Principal Project: B cell response underlying Celiac disease antibody and autoantibody responses

项目摘要 乳糜泻（CD）是一种免疫介导的疾病，其中存在对外源性免疫应答。 抗原谷蛋白（来自小麦、黑麦和大麦）在HLA限制的个体中。这种疾病会导致 十二指肠炎症，但可以逆转从面筋撤出。患者出现口腔功能丧失 对麸质的耐受性（LOT），T细胞和B细胞反应。患者还产生粘膜自身抗体， 谷氨酰胺转移酶2（TG 2），参与麸质代谢。我们之前发现TG 2- 特异性血浆代表患有以下疾病的患者的十二指肠粘膜内10%的抗体分泌细胞（ASC）： 活动CD这些抗TG 2 B细胞和抗体被认为直接增强或延续疾病 通过抗体介导的效应器机制，如补体沉积，或通过麸质的呈递， 肽，通过T细胞使LOT永存。因此，了解抗TG 2抗体的来源非常重要。 自身抗体反应我们以前也发现抗TG 2抗体是由一个高度保守的基因编码的。 限制性IG基因库，主要由VH 5 -51和两个其他VH基因组成。汇辑 这类限制常常使人联想到B细胞的一个独特亚群，主要表达IG 编码为VH 5 -51我们现在有初步的数据确定伊加+ B细胞的再循环亚群， 表现出与抗TG 2抗体相同的库限制，但在所有健康受试者的血液中发现。 值得注意的是，特别是伊加+ B细胞和抗体分泌细胞（ASC）的再循环群体，已经被证实是免疫调节剂。 与微生物群的相互作用有关。我们假设这些细胞代表了一个独特的功能亚群 伊加外周血库，通常提供粘膜保护，但可以诱导， 在麸质暴露后，易感个体会分泌抗TG 2自身抗体。在目标1中，我们将描述 该亚群的功能表型和转录组，我们将确定该亚群是否是克隆连锁的 抗-TG 2粘膜ASC。在目标2中，我们将描述这些血液的微生物群特异性- 来自血液和活组织检查的来自活动性疾病患者和来自对照的粘膜ASC的携带伊加ASC 在单克隆水平上。最后，在目标3中，我们将探索TG 2自身抗体应答的起源。 在粘膜组织中。特定的细胞功能或特定微生物的不同靶向，加上与 对照受试者细胞可以提供对乳糜泻病因学的重要了解。一种新型细胞表面 表型，例如特定CD标志物或特定细胞因子受体的表达，可以 提供了用于疾病治疗干预的不同靶点。

PROJECT SUMMARY Celiac disease (CD) is an immune mediated disorder in which there is an immune response to the exogenous antigen gluten (from wheat, rye, and barley) in individuals who are HLA restricted. The disease causes duodenal inflammation but can be reversed by withdrawal from gluten. Patients experience loss of oral tolerance (LOT) to gluten, with T cells and B cells reactive. Patients also produce mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) which is involved in gluten metabolism. We previously found that TG2- specific plasma represent 10% of antibody-secreting cells (ASCs) within the duodenal mucosa of patients with active CD. These anti-TG2 B cells and antibodies are believed to enhance or perpetuate disease either directly through antibody-mediated effector mechanisms, such as compliment deposition, or by presentation of gluten peptides, perpetuating the LOT by T cells. It is therefore important to understand the origin of anti-TG2 autoantibody responses. We also previously found that anti-TG2 antibodies were encoded by a highly restricted repertoire of Ig genes, consisting predominantly of VH5-51 and two other VH genes. Repertoire restrictions such as this are often reminiscent of a distinct subset of B cells, predominantly expressing Ig encoded by VH5-51. We now have preliminary data identifying a recirculating subset of IgA+ B cells that exhibit the same repertoire restrictions as the anti-TG2 antibodies but found in the blood of all healthy subjects. Notably, the recirculating population of IgA+ B cells and antibody-secreting cells (ASCs) in particular, has been associated with microbiota interactions. We hypothesize that these cells represent a distinct functional subset of the IgA peripheral blood repertoire that normally provides mucosal protection, but that can be induced to secrete anti-TG2 autoantibodies in susceptible individuals upon gluten exposure. In aim 1 we will characterize the functional phenotype and transcriptome of this subset and we will determine if the subset is clonally linked to anti-TG2 mucosal ASCs in patients. In aim 2 we will characterize the microbiota specificity of these blood- borne IgA ASCs from the blood and biopsied mucosal ASCs from patients with active disease and from control subjects at the monoclonal level. Finally, in aim 3 we will explore the origin of the TG2 autoantibody response in mucosal tissues. Particular cellular functions or distinct targeting of particular microbes, plus differences from control subject cells could provide important insight into the etiology of celiac disease. A novel cell-surface phenotype, such as expression of a particular CD marker, for example, or a particular cytokine receptor, could provide distinct targets useful for therapeutic intervention into disease.