Presentation

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