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

X连锁淋巴组织增生综合征（XLP）主要表现为三种表型：1）暴发型 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的三种主要表型在一个家族中发现， 携带相同的突变，遗传背景和/或环境因素必须发挥作用， 疾病的发病机制。THP患者T和B的多克隆扩增剧烈，不受控制 细胞，不可避免地导致肝坏死和骨髓衰竭而死亡。XLP的一个主要原因是 人类是SH 2D 1A基因的缺陷，该基因编码SAP（SLAM相关蛋白），一个单一的游离SH 2- 一种控制CD 4和CD 8 T淋巴细胞中不同关键信号转导途径的结构域蛋白，NK 细胞、血小板和可能的B细胞亚群。SAP作为一个衔接子， SLAM受体家族的六个成员的尾部与信号转导途径，例如Fyn和其他酪氨酸 激酶。 先前的研究表明，XLP患者的获得性免疫反应的几个分支受到影响 SAP相关分子EAT-2A和EAT-2B具有相似的功能。我们 一般的假设是SAP和EAT-2A/B控制部分重叠的机制，这些机制对于 控制体液免疫。本申请中提出的实验将检验以下假设： #1）不同的SAP-/-CD 4 + T细胞亚群和/或NKT细胞促成SAP-/-CD 4 + T细胞亚群的异常丙种球蛋白血症。 小鼠，#2）SAP基因的破坏影响滤泡B细胞的亚群，其参与体液免疫调节。 EAT-2A/B和SAP在抗体控制中相互作用 应答 总之，这些实验应该阐明SAP和EAT-2在T细胞依赖性B细胞应答中的作用 以及为什么SAP功能缺失会导致异常丙种球蛋白血症。这些研究的结果应该 提出了可应用于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.