FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications

Abstract

FcgammaRIIB 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). FcgammaRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcgammaRIIB 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 FcgammaRIIB 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.

Figure 1. Structure, cellular distribution and IgG isotype-binding affinity of human activating and inhibitory FcγRs

Human Fc receptors for IgG (FcγRs) differ in function, affinity for the Fc fragment of antibody and in cellular distribution. There are five activating FcγRs: the high-affinity receptor FcγRI, which can bind monomeric IgG, and four low-affinity receptors (FcγRIIA, FcγRIIC, FcγRIIIA and FcγRIIIB), which bind only immune-complexed IgG. Cross-linking of activating FcγRs by immune complexes results in the phosphorylation of immunoreceptor tyrosine-based activating motifs (ITAMs) that are present either in the cytoplasmic domain of the receptor (FcγRIIA and FcγRIIC), or in the associated FcR common γ-chain (FcγRI and FcγRIIIA), resulting in an activating signalling cascade. FcγRIIIB is a glycosylphosphatidylinositol (GPI)-linked receptor that has no cytoplasmic domain. FcγRIIB is the only inhibitory FcγR. It is a low affinity receptor that binds immune-complexed IgG and contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. FcγRIIB cross-linking by immune complexes results in ITIM phosphorylation and inhibition of the activating signalling cascade. FcγRs differ in their cellular expression; myeloid cells express FcγRI, FcγRIIA and FcγRIIIA, whereas granulocytes express FcγRI, FcγRIIA and FcγRIIIB. In such cells, immune complex-mediated activation of these receptors is negatively regulated by FcγRIIB. FcγRIIB is the only FcγR expressed by B cells and negatively regulates B cell receptor activation by immune-complexed antigen. FcγRs bind different IgG subtypes with differing affinity. For example, in the case of FcγRIIB, binding affinity is highest for IgG1, followed by IgG3, which in turn has higher affinity than IgG4 followed by IgG2. The ratio of binding of an IgG subtype to activating FcγRs and inhibitory FcγRIIB is known as the A/I ratio, and it determines the activation threshold of the cell. DC, dendritic cell; NK, natural killer.

Figure 2. The functions of FcγRIIB

a | Fc receptor IIB for IgG (FcγRIIB) has an important role in controlling humoral immunity by regulating B cell activation, localization of B cells in the germinal centres, as well as plasma cell survival. FcγRIIB regulates B cell activation by increasing the B cell receptor (BCR) activation threshold and suppressing B cell-mediated antigen presentation to T cells. Follicular dendritic cells (FDCs) express FcγRIIB, which is thought to be important for trapping immune-complexed antigen for presentation to germinal centre B cells. The absence of FcγRIIB on germinal centre FDCs results in impaired antibody and memory responses. Terminally differentiated plasma cells express little or no BCR but express high levels of FcγRIIB, and cross-linking FcγRIIB with immune complexes in vitro can induce apoptosis. b | FcγRIIB influences antigen presentation by inhibiting FcγR-dependent internalization of immune-complexed antigen by DCs, as well antigen presentation to both CD4+ and CD8+ T cells (cross-presentation). FcγRIIB is also thought to provide a basal level of inhibition to DC maturation, as blockade of immune complex binding to FcγRIIB results in DC maturation and type I interferon production. There is also a possibility that FcγRIIB may deliver intact antigen to a non-degradative compartment, allowing its recycling to the cell surface where it could interact with the BCR and activate B cells. c | FcγRIIB can also influence innate immunity: in macrophages, FcγRIIB cross-linking inhibits FcγR-mediated phagocytosis and cytokine release (including tumour necrosis factor, interleukin-6 (IL-6) and IL-1α), as well as Toll-like receptor 4 (TLR4)-mediated activation. In neutrophils, cross-linking of activating FcγRs results in phagocytosis, superoxide production and enhanced neutrophil adhesion, rolling and migration, all of which are probably inhibited by ligating FcγRIIB. d | FcγRIIB also inhibits IgE-induced mast cell and basophil degranulation, thus contributing to hypersensitivity responses. FcεR, Fc recpetor for IgE; SCF, stem cell factor.

Figure 3. Mouse Fcgr2b polymorphisms

Fcgr2b polymorphisms include the Ly17 polymorphisms, which are found in the coding region that comprises the Ly17 haplotype. These include three single nucleotide polymorphisms (SNPs) within exon 6 and one in exon 8 that appear to have no effect on receptor function. Regulatory region polymorphisms identified within the promoter region and intron 3 form 3 haplotypes and vary between different strains of inbred mice. In the promoter there is a 13 base pair deletion (region 1) and a 3 base pair deletion (region 2). In intron 3, there is a 4 base pair deletion at nucleotide 4133 to 4136 (region 3) and a 24 base pair deletion at nucleotide 4921 to 4944 (region 4). Inbred strains with the group 1 haplotype (NZB, BXSB, MRL, non-obese diabetic (NOD) and 129 mice) have region 1, region 2 and region 3 deletions (×), have decreased expression of FcγRIIB by macrophages and activated B cells and are prone to autoimmune disease. The precise contribution of deletions in the promoter and intron 3 to autoimmune susceptibility in these strains has yet to be determined. Inbred strains with the group 2 haplotype have a promoter with no deletions but have deletions in region 3 and 4 of intron 3 (which may contain enhancer and repressor elements). Inbred strains with the group 3 haplotype do not have deletions in either the promoter or intron 3 and include BALB/c and C57BL/6 mice.

Figure 4. Human FCGR2B polymorphisms

a | Several single nucleotide polymorphisms (SNPs) have been identified within the promoter and coding regions of FCGR2B. In the promoter, there are two SNPs at nucleotides −386 and −120. These SNPs form two haplotypes, a common −386G:−120T haplotype and a less common −386C:−120A haplotype. These haplotypes may alter transcription factor binding and expression. Seven non-synonymous SNPs have been identified in the human FCGR2B gene but only one has been studied in detail. This non-synonymous T-to-C transition (rs1050501) in exon 5 of the gene results in the substitution of a threonine for isoleucine at position 232 within the transmembrane domain of FcγRIIB (FcγRIIB^T232). The FcγRIIB^T232 variant is excluded from lipid rafts and has notably impaired inhibitory function. The polymorphism that encodes FcγRIIB^T232 has been associated with increased susceptibility to systemic lupus erythematosus (SLE) in both Southeast Asian and Caucasian populations. b | The frequency of the FcγRIIBT232 variant in different populations varies substantially. It is uncommon in Caucasians (1% homozygosity) but more common in populations found in areas of malarial endemicity such as Africa and Southeast Asia (5–11% homozygosity) suggesting that decreased FcγRIIB function may provide a survival advantage against this disease. This might provide the first example of an immune polymorphism predisposing to polygenic autoimmunity, selected and retained by virtue of its protective effect in malaria infection, and thus it is beginning to provide an explanation for the ethnic differences seen in SLE susceptibility.

Figure 5. Potential mechanisms by which FcγRIIB might contribute to the pathogenesis of systemic lupus erythematosus

a | Fc receptor IIB for IgG (FcγRIIB) is important for the maintenance of B cell tolerance through inhibition of B cell activation, promotion of the exclusion of autoreactive cells from follicles and perhaps by mediating apoptosis of autoreactive B cells and plasma cells. In vitro, FcγRIIB cross-linking in pre-B cells can result in apoptosis. This has been proposed as a possible mechanism for the removal of autoreactive B cells that arise during development; however, studies in FcγRIIB-deficient mice do not confirm the importance of this mechanism in central tolerance in vivo. FcγRIIB operates at several stages during later peripheral B cell development, potentially inhibiting B cell receptor (BCR)-mediated activation of autoreactive B cells. In addition, it may be important for the follicular exclusion of low-affinity autoreactive B cells. Autoreactive B cells may arise during somatic hypermutation and affinity maturation. It has been proposed that FcγRIIB cross-linking in the absence of BCR ligation may mediate apoptosis of such autoreactive follicular B cells and may also be important for deleting autoreactive plasma cells. b | Breakdown of B cell tolerance and the emergence of autoantibodies does not necessarily result in autoimmune disease, as there are mechanisms that function to clear circulating immune complexes, preventing them from becoming deposited in tissues. Immune complex clearance is, in part, mediated by binding and internalization by activating FcγRs (particularly on macrophages of the reticuloendothelial system of the liver and spleen). FcγRIIB may enhance or inhibit FcγR-mediated immune complex internalization by phagocytes (depending on the isoform expressed) thus modulating the amount of circulating immune complex present. c | Tissue-deposited immune complexes may initiate inflammation owing to ligation of activating FcγRs on infiltrating macrophages and neutrophils. Pro-inflammatory cytokine release and neutrophil degranulation in response to immune complexes is negatively regulated by FcγRIIB. Thus, FcγRIIB dysfunction might contribute to the pathogenesis of systemic lupus erythematosus at several stages, including the breakdown of self-tolerance, decreased disposal of immune complexes and a failure to modulate the inflammatory response to deposited immune complexes. TCR, T cell receptor.

Figure 6. The proven and potential roles of FcγRIIB in defence against malarial infection

Fc receptor IIB for IgG (FcγRIIB) regulates phagocytosis of parasites and parasitized erythrocytes, antigen presentation to T cells and the production of malarial antibodies by B cells. Macrophages are important in the immune response to malaria, both as antigen-presenting cells (APCs) and phagocytes. In particular, FcγR-mediated phagocytosis is crucial for the elimination of parasitized erythrocytes in mouse malarial models. FcγRIIB inhibits FcγR-mediated phagocytosis of antibody-opsonized parasitized erythrocytes or opsonized merozoites. Subsequent presentation of malarial antigens to T cells may also be potentially modulated by FcγRIIB. Cytokines are important in the immune response to malarial parasites. Tumour necrosis factor (TNF) promotes macrophage phagocytosis and enhances killing of intra-erythrocytic Plasmodium falciparum in humans. FcγRIIB inhibits the production of TNF from macrophages following FcγR-mediated phagocytosis of antibody-opsonized parasitized erythrocytes. IL-12 is crucial for the development of interferon-γ (IFNγ)-mediated protection to mouse malarial infections and for the production of TNF, and its release may also be modulated by FcγRIIB. Antibodies form an important defence to the erythrocytic stages of malaria (as shown by the passive transfer of protective IgG in mice and humans). FcγRIIB-deficient mice generate enhanced levels of malaria-specific IgG following infection with Plasmodium chabaudi chabaudi, suggesting that FcγRIIB may have a role in regulating antibody responses to malarial parasites in humans. IL, interleukin; NK, natural killer; TCR, T cell receptor.