Distinct Autoantibodies Against Endothelial Protein C Receptor in Ulcerative Colitis

Abstract

In a recent article in Gastroenterology, Kuwada et al1Kuwada T. et al.Gastroenterology. 2021; 160: 2383-2394Google Scholar reported novel autoantibodies against integrin αvβ6 in ulcerative colitis (UC). They hypothesized the existence of an autoantigen among the integrin proteins and screened for autoantibodies against them using enzyme-linked immunosorbent assays. The sensitivity and specificity of anti-integrin αvβ6 autoantibodies in UC were surprisingly high, and they conducted elegant experiments regarding the potential pathogenicity of anti-integrin αvβ6 autoantibodies. We express our respect for their incredible work and would like to comment on autoantibodies in UC, because we also recently found distinct autoantibodies in UC. In previous studies, approximately 6.4% of patients with Takayasu arteritis (TAK), a form of large vessel vasculitis, have been found to have a comorbidity of UC and to possess genetic overlap.2Mutoh T. et al.Nat Commun. 2020; 11: 1253Google Scholar In a recent article published in Nature Communications,3Terao C. et al.Arthritis Rheumatol. 2015; 67: 2226-2232Google Scholar we identified 2 novel autoantigens in TAK. We specifically focused on autoantibodies against the endothelium, which have also been detected in UC.4Aldebert D. et al.Gastroenterol Clin Biol. 1995; 19: 867-870Google Scholar Interestingly, most of the patients comorbid with UC and TAK possessed autoantibodies against one of the autoantigens, endothelial protein C receptor (EPCR). Therefore, we investigated whether autoantibodies against EPCR could be detected in patients with primary UC but without TAK. Our results revealed that almost 70% of the sera from patients with UC possessed anti-EPCR autoantibodies.3Terao C. et al.Arthritis Rheumatol. 2015; 67: 2226-2232Google Scholar Several articles have proposed the importance of EPCR in governing microvascular inflammation in inflammatory bowel disease (IBD).5Kondreddy V. et al.Sci Rep (Nat Publisher Group). 2020; 10: 20569Google Scholar,6Scaldaferri F. et al.J Clin Invest. 2007; 117: 1951-1960Google Scholar EPCR is expressed in colonic epithelial cells, as well as in the vascular endothelium. Overall, the expression of EPCR is reported to be decreased in IBD, impairing the anti-inflammatory role normally modulated by protein C. Thus, EPCR seems to negatively regulate intestinal inflammation in IBD. In our research, EPCR played important roles in the differentiation of naive T cells to Th17 cells and in endothelial activation in humans. Autoantibodies against EPCR had the potential to exacerbate inflammation through interference with EPCR functions. In addition to coexistence, TAK and UC share common complications such as spondyloarthritis and pyoderma gangrenosum.7Shirai T. et al.Intern Med. 2018; 57: 1929-1934Google Scholar This finding suggests a similar pathophysiology between TAK and UC, which might be characterized by the presence of anti-EPCR autoantibodies. The common feature of anti-integrin αvβ6 autoantibodies and anti-EPCR autoantibodies is that both autoantibodies target extracellular domain of membrane proteins and therefore have the potential to function as pathogenic autoantibodies. Such pathogenic potentials include direct cytotoxicity to target cells and modifications of the functions of their corresponding autoantigens. In contrast, the immunoglobulin class needs to be IgA to demonstrate pathogenicity against the intact intestinal epithelium. Kuwada et al1Kuwada T. et al.Gastroenterology. 2021; 160: 2383-2394Google Scholar speculated that the generation of anti-integrin αvβ6 autoantibodies was a secondary event after epithelial cell damage. As for the anti-EPCR autoantibodies, we also assume that their generation is a consequence, rather than an initiator, of inflammation. During inflammation, IgG class autoantibodies can reach the inflammatory site from the circulation and demonstrate pathogenic functions. Taken together, these autoantibodies are associated with aberrant immune activation after intestinal inflammation. Although the depletion of B lymphocytes by rituximab had no significant effect on inducing remission in moderately active UC,8Leiper K. et al.Gut. 2011; 60: 1520-1526Google Scholar the discovery of novel autoantibodies supports the importance of B-cell activation in the pathogenesis of UC. We also believe that these autoantibodies may be used as a tool for the diagnosis, classification, or monitoring of UC, and that they may contribute to a comprehensive understanding of the pathophysiology of intestinal inflammation. Identification of an Anti–Integrin αvβ6 Autoantibody in Patients With Ulcerative ColitisGastroenterologyVol. 160Issue 7PreviewUlcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. Full-Text PDF Open AccessReplyGastroenterologyVol. 161Issue 5PreviewReply. We appreciate the valuable comment by Shirai et al on our recent work in which we identified novel autoantibodies against integrin αVβ6 in patients with ulcerative colitis (UC).1 Before our article was published, they reported specific autoantibody anti-endothelial protein C receptor (EPCR) antibodies in nearly 70% of their patients with UC and in one third of patients with Takayasu arteritis.2 EPCR is present on the surface of vascular endothelial cells of the aortic vasa vasorum, particularly under inflammation,3 and Mutoh et al2 indicated that modulation of the anti-inflammatory function of EPCR by anti-EPCR autoantibodies may be involved in not only Takayasu arteritis but also inflammatory bowel disease. Full-Text PDF