Loss of B Cell Tolerance in Primary Immune Deficiency

患有原发性免疫缺陷病（PID）的患者通常会发生自身免疫并发症， 为研究特定基因突变对B细胞耐受性调节的影响提供了难得的机会 自身免疫性疾病患者的缺陷。TNFRSF 13 B基因的C104 R和A181 E突变 编码TACI的基因与常见变异型免疫缺陷病（CVID）的发生有关 自身免疫并发症我们之前报道过TNFRSF 13 B基因突变会影响B细胞 在B细胞发育过程中的2个不同步骤的耐受性;它们干扰发育中的 骨髓中的自身反应性B细胞和TACI突变也诱导抗核抗体的分泌。 抗体（ANA）。我们最近的研究表明TNFRSF 13 B半合子不影响B细胞 提示常见的C104 R和A181 TACI突变可能编码显性负性TACI， 产品.然而，目前还不清楚为什么TACI是B细胞耐受所必需的，以及这种分子如何可能 有助于在发育中的自身反应性B细胞的中枢反选择过程中的自身抗原感应， ANA分泌在外周。 这项研究的目的是确定在健康人中调节B细胞耐受性的机制。 但在自身免疫性疾病患者中可能有缺陷。工作假设是TACI是 因为它在B细胞中介导Toll样受体的致耐受性功能， （TLR），其控制在共刺激时清除骨髓和外周中正在发育的自身反应性B细胞。 由B细胞受体（BCR）触发。我们还将进一步表征整合BCR和 通过分析具有新基因的其他PID患者，发现B细胞耐受所需的TLR/TACI信号传导 突变。

Patients with primary immunodeficiency diseases (PID) often develop autoimmune complications and therefore provide rare opportunities to study the impact of specific gene mutations on the regulation of B-cell tolerance defective in patients with autoimmune diseases. The C104R and A181E mutations in the TNFRSF13B gene encoding TACI are associated with the development of common variable immunodeficiency disease (CVID) with autoimmune complications. We previously reported that mutations in TNFRSF13B gene impact B cell tolerance at 2 distinct steps during B cell development; they interfere with the removal of developing autoreactive B cells in the bone marrow and TACI mutations also induce the secretion of anti-nuclear antibodies (ANAs). Our latest investigation revealed that TNFRSF13B hemizygosity does not affect B cell tolerance, suggesting that the common C104R and A181 TACI mutations may encode dominant negative products. However, it remains unclear why TACI is required for B cell tolerance and how this molecule may contribute to self-antigen sensing during the central counterselection of developing autoreactive B cells or to ANA secretion in the periphery. The goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy subjects but may be defective in patients with autoimmune diseases. The working hypothesis is that TACI is required for B cell tolerance because it mediates in B cells the tolerogenic function of Toll-like receptors (TLRs), which control the removal of developing autoreactive B cells in the marrow and the periphery when co- triggered with B-cell receptors (BCRs). We will also further characterize the pathways integrating BCR and TLR/TACI signaling required for B cell tolerance by analyzing additional PID patients with novel gene mutations.