The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn’s Disease

Abstract

<b><i>Background:</i></b> Crohn’s disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. <b><i>Summary:</i></b> Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1β and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.

TH17 cell: a double-edged sword in the development of inflammatory bowel disease

“…These plasmablasts secrete fibrotic factors like platelet-derived growth factors, which activate fibroblasts and myofibroblasts, leading to uncontrolled fibroblasts. 109 IL-6 and IL-21 promote the expression of amphiregulin in Th17 cells by activating STAT3. STAT3 in turn activates mTOR and mitogen-activated protein (MEK), promotes the proliferation and motility of human intestinal myofibroblasts and the expression of type I collagen.…”

TH17 cell: a double-edged sword in the development of inflammatory bowel disease

“…IL-17 and IL-21 were able to induce the formation of ectopic germinal centers and further induce the differentiation of naïve B cells within these centers into IgG4-producing plasmablasts. These plasmablasts secrete fibrotic factors such as platelet-derived growth factor (PDGF), which activate fibroblasts and myofibroblasts, leading to uncontrolled fibroblasts (83). IL-6 and IL-21 promote the expression of amphiregulin in Th17 cells by activating STAT3, which in turn activates mTOR and MEK, promotes the proliferation and motility of human intestinal myofibroblasts and the expression of type I collagen, thereby promoting the intestinal fibrosis response (84).…”