Loss of B Cell Tolerance in Primary Immune Deficiency

患有原发免疫缺陷疾病(Pid)的患者通常会出现自身免疫并发症，因此 为研究特定基因突变对B细胞耐受调节的影响提供了难得的机会 自身免疫性疾病患者存在缺陷。TNFRSF13B基因C104R和A181E突变 编码TACI与常见变量免疫缺陷病(CVID)的发生有关 患有自身免疫性并发症。我们先前报道了TNFRSF13B基因突变对B细胞的影响 B细胞发育过程中两个不同阶段的耐受性；它们干扰了正在发育的 骨髓中的自身反应性B细胞和TACI突变也诱导抗核分泌 抗体(ANA)。我们最新的研究表明，TNFRSF13B半合子不影响B细胞 耐受性，提示常见的C104R和A181 TACI突变可能编码显性负值 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 在发展中的自身反应性B细胞的中央反选择过程中有助于自我抗原感知或 外周有ANA分泌。 这项拟议的研究的目标是确定调节健康人B细胞耐受性的机制 受试者，但在自身免疫性疾病患者中可能存在缺陷。工作假设是TACI是 B细胞耐受所必需的，因为它在B细胞中介导Toll样受体的耐受功能 (TLRs)，它控制着骨髓和外周血中发育中的自身反应性B细胞的清除。 由B细胞受体(BCR)触发。我们还将进一步描述整合BCR和BCR的途径 B细胞耐受所需的TLR/TACI信号转导途径分析 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.