Loss of B Cell tolerance in Primary Immune Deficiency

免疫功能受损导致的原发免疫缺陷疾病通常与自相矛盾的自身免疫并发症相关。PID患者提供了难得的机会来研究特定缺陷基因对人类B细胞耐受性的调节和对发展中的自身反应性B细胞的去除的影响。在缺乏功能性BTK、CDI 9或介导Toll样受体(TLR)信号的分子(如IRAK-4、MyD88和UNC-93B)的患者中，B细胞受体(BCR)信号的变化导致中央检查点缺陷和未能反选发育中的自身反应性B细胞。事实上，自身抗原与自身反应性BCR和TLR的结合未能在所有这些患者的发育中的B细胞中诱导耐受机制，并且自身反应性B细胞从骨髓渗漏到外周。我们最近的工作表明，编码跨膜激活剂和钙调节亲环素配体相互作用因子(TACI)的基因突变也影响早期B细胞耐受检查点，其功能涉及MyD88。此外，我们确定了激活诱导胞苷脱氨酶(AID)在人类体内清除发育中的自身反应性B细胞的主要作用，这是一种类别切换重组(CSR)和体细胞高突变(SHM)所必需的酶。最后，基因突变 CDI9、TACI和IRAK4基因也改变了一些记忆B细胞的产生，但它们是否参与人类激活的B细胞克隆的选择仍有待确定。 这项拟议研究的长期目标是进一步确定在健康人中调节B细胞耐受性的机制，但在PID患者中可能存在缺陷。工作假说是，TACI与TLR7、TLR9、MyD88以及AID交织在一起，AID在BCR、TLR9和/或TACI触发后在未成熟的B细胞中诱导表达，在清除发展中的自身反应性B细胞方面起着至关重要的作用。此外，我们还将重点分析TLRs、TACI、MyD88和AID的机制，以及通过这些机制在记忆B细胞室中选择发育中的突变克隆。

Impaired immune functions leading to primary immunodeficiency diseases (PID) often correlate with paradoxical autoimmune complications. PID patients provide rare opportunities to study the impact of specific defective genes on the regulation of B cell tolerance and the removal of developing autoreactive B cells in humans. Alterations in B cell receptor (BCR) signaling in patients lacking functional BTK, CDI 9, or molecules mediating Toll-like receptor (TLR) signaling such as IRAK-4, MyD88, and UNC-93B result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells. Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms in all these patients' developing B cells and autoreactive B cells leaks from the bone marrow into the periphery. Our recent work demonstrates that mutations in the gene encoding the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) whose functions involve MyD88, also affect early B cell tolerance checkpoints. In addition, we identified a major and previously unsuspected role for activation-induced cytidine deaminase (AID), an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), in the removal of developing autoreactive B cells in humans. Finally, mutations in CDI 9, TACI and IRAK4 genes also alter the production of some memory B cells yet their involvement in the selection of activated B cell clones in humans remained to be determined. The long range goal ofthe proposed research is to further determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in PID patients. The working hypothesis is that TACI, intertwined with TLR7,TLR9, and MyD88 as well as AID, whose expression is induced in immature B cells after BCR, TLR9 and/or TACI triggering, play essential roles in the removal of developing autoreactive B cells. In addition, we will focus on the analysis ofthe mechanisms involving TLRs, TACI, MyD88 and AID and by which developing mutating clones are selected in the memory B cell compartments.