Humoral Immunity Flashcards
Humoral Immunity is mediated by ______ and secreted _______
B lymphocytes; antibodies
Function of Antibody
Block the ability of microbes or their secreted toxins to bind to and infect or damage host cells
What molecules of the B Cell receptor recognize antigens
Immunoglobulin (Ig)
Epitope
That part of a native protein, lipid, or lipoprotein antigen that is recognized by B lymphocyte antigen receptors
Difference between BCR and TCR constant regions
BCR can change - alters effector functions
TCR is fixed
Affinity for antigen for BCR
BCR has higher initial affinity (Compared to TCR) which increases during response
Difference between checkpoints of T-cell and B-cell development from common lymphoid progenitor
none
Recombination events for BCR antigenic diversity
1) First recombination event is the heavy chain D and J exons
2) Second recombination of V with DJ
3) VDJ recombination of a IgH (heavy chain) constant (Cμ) region gene segment
4) The heavy chain transcript (VDJC) is then processed and expressed within the cell, and then at the cell surface with a surrogate light chain
At the Pre-BCR stage, there is a ___________ which helps ___________ the heavy chain
Surrogate light chain; stabilize
Fab Region
Region on antibody that binds to antigens
Fc region
the tail region of an antibody that interacts with cell surface receptors
The diversity region is only expressed:
In IgH chain transcript (chromosome 14)
Antigenic Diversity (2 types)
Combinatorial - variation amongst possible VDJ and VJ exon combinations
Junctional: Removal of nucelotides and addition of nucleotides by TdT enzyme
Hypervariability in IgH and IgL
CDR1, CDR2, CDR3
Differentiation of B-Cells (4 types)
1) Effector Cells: antibody-secreting plasma cells
2) IgG-expressing B cell
3) High-affinity Ig-expressing B cell
4) Memory B Cell
During the induction phase, antigens are first presented to:
Membrane bound IgM on Naive B cells
3 types of lymphocyte subsets
Follicular B cells
Marginal zone B cells
B-1 cells (mucosal tissues, peritoneal cavity)
2 signals for Naive B cell activation
1st signal: BCR binds Antigen
2nd signal: CR2/CD21 (complement receptor) activated by C3d complement protein OR TLR activated by microbial pathogen associated molecule pattern (PAMP)
ITAM
Immunoreceptor tyrosine-based ACTIVATION motif
First part of B cell Receptor activation
Two or More BCRs must be cross linked by antigen to become activated
Two types of effector B cells
T-Independent: differentiation occurs in the absence of T cell help
T-dependent: T cells provide additional helper stimuli during B cell differentiation (typically protein antigen)
Activation of Naive B cells causes:
1) Entry into cell cycle: mitosis
2) Increased expression of cytokine receptors
3) Migration out of lymphoid follicles
4) Low-level IgM secretion
Presentation of Antigen to T cell by B cell (5 Steps)
1) B cell recognition of native protein antigen
2) Receptor-mediated endocytosis of antigen
3) Antigen processing and presentation
4) T cell recogntion of antigen
5) Activation of B cells by CD40 ligand and cytokines - proliferation and migration back to germinal center
Class switching
Results in antibodies with Fc regions capable of diverse effector functions
Affinity maturation
Produces antibody with higher affinities for antigen binding (triggered by prolonged or repeated antigen stimulation)
Antibody-mediated mechanisms in host defense
- Complement activation - leads to opsonization and or microbial killing
- Phagocytosis- enhanced by antibody and/or complement components
- Neutralization
Isotype switching
The heavy chain variable region is initially found on IgM and IgD but is switched onto other heavy chain constant regions during the course of the response
Switching is controlled by:
T helper cells and varying cytokines
The same ________ remains associated with the variable region during isotype switching, thus ___________ remains the same
Light chain; Antigen specificity
J chain links
2 FCα regions of IgA
2 Fcμ regions of secreted IgM
Idiotype
Shared charactersitic between a group of Ig molecules with shared antigen binding specificity and variable region structure
Isotype
Type of antibody as defined by the constant heavy region
Heavy chain class switching (by Activation Induced Deaminase)
During class switching portions of the antibody heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype
Cytokine that assists in Isotype switching
TGF-β
Somatic hypermutation
Proliferating/differentiating B cells accumulate mutations in the genes encoding the variable regions
High Affinity selection
Maturing B cells will undergo apoptosis unless they receive a survival signal from Ag presented by follicular dendritic cells
Follicular helper T cells
Provide survival signal to maturing B cells
Mutations in variable regions (increase/decrease/stay the same) with increasing antigen exposure
Increase
Effector functions of antibody (B-cells)
- Neutralization of microbe and toxins (IgG, IgA)
- Opsonization and phagocytosis of microbes (IgG)
- Antibody-dependent cellular cytotoxicity (IgG, IgE)
- Lysis of microbes (Complement)
- Phagocytosis of microbes opsonized with complement fragments (Complement)
- Inflammation (Complement)
Opsonization
Process of coating particles for phagocytosis
Antibody neutralization
1) Prevent entry of microbe or antigen
2) Prevent microbe or antigen from binding to host cells
3) Block spread of infectious microbes
4) Block binding of microbial toxins to receptors on host cells
Fc (FcR) binding stimulates:
Phagocytosis of the antibody coated microbe
Activaiton of phagocytes to begin oxidative burst
What is the major site of phagocytosis of opsonized bacteria
Spleen
What antibody functions as an opsonin
IgG
Fc Receptor types and affinity for Ig
FcγRI: high
FcγRIIB: low
FcγRIIIA: low
FcϵRI: high
IgG dependent cellular cytotoxicity
IgG binds antigen on surface of host cells
FcγRIII on NK cells bind IgG Fc portion - stimulates perforin and granzyme mediated killing of antigen coated cell
IgE dependent cellular cytotoxicity
IgE binds epitopes on large helminth parasites
FcϵR on Eosinophils bind IgE Fc portion - stimulates degranulation and release of proteolytic enzymes to digest cell walls of parasite
Complement
A collection of circulating and cell membrane proteins that play critical roles in BOTH innate immunity and antibody-mediated tissue injury
Activation of Complement leads to:
Sequential proteolytic cleavage of complement proteins and production of effector molecules
Alternative (innate) Complement pathway - C3 is spontaneously hydrolyzed
1) C3b is stabilized by binding to microbe
2) Stable C3b substrate for Factor B → cleaved to Bb → Binds to C3b
3) C3bBb = alternative C3-convertase → cleaves C3 into C3b
4) C3bBb3b = C5 convertase
Classical complement pathway (IgG binds microbial surface antigens → C1 binds Fc region of bound Ig)
1) Active C1 cleaves C4 and C2 into C4b and C2a
2) C4b2a = classical C3-convertase → cleaves C3 into C3b
3) C4b2aC3b = C5 convertase
Lectin complement pathway (initiated by circulating mannose-binding lectin - MBL)
Same as classical complement pathway except with MBL as starting point (C1 in classical pathway)
Actions of C5 convertase (common to all pathways)
C5 binds C5-convertase and is converted to C5b
C6, C7, C8 and C9 bind to C5b sequentially → C9 binds C5b and polymerizes to form a pore in the microbe (Membrane attack complex)
Complement functions
1) Opsonization and phagocytosis (C3b → CR1)
2) Cytolysis. MAC formation
3) Inflammation: C3a, C4a, C5a fragments bind complement receptors on PMNs
Key membrane proteins that inhibit complement cascade
MCP: cofactor for Factor I to cleave C3b and C4b into inactive proteins
DAF: inhibits Bb binding to C3b
CR1: cofactor for Factor I to cleave C3b or C4b into inactive forms
Key plasma proteins that inhibit complement cascade
C1 inhibitor: inhibits C1r and C1s protease activity
Factor I: proteolytically cleaves C3b and C4b into inactive forms, thereby preventing formation of the C3 convertase
Factor H: dissociates alternative C3 convertase formation
Deficiencies in C3
Leads to increased succeptibility to infections. Can be fatal in early life
Epithelial Antibody transport: IgA
IGA levels highest in mucosal lymphoid tissues and specialized for transport across mucosal epithelium
Dimers linked together by J-chain protein
Neonatal FcRn
Expressed on epithelial cell surface and transports maternal antibodies to the neonate which acquires the others IgG profile
Live attenuated Vaccine
Micro-organism is modified to decrease pathogenicity, limited growth after injection - mainly induces Cellular response (T-cells)
Inactivated vaccine
Pathogen is inactivated (heat or chemically) but retains an immunologic epitope on surface - mainly induces Humoral Response (B-cells)
Adjuvant
A substance that when mixed with the antigen enhances immunogenicity of that antigen
Aluminum hydroxide gel (alum)
Only adjuvant used in the United States
Used in > 80% of vaccines licensed for human use
