Lymphocyte and Epithelial Contributions to Crohn's Disease Studied in the SAMP1/YitFc Murine Ileitis Model

Olson, Timothy Steven, Department of Molecular Physiology, University of Virginia
Bender, Tim Bender, Department of Microbiology, University of Virginia
Mcduffie, Marcia, Department of Microbiology, University of Virginia
Ravichandran, Kodi, Department of Microbiology, University of Virginia
Pizarro, Theresa
Ley, Klaus, Department of Biomedical Eng, University of Virginia

Immunologic mechanisms and etiologic agents that contribute to the development of human Crohn's disease remain poorly understood. SAMP1/YitFc mice spontaneously develop discontinuous, transmural ileitis with histopathologic features strikingly similar to those observed in human Crohn's disease. I first investigated differences in the composition of mesenteric lymph node (MLN) CD4 + T cell populations in SAMP1/YitFc versus wildtype AKR mice in an attempt to differentiate ileitis-producing and nonpathogenic mucosal CD4 + T lymphocyte populations. I identified increases in several SAMP1/YitFc MLN lymphocyte subsets including overlapping populations of α E integrin + and CD25 + CD4 + T cells that express cytokines characteristic of regulatory T cells. These cells block colitis in vivo and effector cell proliferation in vitro, but are incapable of preventing ileitis both in SAMP1/YitFc mice and when adoptively transferred along with effector cells into SCID mice. Based on the observations that the size of the α + E CD4 + cell population correlates with MLN B cell expansion, and that MLN B cell population size is greatly increased in SAMP1/YitFc versus AKR mice, I next determined the phenotype and pathogenicity of SAMP1/YitFc MLN B cells. These B cells produce increased IgA levels, worsen the severity of adoptively transferred ileitis, and promote effector T cell proliferation by inhibiting regulatory T cell function. Finally I determined if SAMP1/YitFc ileitis originates from a primary defect in immune cells or in non-hematopoietic tissues such as the epithelium by generating chimeric mice using bone marrow transplantation. SAMP1/YitFc mice reconstituted with AKR bone marrow developed substantial ileitis, whereas SAMP1/YitFc bone marrow did not confer ileitis to AKR mice. Increased permeability and decreased expression of the peroxisomeproliferator-activated receptor (Ppar)γ by SAMP1/YitFc epithelium suggest that this 3 primary non-hematopoietic susceptibility leading to SAMP1/YitFc ileitis is derived from epithelial cells. Taken together, the results presented herein indicate that SAMP1/YitFc ileitis is likely caused by epithelial dysfunction leading to the initiation of ileal inflammatory responses involving Th1-polarized T cells and pro-inflammatory B cells that cannot be effectively controlled by regulatory T cells.

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PHD (Doctor of Philosophy)
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