STUDIES OF PRIMARY IMMUNODEFICIENCY DISEASES

这个项目的目的是确定免疫致病机制。 对人类免疫缺陷综合症负责。在过去一年 我们重点研究了T细胞和B细胞的功能能力 常见变异性免疫缺陷(CVI)患者。在CVI研究中 患者T细胞，我们发现当纯化的CD4T细胞增殖时 正常情况下，对PHA增殖的反应是葡萄球菌肠毒素 B(SEB)和抗CD2抗体，这些刺激诱导的 IL-2高于正常的CD4+T细胞。另一方面，固定化抗CD3 抗体及此刺激与抗CD28抗体联合诱导 CVI T细胞产生正常数量的IL-2。因此，这些研究 证明CD4+T细胞中IL-2的产生缺陷是由于 特定的信号通路异常。在第二系列研究中， 在这个案例中，我们首先展示了CVI患者的B细胞功能 循环中的B细胞表达正常数量的Sigm+，但大量 SIgG+和SIgA+的数量减少；这一结果意味着患者 体内存在同型开关分化缺陷。在其他 研究表明，在纯化的患者B细胞被刺激后， 抗CD40抗体加IL-10，患者B细胞表达CMU、Cγ和 此外，用抗CD40抗体加IL-10刺激细胞， 然后用活化的T细胞(表达CD40)刺激 配体)，导致部分恢复免疫球蛋白和免疫球蛋白A的合成。这些 因此，研究表明CVIB细胞可以部分恢复到 体外功能正常，表明细胞不是不可逆转的 阻止同型和顶端分化。

The aim of this project is to define the immunopathogenetic mechanisms responsible for human immunodeficiency syndromes. During the past year we have focused on the functional capacities of T and B cells from patients with common variable immunodeficiency (CVI). In studies of CVI patient T cells, we showed that while purified CD4 T cells proliferate normally in response to proliferation by PHA, staphylococcal enterotoxin B (SEB) and anti-CD2 antibodies, these stimuli induce significantly less IL-2 than normal CD4+ T cells. On the other hand, immobilized anti-CD3 antibody and this stimulus in combination with anti-CD28 antibody induced CVI T cells to produce normal amounts of IL-2. These studies thus demonstrate that the IL-2 production defect in CD4+ T cells is due to a specific signalling pathway abnormality. In a second series of studies, in this case focused on B cell function in CVI patients, we showed first that circulating B cells express normal amounts of sIgM+, but greatly reduced amounts of sIgG+ and sIgA+; this result implies that patients have an in vivo defect of isotype switch differentiation. In other studies, we showed that upon stimulation of purified patient B cells with anti-CD40 antibody plus IL-10, patient B cells expressed Cmu, Cgamma and Calpha mRNA; furthermore, stimulation of cells with anti-CD40 plus IL-10, followed by stimulation with activated T cells (which express the CD40 ligand), led to partial restoration of IgG and IgA synthesis. These studies thus indicate that CVI B cells can be partially restored to normal function in vitro, suggesting that the cells are not irreversibly blocked from isotype and terminal differentiation.