Role of SAP (SH2D1A) gene in T cell-dependent antibody response

X连锁淋巴增生性综合征(XLP)具有三种常见的表型：1)暴发性 传染性单核细胞增多症，2)恶性B细胞淋巴瘤和3)获得性低丙种球蛋白血症 无传染性单核细胞增多症。由于XLP的三种主要表型都在一个家族中发现 携带相同突变、遗传背景和/或环境因素的人必须在 疾病的发病机制。FIM患者T和B细胞出现强烈的、不受控制的多克隆扩增 细胞，不可避免地导致肝脏坏死和骨髓衰竭而死亡。XLP的一个主要原因是 人类是SH2D1A基因的缺陷，该基因编码SAP(SLAM相关蛋白)，一个单一的游离SH2- 控制CD4和CDS T淋巴细胞不同关键信号转导通路的结构域蛋白，NK 细胞、血小板，可能还有B细胞的一个亚群。SAP起到适配器的作用，连接细胞质和 SLAM受体家族中六个成员的尾巴与信号转导通路有关，例如Fyn和其他酪氨酸 激活剂。 先前的研究表明，XLP患者的获得性免疫反应的几个方面受到影响 和SAP缺乏的小鼠，SAP相关分子EAT-2A和-2B具有类似的功能。我们的 一般假设是SAP和EAT-2A/B控制部分重叠的机制，这些机制对 体液免疫的控制。这个应用程序中提出的实验将检验以下假设 #1)不同的SAP-/-CD4T细胞亚群和/或NKT细胞导致SAP-/-丙种球蛋白血症 小鼠，#2)SAP基因的中断影响参与体液的滤泡B细胞亚群 应答和生发中心反应以及#3)EAT-2A/B和SAP在抗体控制中的相互作用 回应。 总之，这些实验应该阐明SAP和EAT-2在T细胞依赖性B细胞反应中的作用 以及为什么SAP功能缺失会导致丙种球蛋白异常血症。这些研究的结果应该是 建议可应用于XLP患者的治疗策略。

X-linked lymphoproliferative syndrome (XLP) is characterized by three prevalent phenotypes: 1) Fulminant Infectious Mononucleosis, 2) malignant B cell lymphoma and 3) acquired hypogammaglobulinema in the absence of infectious mononucleosis. As the three major phenotypes of XLP are found within one family harboring the same mutation, genetic background and/or environmental factors must play a role in the pathogenesis of the disease. FIM patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells, inevitably leading to death by hepatic necrosis and bone marrow failure. A major cause of XLP in humans is a defect in the SH2D1A gene, which encodes SAP (SLAM Associated Protein), a single free SH2- domain protein that controls distinct key signal transduction pathways in CD4 and CDS T lymphocytes, NK cells, platelets and probably a subset of B cells. SAP functions as an adapter, which bridges the cytoplasmic tail of six members of the SLAM receptor family to signal transduction pathways, e.g. Fyn and other tyrosine kinases. Previous studies show that several arms of the acquired immune responses are affected in XLP patients and SAP-deficient mice and that the SAP related molecules EAT-2A and -2B subserve similar functions. Our general hypothesis is that SAP and EAT-2A/B control partially overlapping mechanisms that are critical for the control of humoral immunity. The experiments proposed in this application will test the hypothesis that #1) distinct SAP-/- CD4+ T cell subsets and/or NKT cells contribute to the dysgammaglobulinemia of SAP-/- mice, #2) disruption of the SAP gene affects the subsets of follicular B cells, which participate in humoral responses and in the germinal center reaction and #3) EAT-2A/B and SAP interact in the control of antibody responses. Together these experiments should clarify the role of SAP and EAT-2 in T cell dependent B cell responses and why the absence of SAP functions causes dys-gammaglobulinemia. The results of these studies should suggest therapeutic strategies that can be applied to XLP patients.