Post on 03-Jun-2015
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Ig Isotypes and Fc Receptors
Penny Morel
April 3, 2009
morel@pitt.edu
Ig isotypes: structural features
4:89, 2004
Role of Fc receptors Link Ig to cells of the innate immune
system - macrophages, neutrophils, mast cells, NK cells.
Provides innate immune system with high degree of specificity (Fab portion)
Separate Fc receptors for each isotype (6 for IgG)
4:89, 2004
4:89, 2004
FcR1 gamma chain is required for
expression of several FcR Mice lacking FcR1 chain do not
express FcR1, FcRI (CD64), FcRIII (CD16)
Defect in IgE-triggered anaphylaxis No ADCC by NK cells
FcRIV = FcRIIIA (h) Expressed on neutrophils, Monocytes,
macrophages, DCs Associates with FcR1 chain Induced by IFN-, downregulated by IL-
4, IL-10 and TGF- Binds IgG2a and IgG2b - not IgG1 or
IgG3
FcR isotype binding specificity
FcRIIb
FcRIII
FcRIV
IgG2a is most effective in ADCC
Science 310:1510, 2005
The Journal of Immunology, 2008, 181: 8745-8752
IgG2a also important for Ab-induced glomerular damage
Inhibition via FcR
ITIM motif: (L/V/I/S)xYxx(L/V)
CD32FcRIIB1 B, mast cells Inhibition
No uptakeFcRIIB2 Macs, eos, PMN Inhibition
uptake Two isoforms are generated by alternative splicing
Inhibits IgE mediated degranulation of mast cells
2:773, 2002
FcRIIB on B cells
FcγRIIB as a checkpoint of humoral tolerance. Autoreactive B cells (shown in red) that arise during the random rearrangement of antibody gene segments in developing B cells in the bone marrow or during the process of somatic hypermutation and affinity maturation in the spleen are controlled by several pathways, including receptor editing, clonal deletion or anergy induction. The inhibitory low-affinity Fc receptor for IgG (FcγRIIB) operates at several stages during later peripheral B-cell development. This receptor has been shown to be important for the follicular exclusion of low-affinity autoreactive B cells, for preventing B cells with a higher-affinity self-reactive receptor from becoming IgG positive plasma cells, and for triggering apoptosis of plasma cells upon immune complex binding, which is potentially important for regulating plasma-cell homeostasis during an immune response and deleting autoreactive plasma cells. BCR, B-cell receptor.
FcRIIB -/-
Spontaneously develop autoantibodies More susceptible to autoimmune
disease models - collagen induced arthritis
Enhanced antibody response to antigen
FcRIIB -/- mice developanti-DNA antibodies
Role of FcR in collagen induced
arthritis
FcR1 -/- protected FcRIIB -/- more susceptibleJ. Exp. Med. 191:1611, 2000
Role of FcRIV in KBRN arthritis model
The Journal of Immunology, 2008, 180: 5083-5091.
Activation/inhibition
Cytokines influence FcR expression
Antibody mediated inflammation Type I (immediate hypersensitivity):
requires FcR1 Type 2 (cytotoxic IgG): requires FcRIII
and FcRIV Type 3 (immune complex-induced
damage): requires FcRIII FcRIIB modulates all of these
responses
Other Fc Receptors
FcRII/CD23 Low affinity IgE receptor B cells, T cells, monocytes FDC, eos
etc May act to enhance Ab response to
antigen in presence of IgE:Ag complex Could act by capturing Ab for APC
presentation C-type lectin
FcR1 (CD89) Binds IgA1 and IgA2 Low affinity Macs, PMN and eosinophils Induces Ag uptake and pathogen killing Associates with FcR1 chain
Transport receptors Poly Ig receptor on epithelial cells for
IgA transport FcRn: MHC class I-like, contains 2m,
transports IgG to extracellular spaces, and across placenta