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FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications

Nature Reviews Immunology volume 10, pages 328–343 (2010)Cite this article

Subjects

A Corrigendum to this article was published on 06 August 2010

Key Points

  • Fc receptor IIB for IgG (FcγRIIB) is the only inhibitory Fc receptor, is expressed on many cell types in the immune system and controls humoral responses, pro-inflammatory cytokine release, antigen uptake and presentation, immune complex handling and many other functions.

  • A role for FcγRIIB in controlling B cell tolerance and autoimmunity has been suggested by studies using FcγRIIB-deficient mice and confirmed by in vivo overexpression studies.

  • Spontaneous polymorphic variants alter the expression and/or function of FcγRIIB in both mice and humans, and have been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases.

  • FcγRIIB balances bacterial clearance and the risk of septic shock in mouse models.

  • Genetic studies have shown that an inhibitory, SLE-associated polymorphism of FcγRIIB can protect children from severe malaria, which could drive the high frequency of this polymorphism observed in sub-Saharan Africa and Southeast Asia, and thus begin to explain the increased susceptibility to SLE seen in people of African and Asian ethnicity.

  • The immunosuppressive effect of intravenous immunoglobulin is at least in part dependent on FcγRIIB, and the receptor itself is being investigated as a therapeutic target.

Abstract

FcγRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcγRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcγRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcγRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target.

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Figure 1: Structure, cellular distribution and IgG isotype-binding affinity of human activating and inhibitory FcγRs.
Figure 2: The functions of FcγRIIB.
Figure 3: Mouse Fcgr2b polymorphisms.
Figure 4: Human FCGR2B polymorphisms.
Figure 5: Potential mechanisms by which FcγRIIB might contribute to the pathogenesis of systemic lupus erythematosus.
Figure 6: The proven and potential roles of FcγRIIB in defence against malarial infection.

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Acknowledgements

We thank M. Espeli for review of the manuscript. K.G.C.S is supported by the NIHR Cambridge Biomedical Research Centre and the Wellcome Trust (programme grant number 083650/Z/07/Z) and is a Lister prize fellow. M.R.C. is supported by a Wellcome Trust Intermediate Fellowship (WT081020).

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  1. Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0XY, UK

    Kenneth G. C. Smith & Menna R. Clatworthy

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DATABASES

OMIM

anti-GBM

chronic inflammatory demyelinating polyneuropathy

ITP

multiple sclerosis

rheumatoid arthritis

SLE

type 1 diabetes

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Glossary

Immune complexes

Complexes of antigen bound to antibody and, sometimes, components of the complement system. The number of circulating immune complexes is increased in some autoimmune disorders (particularly SLE) in which they may be deposited in tissues causing inflammation and tissue damage.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism by which FcR-expressing cells kill other cells, such as virus-infected target cells, that are coated with antibodies. The Fc portions of the coating antibodies interact with the FcγR, thereby initiating a signalling cascade that results in the induction of apoptosis of the antibody-coated cell.

Acute-phase proteins

A group of proteins, the plasma concentration of which changes in response to trauma, inflammation and infection. C-reative protein is the prototypical acute-phase protein and binds phosphocholine on pathogens and apoptotic cells, opsonizing them for disposal by phagocytes by FcγR binding.

FcR common γ-chain

A membrane-associated signal adaptor protein that contains an ITAM. It is shared by FcγRI and FcγRIIIA, as well as other receptors, including collagen receptor glycoprotein IV, NKp46, ILT1 (also known as LIR7) and osteoclast-associated immunoglobulin-like receptor (OSCAR).

Follicular DCs

(FDCs). Cells with a dendritic morphology that are present within B cell follicles in secondary lymphoid tissues such as lymph nodes and spleen. They display intact antigens that are held in immune complexes on their surface, accessible to B cells. FDCs are of non-haematopoietic origin and are not related to 'conventional' DCs.

Germinal centre

A lymphoid structure that arises in B cell follicles in secondary lymphoid organs, such as spleen and lymph node, after immunization with, or exposure to, a T cell-dependent antigen. It is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

Intravenous immunoglobulin

(IVIG). A preparation of human polyclonal IgG obtained from pooled plasma samples taken from thousands of healthy blood donors. It is used as a replacement therapy for individuals with hypogammaglobulinaemia, but is also increasingly used, at much higher doses, to treat autoimmune diseases. IVIG is licensed for the treatment of idiopathic thrombocytopenic purpura, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and Kawasaki disease, and is also used in the treatment of other autoimmune diseases, including multiple sclerosis and ANCA-associated vasculitis.

Central tolerance

Immune tolerance to self antigens that is imposed during lymphocyte development in the thymus (T cells) or the bone marrow (B cells). B cells expressing a BCR that recognizes self antigen must undergo further rearrangement of antigen-receptor genes to become self tolerant or they are deleted or rendered anergic. This process does not eliminate all autoreactive lymphocytes and therefore mechanisms exist in the periphery to maintain tolerance in mature lymphocytes (peripheral tolerance).

T cell-dependent antigens

Antigens that require T cell–B cell interactions to activate B cells and produce an antibody response.

Ubiquitin E3 ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Copy number variant

(CNV). A genomic variant characterized by differences in the number of copies of specific repeated DNA fragments that range from 1 kb to several mb long and can contain entire genes.

Haplotype

A set of single nucleotide polymorphisms (SNPs) or other genetic variants in a gene or locus that are inherited together.

Systemic lupus erythematosus

(SLE). A multisystem autoimmune disease characterized by hypergammaglobulinaemia and the development of autoantibodies, including those specific for nuclear self antigens such as DNA. These antibodies form immune complexes that become deposited in tissues, including the kidneys and skin. Deposited immune complexes initiate an inflammatory response causing tissue damage. SLE is a polygenic disease, that is multiple, common polymorphisms confer disease susceptibility.

(NZB × NZW) F1 mice

The F1 generation of the cross between NZB mice and NZW mice. (NZB × NZW) F1 mice spontaneously develop a disease that closely resembles the human disease SLE.

MRL–lpr mouse

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of SLE. The lpr mutation causes a defect in CD95 (also known as FAS), preventing apoptosis of activated lymphocytes. The MRL background contributes other disease-associated genetic variants.

Collagen-induced arthritis

(CIA). A model of rheumatoid arthritis. CIA develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.

Sickle cell anaemia

Sickle cell anaemia is an autosomal recessive disease in which the gene encoding the β-globin chain has a mutation resulting in an amino acid change (a valine for a glutamic acid at position 6), which leads to erythrocytes that are rigid and sickle shaped. Patients develop anaemia and sickle crises, which significantly shorten life expectancy. Heterozygotes are protected from malaria infection, resulting in the retention of this mutation in populations exposed to malaria.

Thalassaemia

Thalassaemia is an autosomal recessive genetic disorder, in which there is a mutation in the gene encoding either the α- or β-globin chains that make up haemoglobin. This leads to reduced globin chain (and hence haemoglobin) synthesis, causing anaemia of variable severity. Carriers of the thalassaemia mutations (thalassaemia trait) are protected from malaria infection. This selective advantage is thought to contribute to the persistence of this potentially harmful mutation in the human genetic pool.

Anti-idiotypic antibody

An antibody that is directed against the antigen-specific binding site of an immunoglobulin or a T cell receptor and therefore may compete with antigen for binding.

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Smith, K., Clatworthy, M. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 10, 328–343 (2010). https://doi.org/10.1038/nri2762

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