Ig Effector Function Flashcards
In order for B cells to respond to most antigens they require T cell help
TRUE OR FALSE
TRUE
B and T cells recognise the same antigen
TRUE OR FALSE
TRUE
T cells provide help to B cells in 2 ways:
- Co-stimulatory signal through ligation of CD40 and CD40L (CD40 ligand)
- Secretion of cytokines which aid in the induction of class/isotype switching
Class Switching:
All B cells begin by making IgM.
IgG, IgA, and IgE isotypes are generated by an irreversible change in DNA in a process known as isotype switching/class switching.
Association of VH exon with different CH genes. Occurs through mechanism of nonhomologous DNA recombination guided by stretches of repetitive DNA called switch regions.
Switch regions contain repeats of GAGCT and GGGGGT sequences
Example of Class Switching: Switching from IgM (and IgD) to IgG1 expression
- Recombination to excise previously expressed C gene
and juxtapose another one with the VH - Depends on action of enzyme named activation-induced cytidine deaminase (AID), only
found in proliferating B cells - AID targets switch regions,
causing nicks in both DNA strands - Nicks facilitate recombination
between switch regions, leading to excision of intervening DNA
Distribution of antibody classes in the body:
- IgG, IgA (monomeric) and IgM predominate in circulation – protect internal tissues of the body
- Dimeric IgA predominates in secretions and protects mucosal surfaces
- IgG and monomeric IgA are major isotypes in extracellular fluid
- Brain devoid of Igs (due to blood-brain barrier)
- IgE found mainly in connective tissue beneath skin, respiratory and GI tracts – provides a mechanism for rapid ejection of pathogens from body
Mothers provide protective antibodies to their young before birth only
TRUE OR FALSE
FALSE
Mothers provide protective antibodies to their young, both before and after birth
During pregnancy, IgG from maternal circulation is transported across the placenta.
After birth, GI tract of baby is protected by dimeric IgA in breast milk.
In first year of life infants have transient decrease in IgG levels as they slowly begin to produce their own IgG.
Neutralising antibodies:
IgG and IgA are examples of neutralising antibodies because they efficient at binding to soluble toxins and preventing them from binding to cell surface receptors (i.e. neutralising their effects).
neutralising antibodies can prevent bacterial infections and also prevent viruses from infecting host cells.
IgG:
- Most abundant Ig in plasma (10 mg/ml)
- Four subclasses - IgG1, IgG2, IgG3, IgG4 – which differ in the sequences of their heavy chain constant regions, particularly in the hinge region. The four subclasses of IgG have different and complementary functions.
- Only Ig class to cross placenta
- Predominant antibody of secondary response
- Human IgG4 antibodies undergo Fab arm exchange
IgM
- Present only in plasma and secretions - too large to enter tissues
- Made of five monomer units joined by J chain and disulphide bridges. μ chain has extra domain in place of hinge.
- Has 10 binding sites for antigen and so is very good at agglutinating particles
- Predominant antibody of primary response
Binding of IgM to antigen on a pathogen’s surface activates complement by the BLANK pathway
Binding of IgM to antigen on a pathogen’s surface activates complement by the classical pathway
Conformational change on binding to antigenic surface prevents inappropriate complement activation by free IgM
Conformational change:
“Planar” -> “Staple” conformation
Activation of classical complement pathway by IgG:
IgG Fab arms bound to antigenic surface
One C1q binds to 2 (or more) IgG molecules.
Requirement for interaction with two or more IgG molecules simultaneously prevents inappropriate complement activation by free IgG.
IgG subclasses ability to activate complement: IgG1: +++ IgG2: +/- IgG3: +++ IgG4: -
FcRn:
A human receptor for IgG Subunits: α1, α2, α3, β2 microglobulin (structurally similar to MHC class 1) Site that binds to IgG Fc region predominantly formed by α1 and α2 domains
Maintains high level of IgG in extracellular fluids
Selectively protects IgG from degradation that turns over other plasma proteins.
As a result, IgG molecules have a longer half-life than most plasma proteins (about 21 days)
FcRn is in part responsible for transport of IgG across placenta
FcRn transports IgG from bloodstream into extracellular spaces
FcRn interacts with the Fc interdomain region of IgG
FcγR:
IgG Receptors: FcγRI, FcγRII, FcγRIII
γ chain possesses signalling motif - ITAM (Immunoreceptor Tyrosine-based Activation Motif)
Human IgG subclasses have differing abilities to bind to and trigger via FcγR
FcγRI is the receptor for IgG1 and IgG3.
FcγRI binds to the lower hinge and CH2 of IgG3.
IgG3 bound to FcγRI binds antigen.
Fc receptor-mediated clearance:
Free Ig does not cross-link Fc receptors = No macrophage activation
Aggregation of Ig on bacterial surface results in cross-linking of Fc receptors = Macrophage activation (and phagocytosis)
Fc receptor ligation enhances the efficiency of phagocytosis
