Antibodies act by a number of mechanisms, most of which engage other arms of the immune system. Antibodies can simply block interactions of molecules or they can activate the classical complement pathway (known as complement dependent cytotoxicity or CDC) by interaction of C1q on the C1 complex with clustered antibodies. Critically antibodies also act as a link between the antibody-mediated and cell-mediated immune responses through engagement of Fc receptors.
- Figure. Antibody modes of action.
Antibodies have several modes of action: i) they can block ligand-receptor interactions; ii) cause cell lysis through activation of complement dependant cytotoxicity (CDC); iii) interact with Fc receptors on effector cells to engage antibody dependent cellular cytotoxicity; iv) signal for ingestion of a pathogen by a phagocyte.
Fc receptors (FcRs) are key immune regulatory receptors connecting the antibody mediated (humoral) immune response to cellular effector functions. Receptors for all classes of immunoglobulins have been identified, including FcγR (IgG), FcεRI (IgE), FcαRI (IgA), FcμR (IgM) and FcδR (IgD). There are three classes of receptors for human IgG found on leukocytes: CD64 (FcγRI), CD32 (FcγRIIa, FcγRIIb and FcγRIIc) and CD16 (FcγRIIIa and FcγRIIIb). FcγRI is classed as a high affinity receptor (nanomolar range KD) while FcγRII and FcγRIII are low to intermediate affinity (micromolar range KD) (1).
In antibody dependent cellular cytotoxicity (ADCC), FcvRs on the surface of effector cells (natural killer cells, macrophages, monocytes and eosinophils) bind to the Fc region of an IgG which itself is bound to a target cell. Upon binding a signalling pathway is triggered which results in the secretion of various substances, such as lytic enzymes, perforin, granzymes and tumour necrosis factor, which mediate in the destruction of the target cell. The level of ADCC effector function various for human IgG subtypes. Although this is dependent on the allotype and specific FcvR in simple terms ADCC effector function is high for human IgG1 and IgG3, and low for IgG2 and IgG4. As shown in the model below FcγRs bind to IgG asymmetrically across the hinge and upper CH2 region. Knowledge of the binding site has resulted in engineering efforts to modulate IgG effector functions – see Fc engineering section for more detail.
- Figure. Human IgG1-FcγRIII complex.
A model of human IgG1 in complex with Fcγ receptor III, which binds asymmetrically across the hinge and upper CH2 region of the antibody. The left hand image shows a ribbon representation and the right hand side a space-filled model. The antibody heavy and light chains are shown in blue and green respectively, glycosylation in orange and FcγRIII in red. Model produced from PDB accession numbers 1IGY and 1E4K.
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<< Antibody overview
Powell, M.S., and Hogarth, P.M. (2008). Fc Receptors. In Multichain Immune Recognition Receptor Signaling, A.B. Sigalov, ed. (Springer New York), pp. 22–34.
The antibody response and the complement system are major effector arms of the immune system. Both have been involved in a plethora of pathological conditions – including autoimmunity, allergy, infections and cancer- and regulate, mainly through their receptors (FcR and CR respectively) cell activation, migration, survival but also metabolism. As the portfolio of antibody- and complement-effector function grow, high-end technological solutions are developed and novel therapeutic applications are proposed.
This Zing conference will focus attention on key advances in both fields with the aim at fostering discussions between antibody experts and complement experts. Some of the critical topics to be covered include
Antibody & complement functions
FcR and CR
Ab glycosylation and anti-inflammatory activity
Structure – function linkage
Complement and antibody therapies
This Antibody & Complement meeting will be a forum for leaders in the field and new investigators coming from academia, industry and research institutes to discuss where the field is going and what challenges lie ahead.