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The Immune System in IBD: Antimicrobial Peptides

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Crohn's Disease and Ulcerative Colitis

Abstract

Antimicrobial peptides are one of the most ancient forms of host defense in nature. Epithelial cells throughout the body express a collection of antimicrobial peptides that have overlapping and complementary activities. In the mammalian intestine, clear and compelling evidence supports that antimicrobial peptides play two fundamental roles: protection from enteric pathogens and shaping the composition of the colonizing microbiota. These functions likely hold relevance to host–microbe interactions that underlie inflammatory bowel disease (IBD) pathogenesis, since prevailing theories on the pathogenesis of IBD invoke a role for detrimental effects of intestinal microbes in the initiation and/or propagation of mucosal inflammation. Specialized epithelial cells of the small intestine named Paneth cells produce and secrete vast quantities of various antimicrobial peptides. The most abundant are the α(alpha)-defensin peptides, human defensin (HD)-5 and HD6, which in turn represent the most abundant antimicrobial peptides found anywhere in human gastrointestinal tract. Other abundant antimicrobials, which are larger in size, but with fundamentally similar physiological roles, are lysozyme, secretory phospholipase A2, and the C-type lectin RegIIIα(alpha). Evidence supports that reduced Paneth cell α(alpha)-defensin expression may be a key factor in the pathogenesis of ileal Crohn’s disease, a major subgroup of IBD. Furthermore, several susceptibility genes for Crohn’s disease appear to manifest their disease-associated activity, in part, through compromise of Paneth cell antimicrobial peptide production. For example, the microbial sensor NOD2, the autophagy-related proteins ATG16L1 and IRGM, the endoplasmic reticulum stress responder XBP1, the calcium dependent potassium channel KCa3.1, the WNT ligand co-receptor LRP6, and the transcription factor TCF7L2 (formerly TCF4) all influence Paneth cell biology and function. While not proven, mounting evidence supports that Paneth cell dysfunction, might substantially contribute to ileal Crohn’s disease pathogenesis.

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Bevins, C.L. (2017). The Immune System in IBD: Antimicrobial Peptides. In: Baumgart, D. (eds) Crohn's Disease and Ulcerative Colitis. Springer, Cham. https://doi.org/10.1007/978-3-319-33703-6_5

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