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A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFN? to generate self-tolerance and prevent colitis.

ABSTRACT: Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFN? were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFN?-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

SUBMITTER: Jeschke JC

PROVIDER: S-EPMC6571016 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.

Jeschke Jonathan C JC Mayne Christopher G CG Ziegelbauer Jennifer J DeCiantis Christopher L CL Singh Selina S Kumar Suresh N SN Suchi Mariko M Iwakura Yoichiro Y Drobyski William R WR Salzman Nita H NH Williams Calvin B CB

Mucosal immunology 20180504 4

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic c ...[more]

PMID: 29728642

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Project description:BackgroundInadequate differentiated diagnostic features of predominantly colonic inflammatory bowel diseases i.e., ulcerative colitis and Crohn's colitis, may lead to inexact diagnosis of "indeterminate colitis". About 15% of indeterminate colitis patients are diagnosed at colonoscopy, in colonic biopsies, and/or at colectomy. Managing outcomes of indeterminate colitis, given its unpredictable clinical presentation, depends on future diagnosis of colitis, Crohn's colitis or ulcerative colitis.ObjectiveOverview the diagnostic efficacy of ectopic colonic ileal metaplasia and human α-defens 5 (DEFA5 alias HD5) for accurate delineation of indeterminate colitis into authentic Crohn's colitis and/ or ulcerative colitis.DesignWe describe a targeted protein for potentially differentiating indeterminate colitis into an accurate clinical subtype diagnosis of inflammatory bowel diseases i.e., ulcerative colitis and Crohn's colitis.PatientsTwenty-one patients with the clinically inexact diagnosis of indeterminate colitis were followed, reassessed and data analyzed.Main outcome measuresWe observed that (i) some patients had their original diagnosis changed from indeterminate colitis to either ulcerative colitis or Crohn's colitis; and (ii) human α-defensin 5 is aberrantly overexpressed in Crohn's colitis.ResultsFifteen of the twenty-one (71.4%) patients with indeterminate colitis had their inconclusive diagnosis changed; nine patients changed to ulcerative colitis and six to Crohn's colitis. In human colon surgical samples, Human α-defensin-5 was significantly upregulated in Crohn's colitis. In addition, Human α-defensin 5 processing enzyme, matrix metalloptotease-7 was inversely expressed compared to Human α- Defensin 5.LimitationDue to the sequence homology of the α-defensin class of proteins, preceding efforts to raise antibodies (Abs) against DEFA5 have limitations to produce adequate specificity. The Abs used in previous assays recognizes the α-defensins, active α-defensins 5 and inactive pro- α-defensins 5. Monoclonal antibodies (mAbs) to determine specificity and sensitivity of α-defensins 5, which is diagnostic of CC disease, and NOT other α-defensins is the limitation to overcome.ConclusionIt is feasible to differentiate ulcerative colitis from Crohn's colitis among patients with inexact diagnosis of indeterminate colitis using Human α-defensin 5 as a molecular biosignature delineator.

Dataset Information

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFN? to generate self-tolerance and prevent colitis.

Publications

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.

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