STUDIES OF PRIMARY IMMUNODEFICIENCY DISEASES

对我们实验室的研究主要集中在确定B细胞的性质 常见变异性免疫缺陷(CVI)患者的细胞和T细胞缺陷 原发性获得性人类免疫缺陷状态的特征是 低丙种球蛋白血症和功能抗体反应受损。 以往对CVI患者纯化的B细胞的研究表明， 尽管细胞具有正常的增殖能力，但它们表现出 多层次的分化缺陷。因此，与 正常B细胞、循环CVI B细胞中Sigg+细胞数量减少 和SIgA+细胞，SIgM+B细胞相应增加，提示 同型转换中的体内缺陷。此外，他们没有经历 分化为产生免疫球蛋白的细胞。 在本研究中，我们发现CVIB表现出一种异常 表面B7的表达与诱导正常T细胞的能力相关 细胞表现出抑制细胞的能力。特别是， 阳性选择的CVI B细胞(即暴露于抗CD19的细胞 抗体)在随后用抗IgM激活时明显过早 B7-1表达增强，B7-2表达降低。自B7-1以来 通过与T细胞表面CTLA-4的相互作用，发挥T细胞的抑制作用 T细胞活性，我们进行了广泛的共培养研究，其中CVI 将T细胞与正常T细胞预先孵育，并对后者进行检测 它们产生淋巴因子和帮助B细胞免疫球蛋白的能力 制作。研究发现，用CVIB预培养的正常T细胞 细胞而不是正常的B细胞产生的辅助T细胞显著减少 活动。因此，这些研究定义了一个功能结果 过早表达B7-1。此外，他们解释了这样一个事实：T CVI患者的细胞已被证明存在过度抑制 功能。 上述对CVI中B7表达的研究有力地提示了 B细胞信号缺陷。因此，我们开始了一项系统化的 寻找CVI中的信号异常并表明CVI B细胞 MAP-Kinase和Stat-1显示正常水平。

Studies on our laboratory have focused on defining the nature of the B cell and T cell defects in Common Variable Immunodeficiency (CVI), a primary acquired human immunodeficiency state characterized by hypogammaglobulinemia and impaired functional antibody responses. Previous studies of purified B cells of patients with CVI show that although the cells have a normal capacity to proliferate, they manifest differentiation defects at multiple levels. Thus, as compared with normal B cells, circulating CVI B cells contain reduced numbers of sIgG+ and sIgA+ cells with a commensurate increase in sIgM+ B cells, suggesting an in vivo defect in isotype switch. In addition, they fail to undergo differentiation into immunoglobulin-producing cells. In the present study, we show that CVI B manifest an abnormality of surface B7 expression associated with the capacity to induce normal T cells to manifest suppression cell capacity. In particular, positively-selected CVI B cells (i.e., cells exposed to anti-CD19 antibody) when subsequently activated with anti-IgM manifest premature expression of B7-1 followed by decreased expression of B7-2. Since B7-1 through its interaction with CTLA-4 on T cells acts as a suppressor of T cell activity, we performed extensive co-culture studies in which CVI T cells were pre-incubated with normal T cells and the latter were tested for their capacity to produce lymphokines and to help B cell Ig production. It was found that normal T cells pre-cultured with CVI B cells but not normal B cells exerted greatly decreased helper T cell activity. These studies thus define a functional consequence of premature B7-1 expression. In addition, they explain the fact that T cells in CVI patients have been shown to manifest excessive suppressor function. The above studies of B7 expression in CVI strongly suggest the presence of a B cell signaling defect. We have therefore begun a systematic search for a signaling abnormality in CVI and have shown that CVI B cells manifest normal levels of MAP Kinase and Stat 1.