch to IgA by plasma cells
what does IL-1 do to NK cell activity?
enhances NK cell activity
what does IL-1 do to ICAMS on vascular endothelial cells?
increases expression of ICAMS on vascular endothelial cells
what does IL-1 do to macrophages and neutrophils?
chemotactically attracts macrophages and neutrophils
what does IL-1 do to acute phase proteins?
induces synthesis of acute phase proteins by hepatocytes
what does IL-1 do in the hypothalamus?
induces fever
what does IL-1 do to Th cells?
costimulates activation of Th cells
what does IL-1 do to B cells?
promotes maturation and clonal expansion of B cells
what does IL-1 do to IL-6 and IL-8?
stimulates the secretion of IL-6 and IL-8
what does IL-1 do to IL-2R?
induces the expression of IL-2R
what does IL-2 do to monocytes and macrophages?
stimulates growth of monocytes and macrophages
what does IL-2 do to NK cells?
enhances proliferation and activation of NK cells
what does IL-2 do to antigen primed T cells?
induces the proliferation, activation of antigen primed T cells
what does IL-2 do to B cells?
Acts on B cells to stimulate proliferation and antibody production
what does IL-3 do to hematopoietic cells?
supports growth and differentiation of hematopoietic cells (myeloid)
what does IL3 do to mast cells?
stimulates growth and histamine prroduction by mast cells
what does IL3 do to monocytes and B cells?
promotes growth of monocytes and B cells
what does IL4 do to hematopoiesis?
regulates some stages of hematopoiesis
what does IL4 do to mast cells?
acts with other cytokines to stimulate mast cell proliferation
what is the role of IL4 in the regulation of the Th1-Th2 axis?
pushes terminal differentiation of Th cells to Th2 (humoral arm)
what does IL4 do to macrophages?
upregulates MHCII expression, antigen presentation, and phagocytosis by macrophages
what does IL4 do to B cells?
stimulates proliferation, differentiation, and activation of antigen activated B cells
what does IL4 do to antibody class switching?
induces antibody class switching to IgE and IgG4
what does IL4 do to MHCII on resting B cells?
acts to increase expression of MHCII on resting B cells
what does IL4 do to thymocytes and T cells
induces proliferation of thymocytes and T cells
what does IL5 do to eosinophils?
promotes growth and differentiation of eosinophils
what does IL5 do to activated B cells?
costimulates the proliferation and differentiation of activated B cells
what does IL5 do to antibody class switching?
induces antibody class switching to IgA
What does IL6 do to acute phase proteins?
induces synthesis of acute phase proteins by hepatocytes
which interleukins induce synthesis of acute phase proteins by hepatocytes?
IL1 • IL6
which interleukins induce fever?
IL1 • IL6
what does IL6 do to myeloid stem cells?
promotes differentiation of myeloid stem cells
what does IL6 do to proliferating B cells?
promotes terminal differentiation of proliferating B cells into plasma cells (antibody secreting cells)
what does IL6 do to plasma cells?
stimulates antibody secretion by plasma cells
what does IL7 do to lymphoid stem cells?
induces differentiation into progenitor B and T cells
what does IL7 do to IL2?
increase expression of IL2 and IL2R on resting T cells
what does IL10 do to macrophages?
blocks production of cytokines by macrophages
what does IL10 do to TNFα?
shuts down transcription of TNF α
what does IL10 do to antigen presenting cells?
down regulates MHCII expression on antigen presenting cells
what does IL 12 do to the Th1:Th2 axis?
regulates; promotes Th1 production
what dos IL12 do to CD8+ cells?
costimulates differentiation of activated CD8+ cells into CTLs
what does IL12 do to NK, LAK, and antigen activated Th1 cells?
stimulates proliferation of NK and LAK cells and antigen activated Th1 cells
what does IL12 do to IFNγ?
stimulates the production of IFN γ by NK cells and CTLs
`what effect does IL13 have on inflammation
it is anti-inflammatory
what does IL13 do to B cell activation?
enhances B cell activation
what does IL17 do to IL6 and IL8?
induces the production of IL6 and IL8
which interleukins affect IL6 and IL8?
IL1- stimulates secretion • IL17- induces production
what does IL17 do to human fibroblasts?
enhances surface expression of ICAM-1 on human fibroblasts
what does IL17 do to complement proteins?
regulates expression of complement proteins
how does IL17 affect neutrophils?
chemotactic for neutrophils
what does IL23 do to T cells?
activation of memory T cells
what does TNF-α do to inflammatory cells?
induces cytokine secretion by inflammatory cells
what does TNF-α do to vascular endothelial cells?
increases expression of CAMS on vascular endothelial cells
what does TNF-α do to circulating neutrophils?
increased expression of ligands on circulating neutrophils
what does TNF-α do to smooth muscle?
causes smooth muscle contraction
what does TNF-α do to acute phase proteins?
induces production of acute phase proteins CRP and MBP
what is the effect of TNF-α on tumor cells?
cytotoxic effect on tumor cells
what does effect does TNF-β have on tumor cells?
cytotoxic effect on tumor cells
which cytokines have a cytotoxic effect on tumor cells?
TNF-α • TNF-β
what does TNF-β do to macrophages and neutrophils?
enhances phagocytic activity of macrophages and neutrophils
what does TNF-β do to lymphoid and hematopoietic cells?
inhibits proliferation of lymphoid and hematopoietic cells
what does IFN-γ do to macrophages?
enhances intracellular killing by macrophages
what does IFN-γ do to MHC I and II?
increases expression of MHC I and II on many cells
what does IFN-γ do to Th1 and Th2?
regulates Th1-Th2 terminal differentiation
what does IFN-γ in excess amounts do to Th2 cells?
inhibit proliferation of Th2 cells
what does excess IFN-γ do to the humoral immune response?
suppresses humoral immune response
what does IFN-γ go to DTH?
mediates effects important in a Th1 driven delayed type hypersensitivity
what does IFN-γ do to the production of antiviral agents by uninfected cells?
promote the production of antiviral agents by uninfected cells by enhancing and inducing productino of 2’-5’ adenylate synthetase, ribonucleases, Mx protein
how does IFN-γ affect capsid assembly?
blocks capsid assembly
what does CXCL8 do to neutrophils?
recruit neutrophils to site of injury • induce neutrophil adherence to endothelium
what does CXCL8 do to blood supply?
induces angiogenesis
What are the cells of the immune system?
- Agranulocytes • 2. Granulocytes • 3. Lymphocytes • 4. Natural Killer Cells • 5. Mast Cells • 6. Platelets
with respect to the nucleus of the cell, what type of cells are agranulocytes?
Mononuclear Cells
with respect to the nucleus of the cell, what type of cells are granulocytes?
polymorphonuclear cells
Agranulocytes comprise what classes of cells?
- monocytes • 2. macrophages • 3. dendritic cells • 4. Langerhans cells
Granulocytes comprise what classes of cells?
- neutrophils • 2. basophils • 3. eosinophils
Lymphocytes are comprise what classes of cells?
- T Lymphocytes • 2. B Lymphocytes
What is CD34?
s a cluster of differentiation molecule present on certain cells within the human body. It is a cell surface glycoprotein and functions as a cell-cell adhesion factor.
What is the main tissue site of hematopoeisis?
Bone Marrow
Hematopoiesis is under the influence of what?
cytokines: • Colony Stimulating Factors
hematopoietic stem cells are the direct precursors to what 3 cells in hematopoiesis?
- common lymphoid progenitor • 2. common myeloid progenitor • 3. common erythroid megakaryocyte progenitor
the common lymphoid progenitor is the direct precursor to what 2 types of cells in hematopoiesis?
- B cell • 2. NK/T cell precursor
the common myeloid progenitor is the direct precursor of what 2 types of cells in hematopoiesis?
- common granulocyte precursor • 2. unknown precursor
the common erythroid megakaryocyte progenitor is the direct precursor of which 2 cell types in hematopoiesis?
- megakaryocyte • 2. erythroblast
the B cell is the direct precursor of what type of cell in hematopoiesis?
plasma cell
the NK/T cell precursor is the direct precursor of which 2 cell types in hematopoiesis?
- T cell • 2. NK cell
the T cell is the direct precursor of what cell type in hematopoiesis?
effector T cell
the common granulocyte precursor gives rise to which 3 cell types in hematopoiesis?
- neutrophil • 2. eosinophil • 3. basophil
the unknown precursor directly gives rise to which 2 cell types in hematopoiesis?
- monocyte • 2. mast cell
the monocyte gives rise to which 2 cell types in hematopoiesis?
- dendritic cell • 2. macrophage
the megakaryocyte gives rise to what type of cells in hematopoiesis?
platelets
the erythroblast gives rise to what type of cells in hematopoiesis?
erythrocyte
are granular leukocytes mostly adaptive or mostly innate immunity?
innate
are agranular leukocytes mostly innate or mostly adaptive immunity?
adaptive
which 2 cell types link innate and adaptive immunity?
monocytic cells: • 1. monocytes/macrophages • 2. dendritic cells
what are the categories of cells that arise from the myeloid lineage?
- thrombocytic • 2. erythroid • 3. granulocytic • 4. monocytic
what categories of cells arise from the lymphoid lineage?
lymphocytic
What are the thrombocytic cells?
platelets
what are the erythroid cells?
erythrocytes
what are the granulocytic cells?
- eosinophils • 2. basophils • 3. neutrophils
what are the monocytic cells?
- macrophages/ monocytes • 2. dendritic cells
what are the lymphocytic cells?
- NK cells • 2. T cells • 3. B cells –> Plasma cells
what are leukocytes?
white blood cells
plasma makes up what % of blood?
55%
White blood cells and platelets make up what % of blood?
<1%
Red Blood Cells make up what % of blood?
45%
neutrophils make up what % of leukocytes?
40-75%
eosinophils make up what % of leukocytes?
1-6%
monocytes make up what % of leukocytes?
2-10%
lymphocytes make up what % of leukocytes?
20-50%
basophils make up what % of leukocytes?
<1%
agranulocytes mainly reside where?
in tissues
macrophages arise from what in blood?
monocytes
macrophages are mainly found in what compartment?
in the tissues
what are the functions of macrophages?
recognize pathogens, engulf, process and present antigen to specific immune system
dendritic cells have a major role in what?
recognizing and processing antigens, • initiating specific immunity
what is the primary function of mast cells?
allergy and against parasites
do monocytes have a long or short life span?
short life span
what do monocytes do when they enter the tissues?
transform into macrophages
do tissue macrophages have a long or short life span?
long life span
which are more destructive, macrophages or monocytes?
macrophages
which have more phagocytic activity, macrophages or monocytes?
macrophages
what is the purpose of monocytes?
circulating precursor to macrophage
what is the purpose of macrophages?
- phagocytosis and killing of microorganisms • 2. activation of T cells and initiation of immune response
what are phagocytes called in the liver?
Kupffer Cells
what are phagocytes called in the kidney?
Mesangial cells
what are phagocytes called in the CNS?
microglial cells
what are phagocytes called in the connective tissue?
histiocytes
what are phagocytes called in the synovial joints?
A cells
what are phagocytes called in bone?
osteoclasts
what are phagocytes called in the lung alveoli?
alveolar macrophages
what are phagocytes called in the spleen?
splenic macrophages
what are phagocytes called in the blood?
monocytes
what are phagocytes called in the lymph nodes?
resident and recirculating macrophages
where are the precursors to the phagocytes?
bone marrow
what class of cells are dendritic cells?
mononuclear phagocytes
what are the distinct structural features of dendritic cells?
several projections into the cytoplasm
where are dendritic cells found?
potential portals of microbial entry in lymphoid tissues and under skin
what are the main engulfing actions of dendritic cells?
phagocytosis and macropinocytosis
can dendritic cells travel?
can travel from infected tissue to lymphoid tissue
what is the profession of the dendritic cell?
professional antigen presenting cell
what is the main role of dendritic cells?
priming of naive T lymphocytes in the initiation of the immune response
what compounds do dendritic cells produce and why?
they produce cytokines which are attractants to T lymphocytes
what types of cells are resident tissue granulocytes?
Mast Cells
where are mast cells found?
connective tissue
what is the function of mast cells?
expulsion of parasites from body through release of histamine and other active agents
what does polymorphonuclear mean?
have lobed irregularly shaped nucleus
how are granulocytes divided into categories?
on the basis of how their cytoplasmic granules stain with acidic and basic dyes
what are the non-phagocytic granulocytes?
- basophils • 2. eosinophils
which are the phagocytic granulocytes?
neutrophils
what is the function of neutrophils?
phagocytosis and killing of microorganisms
what are the structural features of neutrophils?
multilobed (3-5) nucleus
what is the most common and most lethal granulocyte?
neutrophils
are neutrophils capable of traveling?
capable of leaving the blood and entering tissue
what is the lifespan of a neutrophil?
short lived (2-3 days)
where are neutrophils stored and when are they released?
large reserves of neutrophils are stored in the bone marrow and are released when needed to fight an infection
what do neutrophils do in the case of a bacterial infection?
neutrophils travel to and enter the infected tissue where they engulf and kill bacteria. the neutrophils die in the tissue and are engulfed and degraded by macrophages
what type of cells are responsible for pus formation in infected tissue?
dead neutrophils
what is the function of eosinophils
killing of antibody-coated parasites through release of granule contents
what are the structural features of eosinophils?
bilobed, many granules • stain red with acidic dyes
when do eosinophils increase in number?
during parasitic infection –> eosinophilia
are eosinophils capable of phagocytosis?
yes but it is not their main function
when do eosinophils release their contents?
upon stimulation
What is the major function of basophils?
controlling immune responses to parasites
what are the structural features of basophils?
contain deep violet granules, stained with basic dyes
are basophils phagocytic cells?
no
what happens when basophils are activated?
release numerous compounds such as histamine and heparin
are basophils associated with allergic responses?
yes
what type of lymphoid cells are in the bone marrow during lymphocyte maturation?
Lymphoblast, gives rise to: • 1. B lymphocyte • 2. CD4- CD8- T lymphocyte precursor • 3. Natural Killer Lymphocyte
what types of lymphoid cells move into the blood during lymphocyte maturation?
- B lymphocytes • 2. CD4- CD8- T lymphocyte precursor • 3. Natural Killer lymphocyte
which lymphoid cell types continue maturation in the thymus and what is the end product of maturation of these types?
CD4- CD8- T lymphocyte precursor matures in the thymus and gives rise to: • 1. CD4+ lymphocyte • 2. CD8+ lymphocyte
what are the destination tissues of mature lymphoid cells?
- connective tissue • 2. epithelia • 3. secondary lymphoid organs • 4. Blood
what does CD stand for?
cluster of differentiation
what are cluster of differentiation?
surface molecules
how do T and B lymphocytes express CD?
T and B cells express different kinds of CD at different levels of maturation
what are the structural features of lymphocytes?
the nucleus is round and big in that it almost covers the cytoplasm
what are plasma cells and what do they do?
fully differentiated form of B cell that secretes antibodies
what are the types of small lymphocytes?
- B cells • 2. T cells
What are the functions of small lymphocytes?
- Production of antibodies (B cells) • 2. cytotoxic and helper functions (T cells)
what is the function of natural killer cells?
kills cells infected with certain viruses
what % of blood granular lymphocytes are natural killer cells?
15%
what major role does the natural killer cell play?
- innate immunity • 2. early response to pathogenic organisms
what types of cells do natural killer cells attack?
- virally infected cells • 2. cells lacking MHC I • 3. Tumor
into what are the cells of the immune system organized and why?
organized into tissues and organs in order to perform their function effectively
the tissues and organs of the immune system are collectively known as what?
lymphoid system
what are the 2 branches of the lymphoid system?
- Primary (central) • 2. Secondary (peripheral)
what makes up the primary lymphoid system?
- bone marrow • 2. thymus
what happens in the primary lymphoid system?
sites where mature lymphocytes are developed
what makes up the secondary lymphoid system?
- spleen • 2. lymphatic tissues
what happens in the secondary lymphoid system?
sites where specific immune responses to pathogens or molecules are induced
what does it mean when specific immune responses to pathogens or molecules are induced?
proliferation of lymphocytes • differentiation to effector functions
what is the course of the T cell progenitor?
T cell progenitor moves from bone marrow to the thymus and develops further into mature T cells
what lymphoid system cells orginate in the bone marrow?
T and B cells progenitor
what lymphoid cell matures in the bone marrow?
B cell
what is the origin of lymphocytes, central or peripheral lymphoid system?
primary/central
do mature (but still naive) lymphocytes reside in the primary or secondary lymphoid organs/tissues?
secondary
do mature (but still naive) lymphocytes originate in the primary or secondary lymphoid organs/tissues?
primary
which mature (but still naive) lymphocyte originates in the thymus?
T cell: • 1. T CD4 • 2. T CD8
which mature (but still naive) lymphocyte originates in the bone marrow?
B cell
what does lymphocyte maturation involve and is it fast or slow?
maturation is a gradual process involving changing of surface molecule markers: • 1. CD • 2. Antigen receptor
do lymphocytes meet antigen in primary or secondary lymphoid tissue?
secondary
do lymphocytes proliferate in primary or secondary lymphoid tissue?
secondary
do lymphocytes differentiate into effector and memory cells in primary or secondary lymphoid tissues?
secondary
into what do T CD4 differentiate in secondary lymphoid tissue?
Th1 and Th2 memory cells
into what do T CD8 differentiate in secondary lymphoid tissue?
effector cytotoxic cell and memory cell
into what do B cells differentiate in secondary lymphoid tissues?
plasma cell and memory cell
does elimination of lymphocytes with potential of reacting against self antigens occur in primary or secondary lymphoid tissue?
primary
what are the mechanisms by which elimination of lymphocytes with potential of reacting against self antigens occurs?
- negative selection • 2. make them non functional
describe the life cycle of a lymphocyte and infection response in 3 steps
- during development, progenitor cells give rise to large numbers of lymphocytes, each with a different specificity. • 2. During infection lymphocytes with receptors that recognize the pathogen are activated. • 3. proliferation and differentiation of pathogen-activated lymphocytes give effector cells that terminate the infection
what part of the life cycle of a lymphocyte in response to infection takes place in the primary lymphoid organs?
expression of antigen specific receptors: • maturation
what part of the life cycle of a lymphocyte in response to infection takes place in the secondary lymphoid organs?
meet antigen, proliferate and differentiate further into effector cells and memory cells
what part of the life cycle of a lymphocyte in response to infection takes place at the site of infection?
elimination of pathogens
what happens to the thymus with age?
it involutes
what are the 3 major secondary lymphoid organs?
- spleen • 2. lymph nodes • 3. unencapsulated lymphoid tissues
is the spleen encapsulated?
yes
does the spleen have blood supply?
yes
does the spleen have lymphatic supply?
limited, if any
what is the sieving activity of the spleen?
sieves blood borne antigens
are the lymph nodes encapsulated?
yes
do the lymph nodes have blood supply?
yes
do the lymph nodes have lymphatic supply?
afferent and efferent lymphatics
what is the sieving activity of the lymph nodes?
sieves lymph borne antigens
describe the spleen
an encapsulated organ with a blood supply and very limited, if any lymphatic supply
describe the lymph nodes
encapsulated organs with a blood supply and efferent and afferent lymphatics
do the unencapsulated lymphoid tissues have a blood/lymphatic supply?
have both a blood supply and lymphatic drainage
what are the unencapsulated lymphoid tissues?
- tonsils • 2. adenoid tissue • 3. appendix • 4. peyer’s patches • 5. mucosal associated lymphoid tissues (MALT) • 6. skin associated lymphoid tissues (SALT)
where are lymph nodes located?
close to the major junctions of the lymphatic channels
lymph nodes are loaded with what?
- lymphocytes • 2. macrophages • 3. other immune cells
what are lymph nodes good at?
highly efficieny at trapping antigen that enters afferent lymphatic channel
what enters the afferent lymphatic vessels?
- pathogen • 2. dendritic cells carrying pathogen from infected tissue
where do the B and T cells enter the lymph node from the circulation?
post capillary high endothelial venule
what leaves the lymph node through the efferent lymphatics?
- effector cells • 2. antibodies
can lymphocytes cross the high endothelial venule wall?
yes
what is the largest secondary lymphoid organ?
spleen
what does splenic red pulp do?
filters blood • removes damaged/old RBC
what is the splenic white pulp?
lymphocyte aggregate around blood vessel: • T cell and B cell area
what happens in the splenic white pulp?
- filters pathogens from blood • 2. macrophages and dendritic cells in the spleen pick up pathogens from blood and present them to lymphocytes- initiate the adaptive immunity • 3. major organ in antibody synthesis
what is an important part of the splenic white pulp?
periarteriole lymphoid sheath (PALS)
what are the main type of lymphocytes that populate the PALS?
T cells
what are the main types of lymphocytes that populate the lymphoid part of the white pulp of the spleen?
B cells
what is colony stimulating factor?
a major cytokine that stimulated mitosis
how are platelets involved in the immune system?
platelets are indirectly involved in the immune system because they induce inflammation
what is the site of origin of white blood cells?
bone marrow
what does a pluripotential cell do in hematopoiesis?
a pluripotential cell differentiates into progenitor cells and then into precursor cells for the myeloid, lymphoid, and erythroid cell lines.
differentiation of the stem cell from bone marrow is mediated by what?
- cell to cell interaction • 2. cytokines
what cells secrete colony stimulating factor and why?
cells of the bone marrow, endothelial cells, and others secrete colony stimulating factors that promote hematopoiesis
monocyte and macrophage formation is stimulated by what?
M-CSF from osteoblasts
what does GM-CSF do?
stimulates the formation of all three granulocytes and myeloid cells
how are innate and adaptive immune cells classified?
classified by the absence (agranular) or presence (granular) of cytoplasmic inclusions or granules
which cells serve as a link between the innate and adaptive immunity?
monocytes and dendritic cells
in addition to their difference in appearance, cells of innate and adaptive immunity can be distinguished by what?
by molecules on their surface, surface markers, known as CD markers
what is the relationship between CD and cell maturity?
cells express different types of CD at different level of developmental stage
how are WBC separated from RBC?
WBC can be separated from RBC by chemical treatment and centrifugation
do monocytes and macrophages have different functions?
function of monocytes and macrophages is the same
where do macrophages reside for the most part?
in tissues
what type of cell cleans up cellular debris?
macrophage
how long do macrophages live?
macrophages live long in tissues, up to years
are dendritic cells fixed?
no
are dendritic cells found under the skin?
yes
how do dendritic cells act?
they act like messengers
what do dendritic cells do for lymphoid organs?
they carry pathogens to the lymphoid organs
what do dendritic cells do when they encounter a pathogen?
once they encounter a pathogen in tissues - dendritic cells act as messengers by carrying the pathogen to the nearby lymphoid tissue
do you find mast cells in the circulation?
no
what do mast cells do to parasites?
mast cells recognize and kill large parasites
do macrophages and neutrophils die after they kill an invader?
macrophages kill but do not die • neutrophils kill and then die
what is the rate of release and lifespan of neutrophils?
are released from bone marrow at the rate of several million per minute • short lived 2-3 days
are eosinophils similar to mast cells?
similar to mast cells. kill big parasites
when do lymphoid cells express surface antigen receptor?
once fully developed
B lymphocytes in the blood mature into what?
plasma cells
what is the relationship between plasma cells and antibodies?
produce antibodies
what cellular organelle other than the nucleus is visible in plasma cells and why?
plasma cells are full of ER for protein synthesis (antibodies/ immunoglobulins)
what types of cells do NK cells target?
targets virally infected cells, cells lacking MHC1, and tumor
what are the morphological differences between NK cells and B and T lymphocytes?
NK cells are morphologically indistinguishable from lymphocytes
what % of lymphocytes in the blood are NK cells?
15%
where does the lymphocyte meet the pathogen and where does the immune response take place?
secondary (peripheral) lymphoid organs
how is the lymphoid system arranged?
in either discretely encapsulated organs or accumulation of diffuse lymphoid tissue
what are the major lymphoid organs?
- bone marrow • 2. thymus • 3. spleen adenoids • 4. tonsils • 5. appendix • 6. lymph nodes • 7. peyer’s patches
what are peyer’s patches?
They are aggregations of lymphoid tissue that are usually found in the lowest portion of the small intestine, the ileum
how many types of antigens are associated with one cell in primary lymphoid organs?
one cell= one type of antigen
what happens to B and T lymphocytes after maturation in the primary lymphoid organs?
after maturation in the primary organs both B and T lymphocytes circulate through and accumulate in secondary lymphoid organs
how many lobes in the thymus?
2, thymus is bilobed
what are the subdivisions of the lobes of the thymus?
lobules
how many regions per lobule in thymus?
2: cortex, medulla
where are the immature lymphocytes in the lobules of the thymus?
cortex
what are the cells found in the thymus?
- T lymphocytes • 2. epithelial cells • 3. dendritic cells • 4. macrophages
which cells are responsible in the maturation process of T lymphocytes in the thymus?
epithelial cells and dendritic cells
what is the role of macrophages in the thymus?
clean dead cells
what is thymus tissue replaced with as it involutes with age?
fat
growth of the thymus continues until when?
puberty
what happens to the thymus after puberty?
there after it undergoes atrophy with aging
when does T lymphocyte maturation mainly occur?
mainly occurs during fetal development and a short time after birth
what percent of the T cell progenitor survive and leave the thymus as mature T cells?
5-10%
what are the highly organized secondary lymphoid organs?
- lymph nodes • 2. spleen
what peripheral lymphoid organs are the less organized accumulations of lymphoid organs scattered strategically throughout the body?
- tonsils and adenoids • 2. appendix • 3. GALT (including Peyer’s patches) • 4. BALT in bronchi • 5. MALT • 6. SALT beneath the skin
what does the secondary lymphatic system include?
- lymph nodes (glands) • 2. connecting lymph vessels
between where do lymphocytes circulate?
between the blood and lymphatic tissues
into what are the lymph nodes divided?
follicles
which cells dominate the lymphocyte population in the cortex of the lymph node?
B lymphocytes
which cells dominate the paracortical region of the lymph nodes?
T cells
what types of cells bring components of pathogens to the B and T cells in the lymph nodes?
dendritic cells and macrophages
dendritic cells and macrophages bringing components of pathogens to the lymph nodes allows the B cells to do what?
convert into plasma cells and proliferate into germinal centers
what aids in the conversion of B cells to plasma cells?
T cells
T cells cooperate with B cells in the synthesis of what, meanwhile some T cells leave the nodes to provide other functions elsewhere in the immune response?
synthesis of immunoglobulins
where in the lymph nodes are the effector cells?
the medulla
through what do the antibodies exit the lymph nodes?
efferent vessels
Do lymphocytes and dendritic cells enter the lymph nodes by the same route?
no, they enter by different routes
how do most lymphocytes enter the lymph nodes?
most lymphocytes migrating to lymph nodes enter from the peripheral blood
which types of cells can extravasate through HEVs?
although various types of leukocyte are found in the arteries of lymph nodes, only lymphocytes can interact with and extravasate through HEVs
what happens to T cells and B cell after they extravasate through HEVs?
T and B cells subsequently segregate into T cell zones and B cell zones
how do most dendritic cells, together with small numbers of lymphocytes, enter lymph nodes?
through the afferent lymphatics
what types of cells are fixed in lymph nodes?
lymph nodes contain fixed macrophages and dendritic cells
what do the fixed dendritic cells and macrophages do?
- trap the antigens and present them to T lymphocytes • 2. produce cytokines that would influence the activities of lymphocytes
how do naive lymphocytes travel between primary and secondary lymphoid organs?
Naïve lymphocytes leave the primary lymphoid organs and enter the blood circulation and enter • the secondary lymphoid organs through the artery and leave the circulation through the HEV and • stay in these organs for some time
what happens to lymphocytes if they do not meet the specific antigen?
they re-enter the circulation
what happens to lymphocytes if they do meet the specific antigen?
proliferate and differentiate
what are the lymphocytes that have met antigen and subsequently proliferate and differentiate called?
primed lymphocytes
what do primed lymphocytes do?
leave the nodes through the circulation and concentrate at the site of infection
is red pulp of spleen part of the immune system?
no
what happens to people that lose spleen?
they become immunodeficient
what is the largest secondary lymphoid organ?
spleen
what immune components does the spleen contain?
- many reticular fibers that support fixed macrophages and dendritic cells • 2. ever changing populations of circulating B and T lymphocytes
at what is the immune part of the spleen highly efficient?
trapping and concentrating foreign substances carried by blood
what is the major organ in which antibodies are synthesized?
spleen
what MALT cells allow the passage of pathogens through them?
M cells
which tissue tracts are loaded with MALT?
- GI tract • 2. respiratory tract
