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This article provides a summary of the proceedings of the CCFA Microbial-Host Interactions Workshop that was held in St. Petersburg, Florida, on March 16-19, 2006. Approximately 75 senior and junior investigators from around the world shared their most current research findings through oral presentations, poster sessions, and active discussion. Because intestinal microbiota are significant contributors in the development of inflammatory bowel diseases (IBD), understanding the body's responses to and interactions with microbes, especially in the colon and distal small intestine, is critical to elucidating the etiology and pathogenesis of IBD and developing effective therapeutic interventions. Major advances have occurred recently in molecular detection of luminal bacterial species, identifying dominant microbial antigens that drive intestinal inflammation, the mechanisms of innate immune and epithelial responses to bacteria, and regulation of inflammation by innate and acquired immune cells.

Summary: Peroxisome proliferator-activated receptor gamma (PPAR), a member of a nuclear transcription factor family, has been previously demonstrated to have antiinflammatory activity. The effects of PPAR activation in the development of an immune response are less well characterized. Through evaluation of PPAR heterozygote mice (PPAR +/- ) and specific PPAR agonist ligand binding, we evaluated the immunologic effects of PPAR activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPAR +/- mice in comparison to wild-type mice. Three different PPAR ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPAR ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPAR ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL-10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPAR ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPAR ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production. Key Words: Cytokine—T lymphocyte— Transcription factor—Inflammation—Mucosa.

Bevins CL, Stange EF, Wehkamp J. Decreased Paneth cell defensin expression in ileal Crohn’s disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut. 2009;58:882–883; discussion 883–884. Several years ago, Bevins, Stange, Wehkamp and colleagues1 reported decreased human α-defensin 5 and 6 expression in ileal Crohn’s disease (CD) patients harboring the NOD21007fs variant (encoded by NOD23020insC, “snp13”) and hypothesized that decreased Paneth cell antimicrobial activity might contribute to disease pathogenesis in ileal CD. Simms et al2 recently challenged this model by reporting that decreased α-defensin expression is a consequence of inflammation per se and unrelated to the NOD2 polymorphic state, implying that altered antimicrobial function might be secondary to active CD rather than a contributor to intestinal inflammation. This apparent contradiction has now been addressed by Bevins et al3 in a letter published in Gut, which triggered a counter-response by Simms et al4 and a consequent reply by Wehkamp et al.5 Specifically, Bevins et al3 remark that Simms et al have not stratified for the NOD21007fs variant but pooled all 3 major NOD2 variants. Moreover, they pointed to the fact that stratification with regard to inflammation in the ileum did not affect HD5 expression in the Wehkamp et al1 study, nor was human defensin-5 (HD5) regulation observed in non-CD ileal inflammation as deduced from measurements in pouchitis mucosa. Bevins et al speculated that a mix of surgical and biopsy specimens in the CD group might have been a detrimental confounder for the analysis in the Simms et al study, since the control group solely consisted of biopsy specimens. In their response, Simms et al4 now provide a stratification of HD5 and HD6 mRNA levels by NOD2 genotypes, which does not show significant differences including that associated with the NOD21007fs variant. Moreover, these authors claim varying results in the other group’s previous articles with regard to defensin levels, and reject the idea that sample bias might have contributed to the divergent results since statistical analyses included adjustment for confounders including sample type.4 Simms et al bring up another potential confounder distinguishing the Wehkamp et al study from the Simms et al study, namely, medical treatment, as 5-aminosalicylates and immunosuppressants, which were used differentially in the 2 study cohorts, and might have vastly different effects on intestinal bacteria.4

Natural killer T (NKT) cells are a subset of lymphocytes that express cell surface molecules of both conventional T cells and natural killer cells and share the features of both innate and adaptive immune cells. NKT cells have been proposed to make both protective and pathogenic contributions to inflammatory bowel diseases (IBD). On the one hand, recent studies have shown that these cells are involved in the maintenance of mucosal homeostasis. On the other, NKT cells were shown to play a pathogenic role in human ulcerative colitis. Similar contrasting data have been generated in murine models of IBD. Whether the apparent differences in NKT response patterns depend on variations in NKT antigens and/or on the presence of specific subsets of mucosal NKT cells remains to be elucidated. In this article we review the current literature on intestinal NKT cells and their roles in IBD pathogenesis. Specifically, the nomenclature, NKT antigens, and immune mechanisms of NKT cells within the intestinal mucosa are discussed.

It is well recognized that the nature of the immune response is different in the intestinal tract than in peripheral lymphoid organs. The immunologic tone of the gut-associated lymphoid tissue is one of suppression rather than active immunity, distinguishing pathogens from normal flora. Failure to control mucosal immune responses may lead to inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC) and celiac disease. It has been suggested that this normally immunosuppressed state may relate to unique antigen-presenting cells and unique T-cell populations. The intestinal epithelial cell (IEC) has been proposed to act as a nonprofessional antigen-presenting cell (APC). Previous studies have suggested that antigens presented by IECs result in the activation a CD8+ regulatory T-cell subset in a nonclassical MHC I molecule restricted manner. We therefore analyzed the expression of nonclassical MHC I molecules by normal IECs and compared this to those expressed by inflammatory bowel disease (IBD) IECs. Normal surface IEC from the colon and, to a much lesser extent, the small bowel express nonclassical MHC I molecules on their surface. In contrast, mRNA is expressed in all intestinal epithelial cells. Surface IEC express CD1d, MICA/B, and HLA-E protein. In contrast, crypt IECs express less or no nonclassical MHC I molecules but do express mRNA for these molecules. Furthermore, the regulation of expression of distinct nonclassical class I molecules is different depending on the molecule analyzed. Interestingly, IECs derived from patients with UC fail to express any nonclassical MHC I molecules (protein and HLA-E mRNA). IECs from CD patients express HLA-E and MICA/B comparable to that seen in normal controls but fail to express CD1d. Thus, in UC there may be a failure to activate any nonclassical MHC I molecule restricted regulatory T cells that may result in unopposed active inflammatory responses. In CD only the CD1d-regulated T cells would be affected. (Inflamm Bowel Dis 2007)