Exam 3 Flashcards
alpha:beta T cell selections
positive and negative election, only about 2% make it through positive
Positive T cell selection
recognition of peptides on self-MHC molecules, presented by thymic cortex epithelium, after binding the MHC will select the co-receptor, if no bind then apoptosis
Thymic cortex epithelium
produce both MHC classes of molecules and present them to developing T cells, peptides derived from self proteins (appx 10,000 self peptides, 120,000 if hetero for all 6 HLA classes) thus T cell receptor repertoire in order of tens of millions
Allelic Exclusion
Remember the alpha chain doesn’t do this - mature T cells can produce two different functional T-cell receptors (1/3 make 2) but after positive selection this drops to 1-2%.
Positive T Cell selection Time line
If first alpha chain rearrangement is productive, positive selection occurs in a few hours (RAG inactivated and protein destroyed). If not, rearrangement continues and can continue 3-4 days until T-cell receptor can be positively selected for (receptor editing)
T Cell Co-Receptor
positive selection not only selects functional T cell receptors for MHC binding but is driving force for co-receptor commitment. Makes double positive thymocyte become single positive thymocyte
CD8
co-receptor recruited by MHC class I
CD4
co-receptor recruited by MHC class II
Single Positive Gene Expression
Binding of co-receptor stop synthesis of other receptor. Then gene expression changes to provide CD4 cells with capacity for helper function and CD8 cells with capacity for cytotoxic function
Negative Selection T-Cells
deletes T cells that bind to self peptides and self-MHC molecules presented in thymus too strongly. Mediated by thymocytes. Most importantly checks bone derived dendritic cells and macrophages.
Negative Selection general presentation
occurs by the presentation of self peptides derived from proteins that phagocytes have taken up, including ubiquitously expressed proteins. Proteins expressed in multiple cell types, the transcirption factore autoimmune regulatore AIRE expresses tissue-specific genes.
AIRE
transcription factor autoimmune regulator, which expresses tissue specific genes. Important for differentiating between cells that produce the same proteins.
Regulatory CD4 T Cells general
instead of activating macrophages and B cells like helper cells, these guys suppress response of self-reactive T cells.
Regulatory T cells receptors
Have receptors that recognize self antigens an express CD25 and a transcriptional factor called FoxP3
Regulatory T Cell Function
When regulatory T cell binds to MHC class II molecule with self antigen, it suppresses proliferation of naive T cells responding to self antigens on the same antigen presenting cell
FoxP3
expressed only in regulatory T cells, is encoded by a gene on the X chromosome
IPEX
(immune dysregulation, polyendocrinopathy, exteropathy, x-linked syndrome) a deficiency in FoxP3 and causes autoimmunity and only treated via bone marrow transplant
Differentiation of T cells in Secondary Lymphoid Tissue
only 1-2% survive +/- selection, Mature T cells recirculate through blood and to secondary lymphoid tissue and lymph, can circulate many moons, Naieve activated by antigen in secondary lymphoid tissue, causes division and differentiation into effector T cells,
Effector Cells are
CD8 become cytotoxic T cells (intracellular pathogens only so there are not as many), and CD4 become helper/regulatory (depends on nature of pathogen and immune response required for clearance…double number of CD8…attacked in HIV)
T Cell Tumors
most correspond to early or late stages of development, have characteristic rearrangements of their T cell receptor genes (derived from a single transformed cell) so gene rearrangements can be detected to determine presence of T-cell tumor and monitor growth and dissemination.
When T cells are going through positive selection, what provides the driving force for selecting the co-receptor?
recruitment to the bound MHC molecule
What happens during receptor editing in T cells?
Continued rearrangement of alpha chain
First step of primary adaptive immune response
T-cell activation
Location where adaptive immune response generated
secondary lymphoid tissue after macrophages and dendritic cells take up pathogens and present antigens on MHC class 1 and II
Dendritic Cells - Major Function
major function of dendritic cells is to trigger T-cell response - do this well do to dendritic cell mobility. Can be immature or activated.
Immature Dendritic Cells
when dendritic cells are in tissues
Activated Dendritic Cells
when dendritic cells are in the lymph node
General Capabilities of Dendritic cells
numerous receptors for binding pathogens (mannose receptor, TLRs), numerous mechanisms of pathogen uptake, numerous mechanisms of pathogen presentation.
Dendritic cell activation
occurs through TLR signaling - including expression of CCR7 (CCL21 receptor) which allows migration of dendritic cells into draining lymph node
CCR7
CCL21 receptor on T cells, which allows migration of dendritic cells into draining lymph node
T Cells can enter lymph node via
blood capillaries or lymph
Antigen Encounter by Naive T cells
T cells become activated by interaction with antigen-presenting dendritic cell, T cell that will recognize an antigen represents 1 in 10^4 to 10^6 circulating T cells, so draining lymph concentrates the antigen, activated T cells take several days to proliferate and differentiate into effector cells.
Naive T cells into Lymph Node
1) circulating T cells enter high endothelial venule in lymph node. Stromal and dendritic cells express the chemokine CCL21 and CCL19 (bind to CCR7 on T cell)
2) binding of L-selectin(on T cell) onto GlyCAM-1 and CD34 (on endothelium) allows rolling interaction
3) LFA-1 (on T cell) is activated by chemokines bound to extracellular matrix
4) activated LFA-1 binds tightly to ICAM-1 and ICAM-2
5) diapedesis
Naive T cells interact with cells in Lymph Node
1) Interaction between T cell and dendritic cell. Either LFA-A on the T cell interacts with ICAM-1 on dendritic cell, or DC-SIGN on dendritic cell interacts with ICAM-3 on T cell
2) adhesion strengthened by CD2 (T cell) interacting with LFA-3. T cell can now monitor MHC-antigen complex
3) MHC binding strengthens interaction more
4) exit of T cells from lyphoid tissue involves chemoattractant sphigosine-1-phosphate
T Cell activation Co-Stimulation
Need the co-stimulatory signal which is only provided by professional antigen presenting cells (dendritic cells, macrophages, B cells). B7 on antigen presenting cells stimulates CD28
CTLA4
Binds to B7 twenty-fold more stongly than CD28 and is an antagonist in order to dampen T cell activation. This is expressed by activated T cells.
Professional Antigen Presenting cells’ job
Located in secondary lymphoid tissues but in different locations. After uptake of pathogen, they upregulate B7, MHC molecules, chemokines and surface receptors used in naive T cell binding.
The Immunological Synapse
ITAMs associate with protein tyrosine kinases, kinases phosphorylate ITAMs, co-receptors CD4 and CD8 associate with protein kinase Lck, Lck activates the soluble kinase Zap-70 which binds phosphorylated ITAMs
ITAMs
immunoreceptor tyrosine-based activation motifs - these are on the cytoplasmic tails of CD3 component of T cell receptor
Signal Transduction in T Cell Activation
1) Zap-70 activates phospholipase C
2) Phospholipase C cleaves phosphatidylinositol bisphosphate into diacylglycerol (DAG) and inositol triphosphate (IP3)
3) DAG activates protein kinase C-theta to activate NF-kB, and DAG activates RasGRP which activates MAP kinase cascade which acitvates AP-1
4) IP3 increases intracellular Ca, which binds to calcineurin
5) calcineurin acitvates transcription factor NFAT
NFAT
nuclear factor of activated T cells (transcription factor)
Interleukin-2
drives gain of effector functions. secreted by activated T cells. So Naive T cells have a low affinity for IL-2 while activated express a high affinity receptor for IL-2. Stimulates proliferation, target of immunosuppresive drugs cyclosporin A, FK506, rapamycin
T Cell Anergy
T cells that escape negative selection but thus don’t have co stimulation. Anergic T cells cannot express IL-2
Adjuvants
component in immunization that activates co-stimulatory response
Four Types of Helper T Cells
Th1, Th2, Th17, Tfh
T(h)1
secrete IL-12 and INF-gamma to activate macrophages (cell mediated immunity)
T(h)2
Secrete IL-4 and IL-5 to activate B cells (humoral immunity)
T(h)17
secrete IL-17 and IL-6 to activate neutrophils
T(fh)
follicular helper T cells - secrete IL-21 to activate B cells in primary follicles
CD8 Cytotoxic T Cells activate
only dendritic cells can provide the proper co-stimulation of naive CD8 cells to become cytotoxic T cells. CD4 helper T cells can actually help activate CD8 by secreting IL-2 as a growth factor
Which of the following cytokines is also known as the T cell growth factor?
a) Lck
b) ZAP-70
c) LFA-1
d) IL-2
D
Which of the following transcription factors is ultimately activated by an increase in calcium levels within a naive T cell?
a) NF-kB
b) AP-1
c) NFAT
d) all of them
C
______ of thymocytes is necessary to produce T cell repertoire capable of interacting with self-MHC molecules
positive selection
Naive lymphocytes homing to lymphoid tissue use ____ to bind to CD34 and GlyCAM-1 on high endothelial venules
L-Selectin
The co-stimulatory molecule ____ on professional antigen-presenting cells binds ____ on the surface of naive T cells
B7 and CD28
The area of contact between membranes of a T cell and an antigen-presenting cell where a clustering of protein-protein interactions occurs in called a(n) ____
immunological synapse
Clonal expansion and differentiation of naive T cells to effector T cells depends on the activation of the transcription factor(s) ______through ZAP-70-mediated signal transduction
AP-1, NF-kB, NFAT
____ is a second messenger in the T-cell signaling pathway leading to the activation of NFAT
inositol triphosphate
Dendritic cells take up, process or present antigen by which of the following routes?
a) receptor mediated endocytosis of bacteria
b) uptake of viruses using Toll-like receptor TLR0
c) macropinocytosis of soluble antigens
d) cross-presentation from MHC class II pathway to the MHC class I pathway
e) cross-presentation from incoming infected dendritic cells to healthy resident dendritic cells in secondary lymphoid tissue
A, C, D, E
Effector T Cells Activation Requirements
do not require co-stimulatory signal…important so cytotoxic CD8 cells can target any infected cell and increases number of B cells and macrophages that can interact with CD4 helper T…..so activated T cells signal a need to respond to antigen and the removal of co-stimulation requirement ensures effector T cell activation action as needed
Effector T Cell Expression
express 2-4 times more cell adhesion molecules (LAF-1 and CD2) than naive T cells, don’t express L-selectin so cannot re-enter lymph node but do express VLA-4 to bind endothelial cells and enter infected/inflammed tissue.
Cytotoxic T Cell’s cytokines
INF-gamma, LT, IL-2, to kill virus infected cells
T(h)1 Cell’s cytokines
ING-gamma, to activate macrophages
T(h)2 Cell’s cytokines
IL-4, IL-5, and a little IL-10 to activate B cells, basophils, eosinophils, and mast cells to fight parasitic infection
T(fh) Cell’s cytokines
IL-21 and mostly IL-4 to activate B cells and promote isotype switching and affinity maturation
T(h)17 cell’s cytokines
IL-17 to activate neutorphils
T(reg) cell’s cytokines
TFG-beta for T-cell peripheral tolerance
What carries out effector t cell funtion
cytokines and cytotonins and secretion is targeted to cells through polarization of secretion system
Cytokines
alter target cell behavior, made by all effector T cells, work over short distance (autocrine or paracrine), binding causes receptor dimerization, activation of JAKs, and thus activate trascriptional activators STATs
JAKs
Januskinases - most cytokine receptors have cytoplasmic tails that bind this. Will activate transcriptional activators STATs
cytotoxins
kill infected cells (only produced by CD8 cells)
Lytic granules
contained in cytotoxic T cells, contain cytotoxins, made after T cell activation, release directly at target cells once antigen:MHC complex made, as target cell dies the cytotoxic T cell releases and can bind to neighboring cell
Methods Cytotoxic T Cells induce apoptosis
Release of cytotoxins or Fas Lignad
Release of cytotoxins
perforin and granulysin form hoes in membrane for delivery of granzymes which activate apoptosis
Fas LIgand
cytotoxic T cells express to bind to as on target cell…starts signaling cascade to activate apoptosis
T(h)1 cells activating macrophages
Th1 cells can recognize presented antigen on the surface of macrophages and bind tightly to make conjugate pair and then release cytokines to improve macrophage action
Conjugate Pair
Th1 cell binds tightly to macrophage and through INF-gamma and CD40 activate the macrophage for increased lysosome function, increased production of reactive and microbicidal molecules, increased B7
T(fh) Activate B Cells
During infection, T-cell zone of secondary lymphoid tissue. B cells pick up, process, present their specific antigen, if Tfh recognizes MHC:antigen complex, makes CD40 and IL-4 to stimulate B proliferation/clonal expansion
CD4 Regulatory T Cells
autoreactive, suppress CD4 and CD8 autoreactive T cells, express CD25, component of IL-2 receptor for high affinity, FoxP2, and immunosuppressive/anti-inflammatory cytokines (IL-4, IL-10, TGF-beta), might prevent dendritic cells from activating more T cells
Hepatitis B
virus induces large amount of regulatory T cells that present hep B antigens (thought that effector T cells an thus suppressed)
Mycobacterium tuberculosis
during active disease states, number of regulatory T cells increases with corresponding decrease in effector T cells
T(h)1 helper T cells are responsible for activating?
macrophages
Which of the follwing are proteases responsible for inducing apoptosis in cells targeted by ctotoxic T cells?
a) Granulysin
b) Perforin
c) Granzymes
d) Fas Ligand
C! (granulysin and perforin make small holes in the membrane)
Cross-linking of B-cell receptors by antigen
clustering of antigen receptors allows receptor-associated kinases to phosphorylate hte ITAMs
Cross-linking of B-Cell Receptors
upon binding of surface molecules of a microorganism, IgM molecules become cross-linked to each other. This causes signaling via protein kinases associated with B cell receptor
B-Cell ITAMS
located on the cytoplasmic tails of Igalpha and Igbeta chains
Kinases B-Cell ITAMs associate with
Fyn, Lyn, and Blk
Syk
protein kinase recruited by ITAM phosphorylation that goes on to initiate intracellular signaling leading to change in gene expression
B Cell Co-receptor proteins
CR2, CD19, CD81. Needed for activation.
CR2
binds iC3b and C3d
generation of iC3b and C3d
involves the complement receptor CR1, which facilitates cleavage of C3b by factor I to iC3b and C3d
CD19
signaling molecule that is a part of the B cell co-receptor. Gets phosphorylated by Lyn
B-Cell Signaling General
1) IgM clustering/receptor activation causes activation of Blk, Fyn, Lyn and Sy
2) Syk activates CD19, phospholipase C and GEFs
3) PLC cleaves PIP2 into DAG and IP3
4) DAG activates protein kinase C which activates NF-kB
5) IP3 increases intracellular Ca2+, binds to calcineurin, activates NFAT
6) GEFs activate Ras and Rac to activated AP-1
Thymus-Independent Antigens and B-Cell Responses
TI antigens typically repetitive carbohydrates or protein epitopes at high density on the surface of microoorganism. Cross-links receptor and co-receptor. Typically cell-wall plolysaccharides. Still produce IgM but low isotype switching.
GEFs
guanine nucleotide exchange factors….activated by Syk, goes on to acitvate Ras and Tack and thus AP-1 in B cell siganling
Follicular Dendritic Cell Function
dedicated to the development and immune response of B cells. along with T cells, are essential in producing B cells that have undergone affinity maturation and isotype switching. Act as antigen depository, storing antigens for months or years by keeping them at cell surface.
CD4 T cells needed to activate B cells with antigen
dendritic cell presentation of antigen to CD4 T cells in T-cell areas of secondary lymphoid tissue, togehter with the work of IL-4 produce T(fh) helper T cells.
How B/T conjugate pair forms
B cells home to the T cell zone where it may come in contact with its sepcific antigen. recognition of antigen prevent B cell departure from T-cell zone until activated. If B and T recognize the same antigen and interact, for conjugate pair.
T-Cell Dependent B-cell activation
T/B conjugate pair causes T cell to express CD40 which activates B cells to make NF-kB and increase of andhesion molecule ICAM-1 (bind LFA-1 on T cell).
T/B conjugate pair immunological synapse
allows polarization of secretioin of cytokines, most importantly IL-4 which is essentiatl for B cell proiferation and differenation.
Conjugate pair movement
formation of conjugate pair allows T cells and B cells to move out of the T-cell zone and form a primary focus of clonal expansion (B cell starts secreting IgM)
Medullary Cords
where some cells develop from primary focus into IgM-secreting plasma cells
Primary Follicle
when B cells don’t go to medullary cords, the move here with follicular dendritic cells and T cells where they undergo somatic hypermuation and isotype switching
Follicular dendritic cells in primary follicle
make cytokines that convert B cells into centroblasts an T cells induce cells to produce activation-induced cytidine deaminase
Germinal center
Formed when B and T cells proliferate and where development of the B cells continue
Selection of centrocytes in the germinal center
occurs as somatic hypermutation and isotype switching is going on, follicular dendritic cells continue to present antigen to centerocytes, if tight the B cell gets survival signal.
Survival Signal
B cells bind to antigen presented by follicular dendritic cell, continued to be presented induces B cell’s expression of Bcl-XL
Bcl-Xl
apoptosis inhibitor
B cells with low binding affinity
they die via apoptosis
What drives isotype switching?
cytokines from helper T cells promote isotype switching by initiating transcription at switch regions, providing access to the DNA to recombination machinery by remodeling chromatin
Centrocyte Development
will develop into either plasma cells or memory cells depending on the signal recieved from helper T cell (already did isotype swtiching)
centrocyte develop to memory cell
driven by IL-4 secretion from T cell
centrocyte develop to plasma cell
driven by IL-10 secretion from T cells
True or False? All B cells activation events require the action of helper T cells.
False - Thymus Independent Antigens
Which of the following proteins located on the pathogen is responsible for binding to the CR2 component of the B-cell co-receptor during activation?
a) CD19
b) CD81
c) Lyn
d) C3d
D) C3d and also iC3b
IgM pentameric stucture
makes it useful for binding antigenand activating compliment but decreases its ability to penetrate infected tissues
Affinity Maturation
IgM becomes IgG and monomeric IgA which only have two antigen-binding sites but affinity is just as high.
IgG
actively transported to extracellular space and is taken up by pinocytosis and binds to FcRn which protects IgG from degradation
Dimeric IgA transported across epithelium
binds to poly-Ig Receptor on the basolateral surface through disulfide bond formation. receptor mediated endocytosis takes up receptor and transports IgA to apical side (transcytosis)
Secretory component IgA
after transyctosis of dimeric IgA, on the apical side the poly-Ig receptor is cleaved creating this componenet but still bound via carbohydrate at the mucosal surface
Fc(epsilon)RI
an Fc receptor present on mast cells, basophils, and eosinophils that binds to IgE
Mast CEll Activation
leads to release of histamine and other molecules involved in inflammation (inflammatory mediators)
Inflammatory Mediators
increase blood vessel permeability which leads to accumulation of fluid, swelling, reddening, and pain
IgE and Parasites
increases smooth muscle contraction for expulsion of parasite
IgE and Mast Cells binding
IgE usually not soluble so it binds to Fc(epsilon)RI on mast cells. Binding cross-links receptor and secretes mediators that work on smooth muscle causing sneezing, couging, vomiting, diarrhea for forcible ejection of pathogen
IgE reactions
cause allergies and asthma
Passive Transfer of Immunity
How babies get IgA through mother’s milk since it takes about 6 month for babies to start making antibodies.
Mother’s Passing IgG
pass to the fetal bloodstream using FcRn (babies can elicit IgG response but do not have IgA immediatly) so from 3-12 month of age babies have very low IgG
Neutralizing antibodies
prevent interaction between pathogen and host cells. many infections occur at mucosal sufaces so many are dimeric IgA. Bind to bacterial/viral adhesins
IgM and Complement Activation
activate classical pathway by IgM first changing to staple form (starts as planar form) to bind C1. Mimics same function as C-reactive protein. Lead to phagosytosis by neutrophils and macrophages or assembly of membrane-attack complex
IgG and Complement Activation
Only one binding site for C1 thus C1 needs at least two IgG for efficient binding.
Soluble Immune Complex
IgG can form these and become capable of binding multivalent antigen, and when soluble can activate complement by becoming coated in C3b. If activated the whole complex phagocytosed
CR1
mostly expressed on erythrocytes and immune complexes coated in C3b can bind.
Erythrocytes and soluble immune complexes
when coated in C3b, immune complexes can bind to CR1 on erthrocytes. the erthrocytes then deliver them to macrophages in the liver and spleen
Removal of immune complexes
need to remove or else aggregets can form in the blood and can precipitate in small blood vessels (especailly in the kidney glomeruli)
Cells in the Glomerulus
specialized in removing immune complexes and repairing tissue damage caused by immune complexes
IgG and Effector Function
There are several subtypes and are all felxible in their own ways which increases the probability that IgG can bind two antigens and to effector molecules but this means they are suseptible to protyalytic cleavage
IgG1
most protein antigens
IgG2
repetitive carbodyrate antigens
IgG3
best at complement activation
IgG4
can exchange heavy-light chain dimer with another igG4 but can only neutralize and is anti-inflammatory
Fc(gamma)RI
Rc receptor that binds to IgG and is expressed on macrophages, monocytes, and dendritic cells. This facilitates phagocytosis since Fc receptors can bind to antibodies carrying antigen and promote receptor cross-linking and signaling towards phagocytosis
Which of the following is not an example of passive transfer of immunity?
a) infants receiveing IgA from breast milk of mother
b) transplacental transport of IgG
c) immunoglobulin injection against tetanus toxin
d) antibody production during influenza virus vaccinantion
d
Antibodies that bind to the surface of pathogens or toxins and prevent their entry into a target cell are refered to as
a) opsonizing antibodies
b) neutrolizing antibodies
c) soluble immune complexes
d) inflammatory mediators
b
T(fh) cytokines exert which of the following effects?
a) secretion of neutralizing antibodies
b) release of cytotoxins by cytotoxic T cells
c) B cells differentiation
d) secretion of opsonizing antibodies
e) macrophage activation
c
Cyotkine receptors are associated with the cytoplasmic protein kinase called ______, which becomes activated when the cytoking receptors bind to their respective cytokines.
JAKs
Which of the following is not produced by cytotoxic T cells?
a) CD40 ligand
b) INFgamma
c) Fas ligand
d) granulysin
e) perforin
a
signal transducers and activators of transcription (STATs) are _____ that are phsophorylated by _____.
trascription factors; JAKs
The process by which cytotoxic T cells kill their targets involves
release of granzyme, perforin, and granulysin by cytotoxic T and also engaging Fas on the target cell with Fas ligan on the cytotoxic T cell surface
C3d and iC3b are breakdown products of _____ which binds to _____ of the B-cell co-receptor.
C3b: CR2
A primary focus forms after a circulating naive B cells forms a conjugate pare with _____ in the _____ of a lymph node
T(fh) Cell; T-cell zone
For which process do proliferating centroblasts use DNA-modifying enzyme activation-induced cytidine deaminase?
isotype switching and somatic hypermutation
Mucosal epithelia of the gastrointestinal tract, eyes, nose, throat, the respiratory, urinary, a genital tracts, and the mammary glads are protected by ___
dimeric IGA
The process involving receptor-mediated transport of macromolecules from one side of a cell to the other is called ______
transcytosis
Which of the following are examples of passive transfer immunity?
a) transplacental aquisition of TgG during fetal development
b) provision of IgA through breast milk
c) antibody production after vaccination
d) intravenous immunoglobulin therapy for immunocompromised individuals
e) antibody production after influenza infection
f) receiveing antivenom after being bitten by a poisonous snake
a, b, d, f
mucus
contains glycoproteins, proteoglycans, peptides, and enzymes that protect epithelial cells, especailly mucin ;
how much mucus
mucosal surfaces have 200 times the surface area of skin and 3/4 of body’s lymphocytes serve mucosal surfaces
Gut-Associated Secondary Lymphoid Tissue
large maount of secondary lymphoid tissue associated with mucosal tissue (mesenteric lymph nodes, gut-associated lymphoid tissue) and provies local adaptive immune response initiation
tonsils and adenoids
these secondary lymphoid tissues guard the enterance to the gut
Peyer’s Patches
line the small intestines, contain lymphocyte follicles which underly follicle-associated epithelium
microfold cells
M Cells - specialized epithelial cell contained in follicle-associated epithelium. Uptake pathogen and transfer to Peyer’s patch to induce adaptive immunity
Isolated lymphoid follicles
comprised of single follicle with B cells
Intestinal Epithelial Cells and Innate Immunity
epithelial cells are active at uptake of molecules from gut lumen and detection of bacteria in the cytoplasm with an intracellular sensors inducing TLRs and NOD activating NF-kB causing sytnthsis of cytokines, chemokines, mediators
Transport of microbes to gut associated lymphoid tissue
M cells uptake pathogen and transcytos to lymphoid tissue. Pockets in M cell’s basal membrane encloses lymphocytes and dendrtiic cells waiting.
Dendritic cells in gut
can extend processes across the epithelial layer to capture antigen from lumen of gut as to not disturb epitheial integrity
Healthy Mucosae
heavily populated with activated effector lymphocytes and leukocytes mostly effector T cells and plasma cells
intraepithelial lymphocyte
distict CD8 T cells that is integrated into the epithelial layer of the SI and are activated and contain cytotoxic granules
Lamia propria
has variety of effector lymphocytes CD4 and CD8 T cells, plasma cells, and dendritic cells and mast cells
State of healthy mucosae
sustains a chronic adaptive immune response and restrains microbes from entering other tissues
Naive B and T cells enter Peyer’s pathces
get through through homing mechanisms and attraction to CCL21 and CCL19. Activated in the patches and leave to home to the type of mucosa in which they were activated from the blood
B and T gut homing requires
selectins and interins on the lymphocyte and the mucosal addressin MAdCAM-1 through attraction to chemokine CCL25
CCL25
chemokine that attracts activated lymphocytes to gut tissue via mucosal addressin MAdCAM-1
IgM and mucosal surfaces
same benefits and problems as other IgM pentameric structures but affinity matureation allows production of IgG
IgG and mucosal surfaces
actively transported to gut lumen from either the bloodstream or plasma cells in the lamia propria. Taken up by pinocytosis and bind to RcRn for protection from degradation
B cells activated in Peyer’s Patches
preferntially udergo isotype switching to IgA dur to TGF-beta
TGF-beta
transforming growth factor beta which skews isotype switching of B cells to IgA
Lovations where dimeric IgA can bind to antigens
- if infection is in lama propria, can bind and translocate to gut lumen
- bind to antigen in endosomes as it translocates
- free IgA remains associated with mucosal surface
- in gut lumen bound to antigen can bind to M cells and trasport to lymphoid tissue
- internalized IgA in M cells can bind tan neutralize antigens
IgA Subclasses
monomeric and dimeric can be made as two subclasses IgA1 and IgA2
IgA1
longer hinge region making it more flexible but suseptible to protease cleavage and some pathogens like s. pneumoniae, N. meningitidis, and H. influenze target to separate Fac from Fc
Bound Fab
If Fab and Fc are separated from proteases, the bound Fab fragment on the surface of bacteria can actually enhance bacterial penetration across mucosal epithelium to lamia propria to start infection
IgA2
production is driven by cytokine APRIL
IgA Deficiency
1:500 white 1:10000 aa produce little or no IgA but are healthy. Compensation tends to IgM whcih can bind to poly-Ig receptor. Less pressure from parasites like helminth worms since we cook food. But chronic lung disease more common maybe poorer air quality
Helminth Infections
almost everyone has these via hookworm or roundworm and they cause diesase via nutrient competition or damage to epithelium/blood vessels and the host response can cause damage
T(h)2 response to helminth
tend to be protective and promote B cells to swithc to IgE which promote mast cell activation and killing of parasites
T(h)1 response to helminth
tend to cause damage as they promote an inflammatory response
The specialize cells associated with mucosal epithelia that facilitate transcytosis of antigens and pathogens to mucosal secondary lymphoid tissues are
M Cells
The protein family in intestinal epithelial cells that is responsible for pathogen detection in gut is
NOD
Successful primary immune response does
clears infection, temorarily strengthens defenses to prevent further infection since antibodies against a pathogen last in the body for months, and it establishes immunological memory
Why memory cells respond quicker and stronger
higher sensitivity to antigen, more easily activated, more abundant than naive lymphocytes that recognize antigen, and higher affinity receptors (Bcells)
Goal of Vaccination
immunize people with a benign form of pathogen to induce immunological memory. ie smallpox
How long vaccines last
small pox 75 years, diptheria 19 years, measles 200. This is why some need boosters.
Primary Infection give you
first produces IgM and as isotype swithcing ans somatic hypermutation occurs start to produce IgG, IgE, and IgA and a small subset of memory B cells
Secondary infection gives you
10-100 times more pathogen-specific B cells to respond than during the first inection
Memory B Cells are great because
more sensitive to antigen, respond more quickly to antigen, present antigen to T cells more efficiently, express more MHC class II co-stimulatory moleucles . Still need cell-cell interactions but demand is lower because co-stimulation requirement is lost
Who participates in secondary immune response
involves activation of memory B cell clones so naive B cells CANNOT participate. This concentrates IgG, IgE, and IgA needed. No wast in making low-affinity IgM
How to stop naive B cells form participating in secondary response
suppression is mediated by immune complexes composed of pathogens bound to antibody. Bind to B-cell receptor and FcgammaRIIB1
Fc(gamma)RIIB1
inhibitor Fc receptor that binds to pathogen specific naive b cells making a corss=link that delivers a negative inhibitory signal to prevent low-affinity IgM antiboeies which is a waste.
Hemolytic Anemia
disease that affects families where father is positive for the polymorphic erythrocyte antigen called Rhesus and then mother is negative
Treating Hemolytic Anemia
in newborns immune complexes inhitibe naive B cells
Fist v Second Baby and Hemolytic Anemia
If father is Rh+ and mother Rh-, first pregnancy with Rh+ boby is fine since low-affinity IgM can’t cross placenta but the mother produces anti-Rh antiboes. During secondary pregnancy with Rh+ baby, antibodies coat erythrocytes and promote cleaance by the pleen resulting in babies with sever anemia.
Prevention in mothers on hemolytic anemia
pregnant Rh- women infused with RhoGAM to prevent naive cell activation
RhoGAM
anti-Rh IgG
Loss of Immunological Memory
Invariant pathogens are easily killed by secondary response, but mutable pathogenes produces virus variant that escape protective immunity each year and the secondary response only limits antibody production to the original antigentic sin
New Primary Responses
only upon infection where all epitopes of pathogen are lost can an effective primary response to new mutant strain be raised
Memory T Cells vs Naive T Cells
Memory T harder to define because no isotype switching or hypermutation, virus-specific dramatically increase during infection but then drop 10-1000 fold leaving only memory T cells, similar to effector cells but difference between L-selectin/CD44 and CD45 which changes T cell homing
CD45 isoforms
alternative splicing changes tyrosine phosphatase CD45 isoform in naive versus memory T cells
CD45RA
naive T cells have these and has weaker signaling in response to antigen
CD45RO
memory T cells have these and has stronger signaling in response to antigen
Subsets of Memory T cells
Effector memory T cells and central memory T cells
Central memory T cells
L-selectin positive, CCR7 positive, circulate in lymphoid organs, stem-cell like and be activated by antigen any cytokines.
Central memory T cell specilization
specialize in entering T-cell zones of secondary lymphoid tiuuse
Effector memory T cells
L-selectin negative, CCR7 negative, circulate in non-lymphoid tissue, already differentiated with highe levels of effector molecules
Effector memory T cell specilization
specialize in entering inflamed tissue and working there. can differntiate into effecot T cells that further bias towards needed T cell response
Maintenance of memory cells
????? may be due to cytokines produced during other responses that promote memory cell propagation and survival
Fatima, a 25-year old recent immigrant from Sudan, is brought to an obstetrician by her husband for the first time at about 38 weeks of pregnancy. First pregnancy, and she and the baby are in excellent health. No previous anenatal care frearing it would mess up immigration. Delivers healhty girl 18 days later. Why give Fatima RhoGAM?
Fatima is Rh- and the baby is Rh+
One key characteristic difference between naive and memory T cells is the expression of ______ on the surface of memory T cells
CD45RO
variolation
early form of vaccine administered via arm scratch. contained actual smallpox virus and 1% died
Live-attenuated virus vaccine
production of a virus that is still alive but has a reduced ability to grow in humans and is no longer pathogenic. More potent and can replicate for a limited amount of time an mimic real infection. Grown in culture and selected for growth in non-human cells
Subunit Vaccines
viral cell-surface molecules used to generate neutralizing antibodies
Salk Vaccine
approved in 1955, polio vaccine (killed virus containing 3 strains (trivalent), with inactivated
TVOP
trivalent oral polio vaccine developed in 1963 with attenuated virus
Rotavirus
discovered in 1973 and was a major cause of sever childhood diarrhea. all children exposed causing 2million hospitalizations and 600,000 deaths annually
Rotavirus Vaccines
Now Rotrarix and RotaTeq are availible but the problem is coat proteins VP4 and VP7 are variable proteins due to rotavirus mutations. 5 variants cause 90% of disease.
Rotatrix
contains common VP4 and VP7 variants
RotaTeq
contains cattle rotavirus strains expressing common VP4 and VP7 varients
Bacterial Vaccines
not may live-attenuated bacterial vaccines, some are raised against toxins produced by pathogenic bacteria for a antibody response and production of neutralizing antibodies. Others against capsular polysaccharides
Most common live-attenuated bacterial vaccine
BCG vaccine derived from bovine strain of M. tuberculosis
Recent live-attenuated bacterial vaccine
strains of Salmonella for medical and vet use
Diptheria and tetanus toxins
purified and treated with formalin to inactivate the toxin to produce toxoids
DTP Vaccine
diptheria and tetanus toxoids combined with killed preparation of Bordetella pertussis making a combination vaccine
DTaP
combination vaccine from diptheria, tentanus, pertussis used in some countries where aP stands for acellular pertussis component
Capsual polysaccharid vaccine
used for pneumococci salmonellae, meningococci….conjugate vaccine needed in children
Problem with targeting polysaccharide coat
T(fh) cells are responsible for activating B cells and they recognize antigens that are peptides
Conjugate Vaccine
links the polysaccharide B cell antigen with a toxoid component so B cells can produce polysccharide antibodies, present to T cells, promote B cell activation
Adjuvants
added to vaccines to induce inflammation for a good immune response since purified protein antigens are not immunogens
immunogens
antigens capable of eliciting an effective immune response
Freund’s complete adjuvant
most effective adjuvant made from killed mycobactiona in oil. not wasily degrated and continues to stimulate immune system because recognized by NOD in phagocytes
Herd Immunity
vast majority of population vaccinated prevents epidemic spread of the disease
Genomic sequences
allow for direct attenuation of the strain through mutation or removal of virulence genes
Chronic infections
difficult to vaccinate against and depends on proper mounting of CD4 response towards Th1 and Tfh
What strategy is NOT used for developing/utilization of viral vaccine
toxoids (thas bacterial)
What is the purpose of an adjuvant in a vaccine?
to activate an inflammatory response
NK cell receptors
almost every receptor a T cell has but no TCR or CD3 complex. Do express CD56 and NKG2D. Can recognize MHC class I molecules.
CD56
NK cells are the only blood cell to express this. low expression = cyotoxic high = cytokine producing
NKG2D
activating receptor expressed by all NK cells (NK cells are inhibitory and activating)
NK and MHC class 1
Several NK receptors bind to MHC class 1 molecules, but they respond to reduced MHC class 1 levels on cell surface which is characteristic of pathogen-infected cells
NK inhibitory receptors
examine levels of MHC class I molecules while activating recognize MIC and together determine if NK cytotocix action needed
Vav
guanine nucleotide exchange factor - activity of this is at the center of NK activation
NK cell activation
activated by innate and adaptive responses. monitor for intracellularly infected cells but also for cells that have foreign antigens. antibodies that recognize the foreign antigen can bind to the target cell and seve as a bridge with CD16 to NK
Example of NK inhibitory receptor detecting alterations in MHC class 1 levels of epitopes
CD94:NKG2A monitors levels of HLA-A, HLA-B, and HLA-C by the recognition of HLA-E. HLA-E presents leader sequence of the others. Thus if HLA-A, HLA-b, and HLA-C are being processed, there will be an abundant level of HLA-E
KIRs
killer-cell immunoglobulin-like receptors are inhibitory receptors with narrow specificites. Bind polymorphic determinants on HLA-A -B and -C. Thus more capable of determining changes in levels of these moelcules on the surface.
HLA-C Allotypes
all are KIR ligands and only a few HLA-A and -B are. Because HLA-C geared to NK response and the others are more T cell
Nk-Cell Education
need to detect changes in self-MHC class I expression and so need inhibitory receptor that recognizes self HMC class 1 (CD94:NKG2A or KIR)
Testing NK cells
while developing in the bone marrow, testes for ability to recognize self MHC class 1 with inhibitory receptor. If good, education initiated to strike balance between activating and inhibitory.
NI entering circulation
balance shifts in the signaling pathways serve as activating signal
gamma:delta T cells
not subject to positive and negative selection like the alpha:betas are and do not recognize antigens bound to MHC complexes but still respond to a range of pathogens like TB and P. falciparum.
Phosphantigens
intermediates in isoprenoid biosynthesis that gamma:delta T cells can recognize.
gamma: delta T cell express
receptors for inflammatory cytokines so they can enter infected tissues like the other cells. also secrete granulysin.
glycolipids
made by mycobacterial species, effector T cells can recoginze since the lipid tails serve as antigens for CD1 MHC-like moleicules while the hydrophilic head binds to TCR
CD1
only expressed by cells that are infected by mycobateria (dendritic, activated monocytes) and by cortical thymocytes. Assembled in ER with self lipid and can be endocytosed where lipid exchange occurs
Cortical Thymocytes
in the thymus during negative selection of T cells
Endosomes
where glycolifids will present as mcobacterium reside in vesicels
CD1d
can present lipids to subset of T cells known as NKT cells
NKT cells
act during an innate immune response to initiate an inflammatory response and recruit and activate neutrophils, macrophages, B cells, and NK cells.
MAIT Cells
T cells that develop in the thymus but become these mucosa-associated invariant T cells. Produce TCR that recognizes antigens preneted by MR1
MR1
MHC class 1 molecule where antigen binding site is specialized to bind small heterocyclic compounds known as pterins produced during riboflavin synthesis
Mucosaw of a healthy intestinal tract have…
large number of activated T and B cells, contain intraepithelial cells, are populated with a:b and g:d CD8 effector T cells, and harbor T cells bearing a very wide diversity of antigen specificites. ….not large number of resident neutrophils
_____ is the vascular addressing found on endothelial cells of intestinal mucosa that binds integrins of gut-homing effector lymphocytes
MAdCAM-1
Secretory IgA is best described as
a non-inflammatory immunoglobulin that resiricts the passag eof antigens across mucosal surface
In which ways do memory B cells active in a secondary immune response differ from the naive B cell population activated in a primatry immune response?
antibody production or higher affinity, level of somativ hypermutation is higher, memory b cells epress higher levels of MHC class II
which of the following charaerizes immunological memory
host retains the capacity to mount secondary response, host retains ability to respond to pathogen many years later, memory b cells produced higer-affinity antibody and naive B
A conjugate vaccine is one that couples ___ to ____ as to stimulate T cell depented atinbody responses
polysaccharide; protein carrier
