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  • Review Article
  • Published:

Roles of Fc receptors in autoimmunity

Nature Reviews Immunology volume 2, pages 580–592 (2002)Cite this article

Key Points

  • Fc receptors for immunoglobulin G (FcγRs) link humoral and cellular immunity by binding antigen–IgG immune complexes and internalizing the complexes for efficient antigen presentation. FcγRs comprise many activating-type receptors and a unique inhibitory receptor, FcγRIIB.

  • FcγRIIB is a crucial element of peripheral tolerance. Its absence renders B cells and effector cells hyperresponsive to autoantigens.

  • In the absence of the Fc-receptor common γ-chain, a pivotal adaptor for activating signalling, mouse models do not develop spontaneous or induced autoimmune disease due to the lack of activation of effector cells, such as macrophages.

  • FcγRIIb-deficient mice have enhanced responses in some autoimmune disease models. Spontaneous onset of disease is sometimes observed in the mutant mice.

  • Enhanced antigen presentation by Fc receptors on dendritic cells can be an important step in the development of some T-cell-mediated autoimmune diseases.

  • Polymorphisms in the ectodomains of human FcγRs are risk factors for autoimmune diseases.

  • Some polymorphisms are found in the human FcγRIIB gene, but information on their relation to autoimmune diseases is still required.

  • The dynamics of the intimate collaboration between activating and inhibitory FcγRs might determine the balance between tolerance and autoimmunity.

Abstract

The receptors for the Fc of immunoglobulins, Fc receptors (FcRs), link the humoral and cellular branches of the immune system, and they have important functions in the activation and down-modulation of immune responses. Balanced signalling through activating and inhibitory FcRs regulates the activity of various cells in the immune system. Recent work in animal models indicates that the development of many human autoimmune diseases might be caused by impairment of the FcR regulatory system. This review provides an overview of the mechanisms of FcR-based immune regulation and describes how autoimmune disease might result from its dysfunction.

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Figure 1: Main functions of Fc receptors.
Figure 2: Signalling mechanisms of ITAM- and ITIM-induced regulatory FcR signalling.
Figure 3: Overall view of activating Fc receptors and inhibitory FcγRIIB, and related autoimmune diseases.

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Acknowledgements

I would like to thank T. Kurosaki for critical reading of the manuscript and helpful discussion, and N. Tsuchiya and C. Kyogoku for sharing of unpublished data. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and from the CREST Programme of Japan Science and Technology Corporation.

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Authors and Affiliations

  1. Department of Experimental Immunology and the Core Research for Evolutional Science and Technology Programme of Japan Science and Technology Corporation, Institute of Development, Ageing and Cancer, Tohoku University, Seiryo 4-1, Sendai, 980-8575, Japan

    Toshiyuki Takai

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DATABASES

InterPro

immunoglobulin-like domain

ITAM

PH domain

PTB domain

SH2

LocusLink

AKT

BCAP

BTK

C-II

C-IV

CD16

CD19

CD64

DAP12

Fas

FcαR

Fcα/μR

FcɛRI

FcγRIA

FcγRIB

FcγRIC

FcγRIIA

FcγRIIB

FcγRIIb

FcγRIIC

FcγRIIIA

FcγRIIIB

FcRγ

FcRH1

FcRH2

FcRH3

FcRH4

FcRH5

FcRn

FGR

GRB2

HCK

LYN

MOG

p62DOK

PDK1

PI3K

PIR-A

PLCγ

poly-IgR

SHC

SHIP

SHP1

SHP2

SYK

OMIM

AIHA

GBS

GPS

MS

myasthenia gravis

rheumatoid arthritis

SLE

type-1 diabetes

Glossary

CENTRAL TOLERANCE

Refers to the lack of self-responsiveness that is established as lymphoid cells develop. It is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus.

PERIPHERAL TOLERANCE

Refers to the lack of self-responsiveness of mature lymphocytes to specific antigen. It is associated with the suppression of production of self-reactive antibodies by B cells and the inhibition of self-reactive effector cells, such as cytotoxic T cells and natural killer cells.

Fc RECEPTOR COMMON γ-CHAIN

(FcRγ). A membrane signal-adaptor protein that contains an ITAM. It is shared by FcγRI, FcγRIII, FcɛRI, FcαRI and other receptors, including collagen-receptor glycoprotein IV, NKp46, ILT1/LIR7 and PIR.

SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE). A disease of unknown origin in which tissues and cells are damaged by the deposition of pathogenic antibodies and immune complexes. Generally, patients have abnormal B- and T-cell function.

ARTHUS REACTION

An erythematous and oedematous reaction discovered by Maurice Arthus when he injected hyperimmunized rabbits with the same soluble antigen intradermally. The Arthus reaction involves Fc-receptor-mediated inflammation and complement-mediated inflammation.

LEUKOCYTE-RECEPTOR COMPLEX

(LRC). The chromosomal region 19q13.4 contains the human leukocyte-receptor complex, which has been shown to contain more than 25 genes encoding leukocyte-expressed receptors of the immunoglobulin superfamily, such as killer immunoglobulin-like receptors (KIRs) and immunoglobulin-like transpcripts (ILTs)/leukocyte immunoglobulin-like receptors (LIRs).

PHAGOCYTOSIS

An endocytic process in which relatively large (≥1 μm) particles are incorporated into cells in an energy-dependent manner.

CROSS-PRESENTATION

This term refers to the ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, as most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses against viruses that do not infect antigen-presenting cells.

HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions are classified in terms of the antibody classes and effector cells that are responsible, and by the time-course of the reaction. Type I is an immediate reaction mediated by IgE and mast cells. Type II responses are directed against cell-surface or matrix antigens bound by IgG, whereas type III reactions are also IgG-mediated but directed against soluble antigens. Type IV hypersensitivity is a T-cell-mediated reaction.

AUTOIMMUNE HAEMOLYTIC ANAEMIA

Anaemia caused by autoantibodies to red-blood-cell surface antigens, which become targets for destruction by complement and by erythrophagocytosis.

NATURAL ANTIBODIES

Antibodies that can bind pathogens and self-antigens, such as ABO blood-group antigens, which are detected in the sera of normal individuals without any previous sensitization to the antigen.

IDIOPATHIC THROMBOCYTIC PURPURA

(ITP). An autoimmune type II hypersensitivity reaction that develops after the destruction of thrombocytes by the binding of autoantibodies to cell-surface antigens.

ANTI-DNA ANTIBODIES

Anti-DNA autoantibodies are found in autoimmune animal models and patients, and can be subdivided into those that are specific for double- or single-stranded DNA. They are used as a supportive marker for the diagnosis of several autoimmune diseases, such as SLE.

CRYOGLOBULINAEMIA

Refers to the presence of one or more immunoglobulins that precipitate at temperatures below 37°C.

MULTIPLE SCLEROSIS

(MS). A neurological disease that is characterized by focal demyelination in the central nervous system with lymphocytic infiltration.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An experimental model of multiple sclerosis (inflammation of the brain and spinal cord) that is induced in animals by immunization with myelin basic protein, myelin phospholipid protein or myelin oligodendrocyte glycoprotein, or their synthetic peptides.

GUILLAIN-BARRÉ SYNDROME

(GBS). A possible autoimmune disease that is characterized generally by acute muscle weakness and the absence of reflexes, possibly due to the production of autoantibodies that are specific for gangliosides on neuronal cells after Campylobacter jejuni enteritis.

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Takai, T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2, 580–592 (2002). https://doi.org/10.1038/nri856

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