B CELL IMMUNOREGULATION IN CROHN'S DISEASE

肠道共生细菌产品诱导免疫反应，这是人类和IBD动物模型组织破坏性炎症的关键。在上一个资助周期中，我们与项目2合作，识别出CD患者对特定细菌抗原失去耐受性的微生物产品，并根据血清抗体表达模式将这些患者分组。特别是，表达最高幅度和抗原多样性(CD-HIGR)的抗体模式的患者组定义了具有独特侵袭性疾病的患者亚组。在结肠炎的小鼠模型中，最严重和进展最快的疾病发生在为Th1高反应和缺乏调节功能而设计的小鼠身上。我们对小鼠的研究有助于识别出一种“监视”的子集 通过与NKT细胞相互作用参与粘膜免疫调节和保护结肠炎的B细胞，以及抑制Th1结肠炎的CD4+CD8+双阳性(DP)T细胞。 在下一个赠款周期中检验的假设是，粘膜监视B细胞通过有效地激活调节性NKT和DP T细胞，促进对炎症和粘膜组织损伤的保护。因此，我们预测，这个B细胞亚群的形成/功能受损代表了一种免疫调节失败的模式，导致在CDHighR患者群体中观察到的人类CD侵袭性形式。在目标1-3中，我们与Project 4在小鼠身上合作开发分析工具和实验方法来模拟这一假设：(1)定义调节监视B细胞形成的药理学因素；(2)确定B细胞亚群及其与NKT和DP T细胞相互作用的模式；(3)测试B细胞免疫调节减弱是否为侵袭性结肠炎的易感特征。在目标4中，我们与项目1、2和核心B合作，将我们的分析工具翻译到人类身上，并直接测试这一假设，即CD患者的CD-High R亚群是通过受损的B细胞与免疫调节T细胞亚群相互作用来区分的。

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.