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Review
. 2019 Apr 12:10:805.
doi: 10.3389/fimmu.2019.00805. eCollection 2019.

IgG and Fcγ Receptors in Intestinal Immunity and Inflammation

Tomas Castro-Dopico  1 , Menna R Clatworthy  1   2   3
Affiliations
Review

IgG and Fcγ Receptors in Intestinal Immunity and Inflammation

Tomas Castro-Dopico et al. Front Immunol. .

Abstract

Fcγ receptors (FcγR) are cell surface glycoproteins that mediate cellular effector functions of immunoglobulin G (IgG) antibodies. Genetic variation in FcγR genes can influence susceptibility to a variety of antibody-mediated autoimmune and inflammatory disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). More recently, however, genetic studies have implicated altered FcγR signaling in the pathogenesis of inflammatory bowel disease (IBD), a condition classically associated with dysregulated innate and T cell immunity. Specifically, a variant of the activating receptor, FcγRIIA, with low affinity for IgG, confers protection against the development of ulcerative colitis, a subset of IBD, leading to a re-evaluation of the role of IgG and FcγRs in gastrointestinal tract immunity, an organ system traditionally associated with IgA. In this review, we summarize our current understanding of IgG and FcγR function at this unique host-environment interface, from the pathogenesis of colitis and defense against enteropathogens, its contribution to maternal-fetal cross-talk and susceptibility to cancer. Finally, we discuss the therapeutic implications of this information, both in terms of how FcγR signaling pathways may be targeted for the treatment of IBD and how FcγR engagement may influence the efficacy of therapeutic monoclonal antibodies in IBD.

Keywords: Fcγ receptor; IgG; inflammatory bowel disease; intestinal immunity; mucosal infections; neonatal immunity.

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Figures

Figure 1
Figure 1
Human and murine Fcγ receptors. Schematic of human (A) and murine (B) classical Fcγ receptors embedded in the plasma membrane. Activating receptors contain intracellular ITAMs on the intracellular domain of the α chain or in the associated common γ-chain (γ2; encoded by FCER1G). Activating FcγRs are shaded in blue and inhibitory FcγRIIB is shaded in red. IgG affinity-altering variants are highlighted beneath the respective human FcγR, with the low- and high-binding variants and associated IgG affinities colored in purple and orange, respectively, in the table. Binding affinities are indicated as KA (M−1). ITAM, immunoreceptor tyrosine-based activating motif; ITIM, immunoreceptor tyrosine-based inhibitory motif.
Figure 2
Figure 2
Effector functions of IgG antibodies and FcγRs. (A) IgG-opsonized antigens and cells can engage the classical complement pathway via binding to C1q. (B) IgG immune complexes, aggregated, or deposited IgG can bind to activating or inhibitory FcγRs on the surface of immune cells, particularly those of the innate immune system. Activating FcγRs (aFcγR) can also bind to pentraxins, such as CRP, linking to cellular responses to innate humoral immunity. (C) Specific glycosyl variants of IgG can bind to C-type lectin receptors, such as Dectin-1 and SIGN-R1, to mediated activating FcγR-independent immune function.
Figure 3
Figure 3
Schematic of major leukocyte populations in the intestine during homeostasis and their expression of FcγRs. Migratory DCs promote B cell IgA class-switching and T cell polarization in GALT and MLNs, including regulatory T cells (Treg) and Th17 cells. The balance of Tregs and Th17 cells is critical for maintaining intestinal homeostasis and suppressing excessive responses to the microbiota. CD11b+ cDC2s have an A:I ratio skewed toward FcγRIIB expression, as observed in DCs in other organs. FcγR-expressing DCs and monocyte-derived macrophages within the lamina propria support T cell and ILC3 activation via commensal-dependent production of cytokines, including IL-1β and IL-23. Tissue-resident macrophages are dependent on IL-10 for their suppressive function. APRIL and BAFF production by DCs and macrophages supports local plasma cell survival. Macrophage A:I ratio is skewed toward activating FcγRs and tuneable to the local milieu. Plasma cells and B cells express FcγRIIB, regulating survival and BCR activation threshold in these cells, respectively. Blue receptor, activating FcγR; red receptor, inhibitory FcγRIIB; S-IgA, secretory IgA; MLN, mesenteric lymph node; GALT, gut-associated lymphoid tissue; DC, dendritic cell; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; IESC, intestinal epithelial stem cell; ILC3, group 3 innate lymphoid cell.
Figure 4
Figure 4
IgG in intestinal homeostasis. FcRn-mediated placental and epithelial transport contributes to the neonatal anti-microbial IgG repertoire in early life, mediating protection against opportunistic mucosal invasion. Maternally-derived IgG contributes to protection from allergic responses through FcRn-mediated antigen presentation by DCs to T cells for regulatory T cell induction. IgG-mediated transfer of microbial molecules, such as SCFAs, also supports appropriate immune cell development. In adult humans and mice, anti-microbial IgG is generated throughout life in GALT, contributing to systemic protection from infection through engagement of FcγRs on myeloid cells. In humans, FcRn is continuously expressed within the intestinal epithelium, allowing for bidirectional trafficking of IgG and immune complexes between the intestinal lumen and lamina propria for antigen delivery to local FcγR-expressing myeloid cells. SCFA, short-chain fatty acids; ILC3, group 3 innate lymphoid cell; FcRn, neonatal Fc receptor; AHR, aryl hydrocarbon receptor.
Figure 5
Figure 5
Involvement of IgG in intestinal inflammation. (A) There are multiple lines of evidence for the involvement of IgG and FcγR signaling in the pathogenesis in IBD. In genetic studies, the low-affinity FcγRIIA-R131 variant is associated with protection from UC in several independent cohorts. Systemic and local induction of de novo anti-commensal IgG and auto-antibodies, such as pANCA, is observed in human IBD, while IgG+ plasma cells and FcγR-expressing cells are enriched in mucosal biopsies from IBD patients with active disease. In murine studies, de novo IgG production is observed, and passive transfer of anti-flagellin IgG to naïve animals exacerbates DSS-induced colitis. FcγR signaling strength determines the magnitude of intestinal inflammation in this model. In humans, IgG immune complex stimulation of intestinal LPMCs drives inflammatory cytokine production, including IL-1β. (B) IgG and FcγR in intestinal inflammation: Inflammation is characterized by an increase in the generation of local anti-commensal IgG. These immune complexes cross-link FcγR on colonic MNP, leading to NLRP3 and ROS-dependent IL-1β production. IL-1β, in turn drives Th17 immunity propagating inflammation. ROS, reactive oxygen species; MNP, mononuclear phagocyte; LPMCs, lamina propria mononuclear cells.
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