Study on rapid diagnosis of primary immunodeficiency diseases and their abnormalities in immunologic development

在原发性免疫缺陷疾病及其免疫发育异常的快速诊断方面，我们进行了以下研究：1)利用流式细胞术和遗传分析对x -连锁γ -球蛋白血症（XLA）进行全国调查；2)利用生成针对XLP致病产物SAP的单克隆抗体建立x -连锁淋巴细胞增生性综合征（XLP）的流式细胞术快速诊断；4) xla致病产物BTK的功能分析；5)原发性免疫缺陷疾病的临床和遗传特征。这里得到的结果如下。1)基于流式细胞术与遗传分析相结合鉴定的100多例XLA病例的数据，我们展示了日本XLA的临床和突变特征。我们发现了第一例女性XLA，这是由女性XLA携带者的正常x染色体偏斜失活引起的。2)我们首次通过基因分析证实了XLP患者的存在。3)在土耳其、韩国、巴西、伊朗和中国开展了原发性免疫缺陷疾病（尤其是XLP）遗传诊断的国际合作。4)我们发现xla致病产物BTK在B细胞活化的信号转导中起关键作用。此外，我们发现XLP衍生的树突状细胞的细胞因子产生与正常人相当，但来自XLP患者的单核细胞在吞噬和趋化能力方面存在缺陷。5)我们报道了一些原发性免疫缺陷疾病的临床重要病例。我们还研究了从未接受过基因分析的低丙种球蛋白血症成年患者。结果，我们发现了几个病例在导致原发性免疫缺陷疾病的致病基因中存在突变。少

Regarding rapid diagnosis of primary immunodeficiency diseases and their abnormalities in immunologic development, we have studied on 1)nation-survey of X-linked qgammaglobulinemia(XLA) by flow cytometric assay and genetic analysis, 2)establishment of flow cytometric rapid diagnosis of X-linked lymphoproliferative syndrome(XLP) by generation of a monoclonal antibody against XLP-causative product SAP, 3)international collaboration of genetic diagnosis of primary immunodeficiency diseases, 4)functional analysis of XLA-causative product BTK, 5)clinical and genetic characteristics of primary immunodeficiency diseases. The results obtained here are as follows.1)We demonstrated clinical and mutational features of XLA in Japan, on the basis of data obtained from more than 100 cases of XLA identified by a combined use of flow cytometric assay with genetic analysis. We identified the first case of female XLA, who was caused by skewed inactivation of normal X-chromosome in the female XLA carrier … More .2)We for the first time demonstrated the presence of patients with XLP by a genetic analysis. We newly generated anti-SAP monoclonal antibody, and confirmed its possible use in flow cytometric rapid diagnosis of XLP.3)We conducted international collaboration of genetic diagnosis of primary immunodeficiency diseases, especially of XLP, in Turkey, Korea, Brazil, Iran and China.4)We showed that XLA-causative product BTK play a critical role for signal transduction in activation of B cells. In addition, we found that cytokine production of XLP-derived dendritic cells was comparable to that in normals, but monocytes from XLP patients were deficient regarding their phagocytic and chemotactic capabilities.5)We reported clinically important cases with some primary immunodeficiency diseases. We also searched for adult patients with hypogammaglobulinemia, who had never received genetic analysis. As a result, we found several cases harboring mutations in the causative genes responsible for primary immunodeficiency diseases. Less