Lecture 15 – Antibody Effector Mechanisms

Antibodies
-Abs exist to protect us from extra and intracellular bacteria and parasites, extracellular fungi, viruses, and parasitic worms

Effector Function of Abs
-neutralization
-opsonization
-complement activation
-antibody dependant cell cytotoxicity or ADCC (cell killing)
-mast cell activation

Ab Structure
-the N-terminus end of the Ab polypeptide is the variable region, which is ‘variable’ as a result of VDJ recombination
-the C-terminus end is the constant region and the effector function of the Ab is determined within this domain
-the structural variations in the constant regions determine which class of Ig that the Ab is part of
-isotypic differences are the type of constant domain that the Abs have (IgA, IgB etc.)
-allotypic differences are the variation between the constant domains of Abs in the same class (differing primary amino acid sequence, same effector function)
-idiotypic differences are the variations on the variable region of a given Ab

Properties of Different Isotypes
-IgM: major function – neutralization; minor function – complement activation
-IgM also switches to IgG, which is a T cell dependant event
-IgD:
-IgG: major function – neutralization, opsonization, ADCC, complement activation
-IgA: major function – neutralization; minor function – opsonization, complement activation
-IgA is present on mucosal surfaces
-IgE: major function – mast cells sensitization

Effector Mechanisms
Neutralization of Bacterial Toxins
-some bacteria secrete toxins which have negative effects on the human body (e.g. tetanus, anthrax)
1) Normally, bacterial toxins binds to cellular receptors
2) Endocytosis of toxin:receptor complexes then occurs
3) The toxin then dissociates to release the active chain which poisons the cell
4) Abs prevent toxins binding to the cellular receptors

Neturalization of a Virus
1) Normally, the virus binds to the cell surface
2) It is endocytosed via receptor mediated endocytosis
3) Acidification of endosome after endocytosis triggers fusion of virus with cell and entry of viral DNA into
4) Ab blocks binding to virus receptor and can also block fusion event

Neutralization of Bacteria
1) Normally, colonization of cell surface by bacteria via bacterial adhesions
2) Some bacteria are internalized and propagate in internal vesicles
3) Abs against adhesions block colonization and uptake

Complement Activation by Ab:Ag Complexes
-Abs activate complement in one of two ways:
1) With IgM, pentameric IgM molecules bind to Ags on the bacterial surface and adopt the “staple form”
2) With IgG, IgG molecules bind to Ags on the bacterial surface
-in both cases, Ig binding facilitates C1q binding which activates the complement cascade
-complement activation leads to the release of inflammatory mediators (C3a, C5a), opsonization of the pathogen for phagocytosis (C3b), or activation of the membrane attack complex and lysis of certain pathogens and cells

Clearance of Immune Complexes
-once a toxin is neutralized, it must be eliminated:
1) Ag:Ab complexes form in the circulation and activate complement
2) Molecules of C3b bind covalently to the complex
3) These C3bs then bind to the CR1 receptor on RBC surfaces
4) In the spleen and liver, phagocytic cells (macrophages, basophils etc) remove the immune complexes

Fc Receptors
-Abs are bound by various cells because of their Fc (constant) region
-Fc receptors on those cells bind these Fc regions of the Abs
-B, T, and NK cells, dendritic cells, mast cells, platelets, macrophages

Fcγ Receptors (FcγR)
-bind IgG
-uptake of bacteria
-activate macrophages
-release bactericidal/toxic granules (eosinophils, neutrophils)
-induce killing by NK cells
-some Fcγ receptors are also inhibitory

FcεR
-bind IgE
-involved in