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

项目总结 乳糜泻(CD)是一种免疫介导的疾病，在这种疾病中，对外源性 人类白细胞抗原受限个体的抗原面筋(来自小麦、黑麦和大麦)。疾病引起的 十二指肠炎症，但可以通过停用面筋来逆转。患者经历口腔功能丧失 对面筋的耐受性(LOT)，与T细胞和B细胞反应。患者也会产生粘膜自身抗体 谷氨酰胺转氨酶2(TG2)，参与面筋代谢。我们之前发现TG2- 特异性血浆占十二指肠粘膜抗体分泌细胞的10%。 活动光盘。这些抗TG2 B细胞和抗体被认为可以直接增强或延续疾病 通过抗体介导的效应机制，如赞誉沉积，或通过面筋的呈递 多肽，通过T细胞使其永久化。因此了解抗TG2抗体的来源是很重要的 自身抗体反应。我们之前还发现，抗TG2抗体是由高度编码的 限制性免疫球蛋白基因谱系，主要由VH5-51和另外两个VH基因组成。曲目 这样的限制通常让人想起B细胞的一个不同的亚群，主要表达Ig 由VH5-51编码。我们现在有了初步数据，确定了循环中的IgA+B细胞亚群 表现出与抗TG2抗体相同的限制，但在所有健康受试者的血液中发现。 值得注意的是，尤其是IgA+B细胞和抗体分泌细胞(ASCs)的循环群体 与微生物区系的相互作用有关。我们假设这些细胞代表一个不同的功能子集 正常情况下提供粘膜保护的IgA外周血库，但这可能被诱导为 面筋暴露时易感个体分泌抗TG2自身抗体。在目标1中，我们将描述 这个子集的功能表型和转录组，我们将确定该子集是否克隆连锁 抗TG2粘膜ASCs在患者中的应用。在目标2中，我们将表征这些血液的微生物区系特异性- 活动期疾病患者和对照患者血液和粘膜活检ASCs携带的IgA ASCs 受试者处于单克隆化水平。最后，在目标3中，我们将探索TG2自身抗体反应的起源。 在粘膜组织中。特定的细胞功能或对特定微生物的不同靶向，加上与 对照受试者细胞可以为乳糜泻的病因学提供重要的见解。一种新颖的细胞表面 表型，如特定CD标记的表达，或特定细胞因子受体的表达，可能 为疾病的治疗干预提供有用的明确目标。

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.