B CELL IMMUNOREGULATION IN CROHN 'S DISEASE

肠道共生细菌产物引发免疫反应，这是人类和动物IBD模型中组织损伤炎症的关键。在上一个资助周期中，我们与项目2合作鉴定了揭示CD患者对特定细菌抗原耐受性丧失的微生物产物，并根据血清抗体表达模式将这些患者分组。特别是，表达最高振幅抗体模式和抗原多样性（CD-highR）的患者组定义了具有独特侵袭性疾病的患者亚群。在小鼠结肠炎模型中，最严重和进展性的疾病发生在Th1高反应和缺乏调节功能的小鼠身上。我们的小鼠研究有助于识别的“监视”子集

Enteric commensal bacterial products elicit immune responses that are key to the tissue-damaging inflammation in humans and animal models with IBD. In the last grant cycle, we collaborated with Project 2 to identify microbial products that reveal a loss of tolerance in CD patients to specific bacterial antigens, and that such patients cluster into groups defined by patterns of serum antibody expression. In particular, patient groups expressing an antibody pattern of the highest amplitude and antigenic diversity (CD-highR) defined a patient subset with uniquely aggressive disease. In mouse models of colitis, the most severe and progressive disease occurs in mice engineered for both high Th1 responses and a lack of regulatory function. Our mouse studies have contributed to the recognition of a "surveillance" subset of B cells that particpate in mucosal immunoregulation and colitis protection through interaction with NKT cells, and CD4+CD8+double-positive (DP) T cells with suppression of Th1 colitis. The hypothesis tested in this next grant cycle is that mucosal surveillance B cells, by their efficient activation of regulatory NKT and DP T cells, promote protection against inflammation and mucosal tissue damage. Accordingly, we predict that impaired formation/function of this B cell subset represents a mode of immunoregulatory failure leading to the aggressive form of human CD observed in the CDhighR patient population. In Aims 1-3, we collaborate with Project 4 in the mouse to develop analytic tools and experimental approaches that model this hypothesis: (1) To define pharmacologic factors that regulate formation of surveillance B cells; (2) To identify the subset of B cells and their mode of interaction with NKT and DP T cells; (3) To test whether attenuated B cell immunoregulation is a susceptibility trait for aggressive colitis. In Aim 4, we collaborate with Projects 1, 2, and Core B to translate our analytic tools to the human, and directly test the hypothesis that the CD-highR subset of human CD patient patients is distinguished by impaired B-cell interaction with immunoregulatory T cell subsets.