The Journal of Experimental Medicine
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Published online 27 February 2006 doi:10.1084/jem.20050407
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 541-552
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ARTICLE

 The primary defect in experimental ileitis originates from a nonhematopoietic source

Timothy S. Olson1,3, Brian K. Reuter2, Kevin G-E. Scott2, Margaret A. Morris3,4, Xiao-Ming Wang2, Leslie N. Hancock2, Tracy L. Burcin3,4, Steven M. Cohn2, Peter B. Ernst2, Fabio Cominelli2, Jonathan B. Meddings5, Klaus Ley3,4, and Theresa T. Pizarro2

1 Department of Molecular Physiology, 2 Digestive Health Center of Excellence, 3 Robert M. Berne Cardiovascular Research Center, and 4 Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, VA 22908 5 Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2B7

CORRESPONDENCE Theresa T. Pizarro: ttp4e{at}virginia.edu

The initiating etiologic factor in Crohn's disease (CD) remains unclear. SAMP1/YitFc (SAMP) mice develop chronic ileitis similar to human CD. We used bone marrow chimeras to determine if SAMP ileitis results from a primary immunological defect or from dysregulated mucosal immunity secondary to intrinsic, nonhematopoietic (e.g., epithelial) dysfunction. SAMP mice receiving wild-type (AKR) BM developed severe ileitis, whereas SAMP BM did not confer ileitis to WT recipients. WT lymphocytes from reconstituted SAMP mice resembled native SAMP populations in regard to surface phenotype and cytokine production. Ilea from native SAMP mice and SAMP recipients of wild-type BM displayed decreased epithelial barrier resistance ex vivo and increased epithelial permeability in vivo compared to native WT mice and AKR recipients of SAMP BM. This permeability defect preceded the development of ileal inflammation, was present in the absence of commensal bacteria, and was accompanied by altered ileal mRNA expression of the tight junction proteins claudin-2 and occludin. Our results provide evidence that the primary defect conferring ileitis in SAMP mice originates from a nonhematopoietic source. Generation of pathogenic lymphocytes is a consequence of this defect and does not reflect intrinsic proinflammatory leukocyte properties. Decreased barrier function suggests that defects in the epithelium may represent the primary source of SAMP ileitis susceptibility.

Abbreviations used: BMT, bone marrow transplant; CD, Crohn's disease; CLDN, claudin; FE, fractional excretion; GF, germ-free; HGPRT, hypoxanthine-guanine phosphoribosyl transferase; MLN, mesenteric lymph node; MPO, myeloperoxidase; SAMP, SAMP1/YitFc; SPF, specific pathogen-free; TEER, transepithelial electrical resistance; TJ, tight junction.

T.S. Olson and B.K. Reuter contributed equally to this work.


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