Immunity exam 1 Flashcards
What are the two types of immune systems
innate
adaptive
(dendritic cells link them)
What does serum do in the blood
Soluble proteins that perform important functions in immune system
-protection, Ig
Phosphate and bicarbonate buffered saline solution
-control pH, correct osmolarity, salts, electrolytes
An antibody molecule is composed of _____ polypeptides, ____ identical heavy (H) chains and ____ identical light (L) chains
4, 2, 2
Antigen = the structure bound by the ________
antibody
What is an antigen
Any substance that can induce an immune response. It can be a protein, carbohydrate, lipid or nucleic acid. Any foreign substance (not necessarily infectious). Foreign meaning not self molecules, not present as the individual develops.
What are antigens recognized by
lymphocytes (receptors that specifically recognize “antigens” from microbes or noninfectious molecules)
What is an epitope
the portion of an antigen recognized by an antibody
What is innate immunity
0-12 hours
-Innate responses are general responses that are nonadaptive (don’t change with repeated exposure) and are not antigen specific.
-Innate responses are the first lines of defense against any invading pathogen to block entry or rapidly eliminate microbes
What is adaptive immunity
12h-5d
-The important features of adaptive immunity are specificity and memory.
-Adaptive immunity includes lymphocytes and their products, such as antibodies.
what are b lymphocytes or b cells
Mediate humoral immunity
The only cells capable of producing antibodies.
Have antigen specific receptors (cell-surface antibody).
The B cell binds the same antigen as the antibodies it produces.
Effector cells (antibody-secreting cells) are plasma cells
what are t lymphocytes or t cells
-Responsible for cell-mediated immunity
-Help B cells make more and better antibodies
-Some T cells can also kill infected cells directly
T cells recognize peptide fragments of protein antigens displayed on other cells using antigen specific receptors
Primary immune response
Naïve (immunologically inexperienced) lymphocytes that are seeing antigen for the first time
Secondary immune response
-Subsequent encounters with the same antigen lead to more rapid, larger, and more effective immune responses.
-Due to memory cells generated in the primary response.
Immune Response: Antigen recognition
During recognition, naïve lymphocytes locate and recognize specific antigens
Immune Response: Activation of lymphocytes
Activation requires antigen binding to antigen receptors and other signals. During activation, clonal expansion and differentiation of lymphocytes that have encountered antigen occurs
Immune Response: Elimination of antigen
During the effector phase, effector cells and their products eliminate the microbe
Immune Response: Contraction
Most of the cells that were activated by the antigens die by apoptosis, and the dead cells are cleared
Immune Response: Memory
The cells that remain are memory lymphocytes
what are the phases of immune responses
antigen recognition
activation of lymphocytes
elimination of antigen
contraction
memory
Active immunity
induced by infection or vaccination
Passive immunity
A naïve individual receives cells or molecules from an immune individual. The immunity lasts for the lifetime of the transferred cell or molecules, but then goes away.
What are generative lymphoid organs
All blood cells develop from bone marrow stem cells
B cells mature in the bone marrow
T cells mature in the thymus
Peripheral lymphoid organs
-lymph nodes
-spleen
These organs are organized to concentrate antigen, antigen presenting cells (APCs) and lymphocytes in a way that optimizes interactions among these cells and the development of adaptive immunity
The _____ is abdominal and traps blood borne antigens that are trapped and presented to T cells. The _______ also contains many phagocytes that can destroy blood borne microbes.
spleen
spleen
_______ and _________ lymphoid systems (tonsils and Peyers patches) are sites of immune responses to pathogens that breach the epithelia of the skin, gastrointestinal tract and respiratory tract.
Cutaneous and mucosal
Leukocytes (agranular)
You can’t distinguish naïve B cells and T cells by just looking at them. Monocytes are rare in blood.
Lymphocytes are commonly in the blood and lymphoid organs and constantly move throughout the body.
Granulocytes
eosinophil
basophil
neutrophil (common in blood)
what are lymphocytes
Lymphocytes are the only cells with specific receptors for antigens and thus mediate adaptive immunity.
Lymphocytes are heterogeneous in lineage, function and phenotype.
Natural killer cells
Natural Killer (NK) cells are large granular lymphocytes that can recognize infected targets by methods other than antigen specific receptors and can kill the target by release of granules. They are part of the innate system.
Antigen-Presenting Cells (APC)
Found in the skin, GI tract and respiratory tract. Waiting to encounter pathogens.
Capture and present antigens to T (and B) lymphocytes, which then are activated, proliferate and differentiate into effector cells and memory cells.
APC reside in or circulate between peripheral lymphoid organs. Monocyte → Macrophage
what cells are found in lymphocytes
Adaptive: B cell, T cells,
Innate: natural killer cells
what cells are found in APC
Dendritic cells, Macrophages (innate)
B cells (adaptive)
What cells produce an innate response to pathogens
Neutrophils, eosinophils, basophils
Movement of cells during an immune response
-Bacteria are picked up by macrophages and dendritic cells (DCs) at the site of infection.
-Carried through the lymph to the nearest lymph node.
-B cells and T cells travel from the blood through the lymph nodes and stop if they recognize a bacterial antigen.
-The responding cells make antibodies and activated cells that can move back to the site of infection.
What are the components of innate immunity
epithelial cells
cells in the circulation and tissues
-phagocytes, NK cells
Plasma proteins
Microbes can enter the body through the skin, GI tract and respiratory tract, all areas that are protected by continuous ________ that provides a physical barrier.
epithelia
__________ are blood cells that are recruited to sites of infection, where they recognize and ingest microbes for intracellular killing. Neutrophils, macrophages, and dendritic cells
phagocytes
what are the three functions of epithelial barriers
physical barrier to infection
killing of microbes by locally produced antibiotics
killing of microbes and infected cells by intraepithelial lymphocytes
What are neutrophils
The most abundant leukocyte in the blood.
The first cell type to move to respond to most infections.
They ingest microbes in circulation and tissue and have a short life span (hours).
They rapidly kill phagocytosed microbes.
cells found in pus are mostly _______
neutrophils
neutrophils release _____ that contain chromatin, lysozyme, antibacterial peptides, bacteria-sensing proteins
NETS
What are monocytes
They ingest microbes in the blood and tissue.
Monocytes differentiate into cells called macrophages in tissues
They are long lived and found in connective tissue
What are dendritic cells
low abundance in tissues and do not circulate
ingest microbes and being them to lymph nodes
they preserve antigens that can be recognized by the adaptive immune system
most important APC to initiate adaptive immune response
How do innate immune cells recognize microbes?
-Innate immune cells recognize structures that are shared by various classes of microbes and are not present on host cells.
-The shared structures are called molecular patterns and the receptors expressed by innate immune cells are called pattern recognition receptors.
What are the 2 innate system receptors
mannose receptor - mannose on carbs
N-formyl met receptor - N terminus on A.A.
Ligand binding to the ____ activates gene expression in the cell to produce acute inflammation, stimulation of adaptive immunity, and antiviral state
TLR
How do TLRs shape the innate response
-differ innate cells express different levels of TLRs
-expression varies with the activation state of the innate cell or its location in tissues
What do TLR 7 and 8 do
bind single stranded RNA
virus particles taken up into endosomes or phagosomes by macrophages release ssRNA
stimulate type 1 interferon production
NOD-like receptors (NLRs)
-recognize many PAMPS and DAMPS
-even from self damage if damage
-activate the inflammasome
-produce cytokine interleukin 1beta resulting in inflammation
innate system receptors
germline encoded
binding activates cell response
no adaption
What are the 2 main responses of phagocytes to recognition of microbes
activation of gene expression
production of cytokines and chemokines
what are cytokines
small proteins produced by many cell types that mediate immune reactions
act on same cell or other cells
main communication btw cells of immune system
what are the hormones of the immune system
cytokines
What are the major cytokines of macrophages
TNF
IL-1
Activation of endothelial cells, neutrophils (TNF) does what
Movement, extravasation, and phagocytosis
Initiates inflammation
Fever, acute phase response of cytokines does what
“endogenous pyrogen” causes fever
Liver produces proteins that enhance microbe removal such as C-reactive protein and mannose binding protein
Catabolism of muscle (cachexia, TNF) does what
TNF originally called cachectin because it caused muscle wasting
IL-12 increases _____ from NK cells and T cells which further activate macrophages
IFN-gamma
IL-15 causes ___ cell proliferation
NK
What are type 1 interferons
made by lymphocytes and others
Anti-viral, prevent viral replication
Increase antigen presentation to T cells
Activate NK cells to kill infected cells
What are interferon-gamma
made by NK cells and T cells, but also others
Anti-viral, prevents viral replication
Increases antigen presentation to T cells
Activates NK cells to kill infected cells
What are chemokines
A family of molecules that induce directed movement in cells with the corresponding receptors
What are IL-8
A chemokine that recruits neutrophils and other cells to sites of infection
Activates phagocytosis by neutrophils
what is chemotaxis
movement toward chemokines
What is acute inflammatory response
macrophage - eliminate microbes, dead tissue
plasma proteins - mediate inflammation and eliminate microbes
How do leukocytes (white blood cells) get to the site of inflammation?
use adhesion molecules (integrins) to identify where to move
what is phagocytosis
lysosomal proteases (phagosome form, fuse with lysosome)
Phagocyte oxidase creates ROS
Inducible NO synthase
what chemokines stimulate the movement of leukocyte migration
TNF and IL-1, then selectins bind, bonds break causing rolling of cells
Some damage from an infection can be due to an overabundant innate immune system response. How is this
too many TNF, IL-1
septic shock (or atherosclerosis)
inflammatory disease
what is frustrated phagocytosis
Neutrophils or macrophages try to endocytose something that is too large
ROS are released to the surrounding tissue
Activated macrophages can help what
Wound repair
Anti-inflammatory cytokines can reduce inflammation
Activated macrophages can hurt if too much
Inflammation, recruitment of other cells
Reactive oxygen species
Antigen presentation to self reactive T cells
what is the complement system
a collection of circulating and membrane-associated proteins that are important in defense against microbes.
what 3 pathways can activate a protease cascade
alternative pathway
classical pathway
lectin pathway
What is alternative pathway
is triggered when complement proteins are activated on microbial surfaces and cannot be controlled because regulatory proteins are not present.
What is classical pathway
triggered after antibodies bind to microbes or other antigens (part of the adaptive response)
What is lectin pathway
activated when a plasma protein binds to terminal mannose residues on the surface of microbes
C3 and C4 contain reactive thioesters that become accessible in C3__ and C4__. These can react with microbial proteins or sugars. If not, they are quickly hydrolyzed and inactivated.
b
b
in late steps of complement activation, the The cell-bound complement components activate the formation of the?
membrane attack complex (MAC)
Complement components (____) coat microbes (opsonization) and promote binding of microbes to phagocytes which have receptors for _____. Aids phagocytosis. Most important function
C3b
C3b
what is opsonization
a process that helps your immune system identify and destroy old cells or germs (pathogens)
The _____ induces osmotic lysis of cells. Only good for microbes that have thin cell walls (Gram-negative bacteria). Also can kill other cells.
MAC
Peptide fragments ____ and ____ are chemotactic for neutrophils, stimulate release of inflammatory mediators, and enhance movement of leukocytes into tissues.
C3a
C5a
What are the functions of complement
promotes inflammation
forms pores leading to death of the microbe
C3 is converted to C3a and C3b which starts the complement cascade (causing amplification)
Complement Inhibitors
Decay accelerating factor (CD55) inhibits C3 convertase
CD59 blocks MAC formation
Several others block proteolytic steps or cleave C3b to prevent opsonization
Pneumococci mechanism of immune evasion
resistance to phagocytosis
Staphylococci mechanism of immune evasion
resistance to ROS
Neisseria meningitidis and streptococci mechanism of immune evasion
resistance to complement activation (alternative pathway)
Pseudomonas mechanism of immunr evasion
resistance to antimictbial peptide antibodies
Interferon __ and ___ (Type __) create an anti-viral state in cells that bind the cytokine. This prevents viral replication and transmission.
alpha
beta
type 1
Type ___ interferon is made by dendritic cells, macrophages, and others, as well as by virus-infected cells.
type 1 (this leads to inhibition of viral replication by inhibition of protein synthesis, degradation of viral RNA, inhibition of viral gene expression and virion assembly)
________________ cells also kill virus infected cells by recognizing indicators of an unhealthy cell. They release granules that form pores in the cell and initiate apoptosis (induced cell death) in the infected cell.
Natural Killer cells
______ activates natural killer cells to release interferon gamma (IFN-γ). This further activates the macrophages and makes them more efficient killers of phagocytosed microbes.
IL-12
What is adjuvant
A substance that enhances adaptive immunity
-Trigger the innate response to simulate the infected environment
-Can be ligands for pattern recognition receptors like TLR’s
What does antigen presentation have to do with T cells
Needed for good adaptive responses
T cells cannot recognize soluble antigens like B cells can
Antigens must be “presented” to T cells on specialized proteins on other cells, called ‘antigen presenting cells’
Innate immune system
What are the 2 major types of T cells
CD4+ T cells usually become helper T cells.
CD8+ T cells usually become cytotoxic (or cytolytic) T lymphocytes (CTL’s).
T cells need antigen presenting cells (APC) to recognize ______
antigens
Antigen is recognized together with a protein encoded in the “_______ ________ _______” or ____. What does this do?
“major histocompatibility complex” or MHC
it controls which cells can stimulate an immune response by T cells (must have MHC)
Polymorhic cell-surface molecules on MHC molecules are important for transplantation. What on the genes help with this
Alleles for each gene gives individuals different expression
HLA-A and HLA-DR on the HLA MHC complex gives the allele what
transportation of the gene
Class ___ can make hybrid molecules because each protein has two chains from two genes
II
(class 2 = 2 genes, class 1 = 1 gene)
For MHC restriction T cells sees both antigen and MHC together, what two things are needed for the binding of the molecule
T cells and Antigen Presenting Cells
(if one is off then the whole thing will not bind)
How are MHC and antigen recognized by the T cell receptor?
Requires correct protein antigen
Requires the same MHC molecule that was originally recognized by the T cell
Structure of Class I MHC
Class I on almost all nucleated cells of the body
Polymorphic part is α1 and α2
CD8 binds a site in α3
CD8+ cells recognize peptide + MHC class I
(disulfide bond, Ig domain)
Structure of Class II MHC
Class II on “professional” APC, dendritic cells, macrophages, B cells
Polymorphic part is α1 and β1
CD4 binds a site in β2
CD4+ cells recognize peptide + MHC class II
Binding of Peptides to MHC
Peptide-binding clefts display peptides to T cells
Each MHC binds one peptide at a time
Each MHC could bind many different peptides
Class I 8-11 aa long
Class II 10-30 aa long
Peptide Binding by MHC
low affinity, broad specificity
slow off rate (time to encounter T cell)
needs peptide
Peptides are acquired during intracellular assembly of new MHC proteins. Class 1 cells are recognized by _______ and class 2 cells are recognized by _______
1 = CD8+ T cells
2 = CD4+ T cells
How do T cell receptors bund to MHC
T cell contact residue of peptide
Polymorphic residue of MHC
Anchor residue of peptide
Pocket of MHC
(specific places btw T cell receptor and MHC where peptide can bind)
Adaptive immune responses are initiated when the antigen receptors of lymphocytes recognize antigens. How does this work for B cells and T cells
The antigen receptors of B lymphocytes can recognize a wide variety of macromolecules, in solution or on cells
T lymphocytes can only recognize peptide fragments of protein antigens, and only when the peptides are presented by MHC molecules
Antigen processing is the mechanism of converting naturally occurring proteins into _______ able to bind to MHC molecules
peptides
What are the 2 antigen presenting cells in the tissues
dendritic cells
macrophages
Protein antigens of microbes that enter the body are captured by ________ ________ ______.
antigen presenting cells
(the microbes can enter through skin, GI, respiratory)
Activated dendritic cells move to the peripheral lymphoid organs (lymph nodes and spleen) where ______ responses are initiated.
immune
(usually adaptive because of the lymph nodes and spleen, so it takes longer for the system to ativate)
Dendritic cells mature into antigen presenting cells (APC) with stable ____ expression and costimulatory molecules for full T cell responses.
MHC
Different types of “professional” APC serve distinct functions in T cell-dependent immune responses.
(APC for CD4+ T cells, Class 2). What are the 3 functions
-Dendritic cells are the most potent APC for activating naïve T cells.
-Macrophages display antigens to effector T cells, which secrete cytokines to active macrophages for intracellular killing
-B cells ingest protein antigens and display them to antigen specific T cells for development of humoral responses
Extracellular proteins are internalized, processed, and presented by class __ MHC molecules for presentation to CD__+ T cells
Class 2
CD4+
Intracellular proteins in the cytosol of nucleated cells are processed and displayed by class ___ MHC molecules to CD__+ T cells.
class 1
CD8+
In class 2 MHC pathway which cells express MHC
dendritic cells, mononuclear phagocytes, B lymphocytes, endothelial cells, thymic epithelium
In class 1 MHC pathway which cells express MHC
all nucleated cells
Where does the source of protein antigens come from in class 2 MHC pathway
endosomal/lysosomal proteins (external)
Where does the source of proteins antigens come from in class 1 MHC pathways
cytosolic proteins (inside cell)
B lymphocytes also internalize extracellular proteins that specifically bind to the B cell antigen receptor (BCR), surface antibody. Once internalized they are broken down and microbial peptides enter the class ___ pathway for presentation to antigen-specific CD__+ T cells.
class 2 CD4+ T cells
(also express cytosolic peptides on class 1 CD8+ cells)
What is the physiologic significance of MHC associated antigen presentation
that T cells will see and respond only to cell-associated antigens
T lymphocytes recognize antigens of phagocytosed or intracellular microbes
Class II Presentation Activates ______ __ Cells
helper T
(Helper T cells help B lymphocytes produce antibodies, which can bind extracellular microbes. Helper T cells aid phagocytes to destroy internalized microbes.)
Class I Presentation Activates _______ __ Cells
cytotoxic T
(They are then recognized by CD8 T lymphocytes, which can kill infected cells and eradicate the infection)
Secreted antibodies enter the circulation and muscosal fluids and can bind to the antigens, leading to their ___________
elimination
Follicular dendritic cells (FDC) display antigens to activated B cells in the B cell areas of the _______ and ________
lymph nodes
spleen
T helper cells, cytotoxic T cells, and B cells all recognize different parts of the virus. Why is this important for virus mutations?
If the virus mutates so that one epitope is lost, other epitopes remain to help protect the host (all epitopes have different areas of the core that they encode for in the AA sequence leading to many mutations of the virus is needed to infect the whole cell)
What is MHC
set of genes that encode a specific protein (part of the DNA)
MHC binds to proteins and antigens on pathogens, display them on cell surface for recognition by appropriate immune cells
With the help of their recognition, can help identify intruder and develop immune response
Issues with MCH can lead to _________ disorders in transplants
autoimmune
HLA is the human MHC. What class 1 HLAs are there?
HLA-A
HLA-B
HLA-C
(found on almost all nucleated cells in body)
What class 2 HLA are there and where are they found?
HLA-DP
HLA-DQ
HLA-DR
(b-cells, APC, activated T-cells
What are the different HLA testing methods
serological (blood test)
DNA-based (blood, buccal swabs, biopsy, tissue)
Why is HLA testing important
performed to assess compatibility of recipients and potential donors
What are the 3 causes of HLA antibody production
blood or platelet transfusions
prior transplant
pregnancy
ABO antigens not only on RBCs but also on the epithelial and endothelial cells lining the blood vessels. Mismatch leads to ________ rejection
hyperacute
Does Rh positive or Rh negative have antigens of RBC
Rh positive
What is the special case where there can be antibodies in Rh negative blood
pregnancy
What is Panel of reactive antibodies (PRA)
Estimate of the percentage of the donor population that a specific organ recipient might be incompatible with due to preformed human leukocyte antigen (HLA) antibodies
(The greater the PRA the greater the risk of immune injury)
What are the 3 types of graft rejections
hyperacute
acute
chronic
what is hyperacute graft rejection
rejection immediate
caused by blood type mismatch
Occlusion leads to ischemia & necrosis of graft
(The reaction is irreversible…therefore MUST be prevented cannot be treated)
what is acute graph rejection
Delayed: days, weeks, months, years
Occurs most frequently within 3 months, but can occur any time
(mismatches of some MHC class I and/or II)
Preventable – by perfect HLA match or immunosuppression therapy
Direct Allorecognition
Donor APCs migrate out of graft to lymph nodes
(Recognition/presentation of non-self MHC (I & II) on graft/donor dendritic and tissue cells (allorecognition) to T cells)
In direct allorecognition what happens to CD8 cells
they migrate to the organ and directly kill the cells of the transplanted organ- activated by MHC I mismatch
In direct allorecognition what happens to CD4 cells
they migrate to the organ and release cytokines causing inflammation- activated by MHC II mismatch
What is indirect allorecognition
Recipient APCs enter the transplanted organ and process proteins/antigens which differ from the host
(proteins bound to MHC 2 for presentation, no direct MHC 1 activation)
The Fab (fragment antigen binding) is involved in antigen ___________
recognition
The Fc (fragment crystalline) is involved in _________ functions
effector (complement and Fc receptor binding)
Each variable region of the heavy chain and each variable region of the light chain contains _______ hypervariable regions.
three (different AA for the different binding sites) called CDR (complementarity-determining regions)
The __ hypervariable regions from the Light chain and the __ hypervariable regions from the Heavy chain come together to form the pocket that binds antigen.
3, 3
What is specificity
Ability of an individual antibody combining site to react with only one epitope or the ability of a population of antibody molecules to react with only one antigen. One Ab-one Ag.
What is cross reactivity
Ability of an individual antibody combining site to react with more than one epitope or the ability of a population of antibody molecules to react with more than one antigen.
There are five isotypes of heavy chains, called μ, δ, γ, ε, and α, that differ in their __ regions.
C
(Type of H chain determines isotype or class,
Different properties and effector functions, B cell can change its isotype without changing its antigen specificity)
There are two types of light chains, called κ and λ, that differ in their __ regions but do not differ in function.
C
Each type of light chain may complex with any type of heavy chain in an antibody molecule.
Only one type of H and L in one _______
antibody
What is IgM
H chain is μ chain
-Membrane bound monomer is B cell receptor, usually low affinity
Usually low affinity, high avidity
Complement activation
Dominates primary response
What is IgG
H chain is γ chain
Secreted as a monomer, usually higher affinity, secondary response
Complement activation, regulates B cells
Most abundant serum immunoglobulin
What is IgD
H chain is δ chain
No secreted form, only transmembrane monomeric form
Ag receptor on B cells
No other known function
What is IgA
H chain is α chain
Secreted as monomer, dimer, or trimer
Main antibody in mucosal immunity, neonatal immunity
What is IgE
H chain is ε chain
Secreted as monomer
Allergic response, Fc region binds to IgE receptor on mast cells
Little circulating IgE
How is diversity generated in antibodies
Antibody genes are made up of gene segments; pick one from each type
Antibody DNA in a B cell is different from that in other cells of the body
-DNA rearrangement
Human heavy chain gene locus is also called a _________ arrangement
germline
What is Ig gene recombination
First one D and one J are joined by V(D)J recombinase
Then one V joined to DJ to make VH domain
Joining region makes the hypervariable CDR3
Recombination only happens in B cells as they develop
Lack of recombinase leads to severe combined immunodeficiency (SCID)
Generation of Ab diversity. Antibody heavy chain gene had many gene segments
Different segments on the same chromosome
one segment of each type is randomly chosen to be expressed
After rearrangement, genes in different B cells are different from each other and from all other cells of the body
What is combinatorial diversity
-One million different V-D-J segment combinations possible to make H chains
-Recombinase enzymes RAG-1 and RAG-2 only in immature B and T cells
What is junctional diversity
-Ragged ends and random nucleotide additions make new sequences that were not present in germline
-different H chain sequences (100 billion)
H and L Combinations
L chains also have gene fragments (kappa and lambda)
One heavy chain can be combined with different light chains to make different binding sites in different cells
Only one H and one L type of antigen binding site per B cell
Surface specificity equals secreted antibody specificity
The cell has surface IgM and IgD and then secretes IgM using the same rearranged gene
Same binding site VDJ segment
Only one antibody binding type per cell but tail can change
Surface IgM and IgD and secreted IgM are made by ____ _______
RNA splicing
Isotype Production/DNA level class switching
-To change isotype, a different C region is moved closer to the VDJ segment
-DNA between is deleted, cell can’t go back to making lost isotypes
-Light chain doesn’t change
-Needs T cell help
The development and maturation of lymphocytes from bone marrow stem cells consists of three processes giving us the lymphocytes that we have. What are those 3 processes
proliferation of immature cells
expression of antigen receptor genes (randomly)
selection of lymphocytes that express antigen receptors with useful specificities
Where do B cells mature
bone marrow and fetal liver
Maturation of B Cells
The B cell first produces a µ heavy chain and then one κ or λ light chain. The immature B cell expresses this IgM.
Strong recognition of self proteins leads to death or to making a different light chain.
If self-reactive B cells escape the bone marrow, this can lead to autoimmune disease.
T cells only recognize processed peptides presented by ____ molecules
MHC (they do not recognize soluble antigens)
Antigen recognition is more tightly regulated on which cells B or T cells and what are these receptors called
T cells, TCR
Each clone of ___ lymphocytes with a particular specificity has a unique receptor, different from the receptors of all other clones
T
TCR are antigen specific but have different properties from _______
antibodies
What are the chains of the TCR called
alpha and beta (CD3 molecule associates and sends signal to cell interior)
TCR genes are __________ meaning they have no change during development
germline
In immunoglobulin what are the antigens that bind
3 CDRs in Vh and 3 CDRs in Vl
In immunoglobulin what changes in constant regions
heavy chain class switching and change from membrane to secretory Ig
In immunoglobulin what is the affinity of antigen binding
really high affinity and increases more during an immune responce
In immunoglobulin what is the on rate and off rate
rapid on rate
variable off rate
In TCRs what are the antigens that bind
3 CRDRs in Valpha and 3 CDRs in Vbeta
In TCRs what changes in constant regions
nothing
In TCRs what is the affinity of antigen binding
not as high as Ig and does not change during immune response
In TCRs what is the on rate and off rate
slow on rate
slow off rate
What happens during T cell development
T cells precursors leave bone marrow and go to thymus
1 TCR beta chain made, randomly expressed (recognize anything)
TCR expressed in thymus
All alpha beta T cells see ____ plus __________, and what low to intermediate affinity
MHC, peptide
T cells in the thymus that bind MHC survive is called what
positive selection
self reactive cells with high affinity are removed is called what
negative selection
In the thymus, T cells have a rapid turnover of ________, many lost during selection, only a few percent emerge as mature cells
thymocytes (if you are not properly educated, you will be negatively selected)
What is beta 2 microglobulin knockout mice
No class 1 MHC, no positive selection
No CD8+ T cells
Normal CD4+ T cells
What is class 2 beta chain knockout mice
No class 2 MHC, no positive selection
No CD4+ T cells
Normal CD8+ T cell
Why do people make different immune responses
B cell receptors and T cell receptors made randomly
Different MHC molecules present different peptides
T cells with different TCRs are selected to survive
Regulation and environmental factors are different ro
Antibodies are used in the immune system to identify and neutralize ________ _________. They specifically recognize unique _________ they were made against
foreign antigens
antigens
What are polyclonal antibodies
mixture of antibodies (heterogeneous) derived from distinctly different precursor cells
produced by multiple clones of B cells and bind to variety of epitopes
What are monoclonal antibodies
homogeneous single antibody type produced by one type of immune cell (B cell)
all identical clones of a single parent cell
What is hyperimmune Ig
derived from individuals or animals who have developed a high titer of antibodies against certain disease-related antigens following recovery of infection
What is hybridoma
a single immoralized B lymphocyte clone that secretes antibodies with the desired characteristics
monoclonal or polyclonal:
inexpensive, low skills, quick to produce, non-specific antibody, recognize multiple epitopes, variability
polyclonal
monoclonal or polyclonal:
expensive, highly trained, take time to produce, specific antibodies, recognize single epitope, low to no variability, once made renewable constant source
monoclonal
during nomenclature of antibodies what does “-o,” “-u,” “-xi,” and “-zu” mean
o: mouse
u: human
xi: chimeric
zu: humanized
Major problems associated with murine antibodies include
Reduced stimulation of cytotoxicity
mild allergic reactions and sometimes anaphylactic shock
Chimeric Mabs MOA
-murine molecules made to remove immunogenic content and increase immunlogic efficiency
-antibodies have CDR fused into human constant regions
-human sequence from kappa light chain and IgG1 heavy chain
What are the adverse effects of chimeric mabs
highest risk of type I reactions (anaphylaxis)
type III hypersensitivity reactions (vasculitis, serum-sickness, pneumonitis)
Tuberculosis
Upper respiratory tract infections
Drug-induced lupus
Sudden death (tumor-lysis syndrome)
Humanized Mabs MOA
-produced by grafting murine hypervariable amino acid domains into human antibodies
-human antibodies have weaker binding to antigen than murine monoclonal which decreases in affinity
What are some common Humanized Mabs- ADRS
Headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea, and rash
What are some serious Humanized Mabs- ADRS
Progressive Multifocal Leukoencephalopathy (PML): brain infection with high mortality rate, significant morbidity if survive
Anaphylaxis
Heart attack
Stroke
Human Mabs (Recombinant) MOA
produced by transgenic mice
antibodies produced by transferring human Ig genes into murine genome, after mouse vaccinates against the Ig, leading to production of monoclonal antibodies
Human Mabs- ADRS
Tuberculosis
Invasive fungal infections
Other serious infections
Rank the potential for immunogenicity for chimer, humanized, murine, and fully human MABs
High Low
murine, chimeric, humanized, fully human
Antibody Fragments
Smaller fragments penetrate tissue faster
cleared faster
less hepatic binding
synthetically (Fab-Ag binding fragment)
DNA inserted into plasmid or phage and introduced into bacteria which makes the fragment
What are biosimilar products
-no clinical meaningful differences from the reference product
-minor difference in inactive components
-a biosimilar can be approved for fewer than all the indications and conditions of use approved for the reference product
-denoted with 4 random letters after the name
What is cell-mediated immunity
mediated by T lymphocytes
Hypersensitivity reactions, anti-tumor responses, and graft rejection reactions. Against intracellular pathogens or ingested pathogens.
What is the T cell response induction phase
primary response by naive T cells becoming primed cells
What is the T cell response effector phase
T cells perform their functions
How does the T cell go from the induction phase to the effector phase
antigen recognition
differentiation cells enter circulation
T cells and leukocytes migrate to site of infection
effector T cells encounter antigens
activation of effecter T cells
Leukocyte activation and killing of microbes
Signaling of TCR Antigen Recognition is by ___
CD3
Adhesion molecules on T cells recognize their ligands on the ____ or target cell
APC
Integrin affinity is increased by what
chemokines form the innate response and by T cells receptor signaling
Costimulators are accessory, invariant molecules that provide the ________ signal for activation of naïve T cells
second (second signal NEEDED for the first time activation but not after that so effector and memory cells do not need it)
Co-stimulators are recognized by _____ on T cells
CD28
Activation of CD8+ T cells
dendritic cell or tissue cell infected with microbe
CD8+ and CD4+ T cells recognize antigen presented by APC
clonal expansion and differentiation of CD8+ T cells
How are cytokines and Cytokine Receptors produced
antigen and co-stimulators cause T cells (CD4+ helper T cells) to transiently produce them
What kind of cells do cytokines act on and what does the effect depend on
same cell or nearby cells
depends on the type of cell responding to the cytokine
What is interleukin 2 (IL-2)
first cytokine produced by CD4+ cells after activation
major cytokine needed for T cell proliferation and regulation
Can be used by NK cells and B cells for survival
What is the T cell response to IL-2
T cell activation
Secretion of IL-2
expression of IL-2 with alpha for high affinity
T cell proliferation
How do selectins cause the movement of T cells to lymph nodes
naive T cells have L-selectin that targets them to high endothelial venule (HEV) in lymph nodes
effector cells gain ligands for E and P selectin, expressed on endothelial cells that have responded to cytokines to enter tissues causing accumulation and inflammation
What do helper T cells produce
IL-2 and other cytokines
T cells express CD40 ligand which does what
TH cell upregulates costimulatory molecule
CD40 on macrophages and B cells
What does CD4+ T cells secrete
IL-2, IL-4, IL-5, IFgamma, TNF, TGFbeta
What do TH1 cells produce
IFN gamma
IL-2
TNF
What are the three important effects of TH1 cells effector phase
macrophage activation
inflammation
help for B cells and T cells
What do TH2 cells produce
IL-4, IL-5, IL-13, IL-10
What happens during the effector phase of TH2
production of antibody (IgE)
activation and differentiation of eosinophils
inhibit macrophage activation
What happens during subset differentiation
macrophages and dendritic cells produce IL-12 favors TH1
IL-4 favors TH2
Balance favors appropriate type of immune response
What do cytotoxic T cells (CTLs) do during the effector phase of CD8+ cells
activation of caspases in the target causes apoptosis
CTL recycles to a new target cell after killing the first target cell
CD4+ cells provide _____ to CD8+ cells and make IFN-γ to activate macrophages.
IL-2
Microbes that evade killing in phagolysosomes by entering the cytoplasm are recognized and killed by ______ CTL.
CD8+
Lack of ____ can lead to death in the decline of the immune response
IL-2
Expression of inhibitory ___________ on the T cells leads to regulation of the antigen response and loss of T cells
costimulators
Inhibitory Costimulators Provide Immune Checkpoints what are they
CTLA-4 expressed on T cells
PD-1 expressed on exhausted T cells
