Mucosal IgG in inflammatory bowel disease - a question of (sub)class?

Abstract

Immunoglobulins (Igs) form a cornerstone of mucosal immunity. In the gastrointestinal tract, secretory IgA and IgM bind to commensal microorganisms within the intestinal lumen to prevent them from breaching the intestinal epithelium - a process known as immune exclusion. In recent years, there has been renewed interest in the role of IgG in intestinal immunity, driven in part by a genetic association of an affinity-lowering variant of an IgG receptor, FcγRIIA, with protection from ulcerative colitis (UC), a subclass of inflammatory bowel disease (IBD). We recently demonstrated a role for IgG and Fcγ receptor signalling in driving pathogenic IL-1β production by colonic mononuclear phagocytes and the subsequent induction of a local type 17 response in UC. Here, we discuss the potential relevance of our observations to the other major subclass of IBD - Crohn's disease (CD) - where the genetic association with FCGR variants is less robust and consider how this may impact therapeutic interventions in these disease subsets.

Keywords: Crohn’s disease; Fcγ receptors; IgG; inflammatory bowel disease; subclasses; ulcerative colitis.

Figure 1.

Major genetic associations in inflammatory bowel disease. Venn diagram of major genetic associations in IBD (candidate genes from single nucleotide polymorphisms (SNPs) with P value <1 × 10⁻¹³. Common genes are subdivided based on greater association with CD (blue) or UC (red).

Figure 2.

IgG characteristics in Crohn’s disease and ulcerative colitis. Summary of the differences in IgG responses between CD and UC patients, including frequency of plasma cell pool, IgG subclass distribution, glycosylation status, and antigen specificity. pANCA = perinuclear anti-neutrophil cytoplasmic antibodies; GM-CSF = granulocyte macrophage-colony stimulating factor.

Figure 3.

FcγR expression in IBD mucosal biopsies. Transcriptomic analysis of FCGR gene expression in mucosal biopsies from UC (n = 24), colonic CD (CDc; n = 19), and ileal CD (CDi; n = 18) patients and healthy controls (ileum n = 6; colon n = 6). Data generated from GEO: GSE16879.