Study on rapid diagnosis and B cell defect of X-linked agammaglobulinemia

X-连锁无丙种球蛋白血症(XLA)是一种相对常见的免疫缺陷性疾病，其特征是外周血B细胞稀少，血清免疫球蛋白水平显著降低，并在婴儿早期发生严重的细菌感染。1993年，XLA的致病基因被确定为Bruton酪氨酸激酶(BTK)，它在B细胞活化和早期B细胞分化中起关键作用。国际上对XLA患者和携带者的检测是通过展示BTK突变来进行的。本研究建立了一种临床实用、简便的XLA及其携带者鉴定方法，结合BTK基因分析，寻找XLA在日本的分布，阐明XLA的临床变异性。此外，我们还试图了解BTK在XLA中的一些致病意义。主要研究结果如下：1)在单核细胞中表达Btk，我们发现…此外，使用抗BTK单抗的流式细胞仪分析可以方便、快速地检测出XLA及其携带者。2)通过使用流式细胞仪和遗传分析，我们新发现了65例XLA，从而我们确认了日本共有100个XLA家系。3)不典型的XLA病例，其血清IgG正常范围或成人起病，4)日本免疫缺陷登记处的调查表明，许多无家族史的XLA病例经常被误诊为CVID。5)首次使用抗VpreB单抗对XLA的骨髓进行检测表明，XLA的遗传缺陷可能阻碍了前B细胞在B细胞分化途径中成熟进化到前B细胞的后期。6)研究表明，中性粒细胞减少症偶尔与XLA有关，BTK可能通过产生某些细胞因子参与单核/巨噬细胞在中性粒细胞生成中的基本功能。较少

X-linked agammaglobulinemia (XLA), a relatively common immunodeficieny disorder, is characterized by the paucity of peripheral blood B cells, markedly reduced levels of serum immunoglobulins, and the occurrence of severe bacterial infection during the early period of infancy. In 1993, the causative gene for XLA has been identified as Bruton's tyrosine kinase (Btk), which plays a pivotal role in B cell activation and early B cell differentiation. The detection of XLA patients and carriers has been performed by demonstration of Btk mutations internationally. In the present study, we developed the clinically useful and simple method for identification of XLA and its carrier, searched for the distribution of XLA in Japan by the combined use with Btk genetic analysis, and elucidated clinical variability of XLA. In addition, we attempted to learn some of the pathogenic significance of Btk in XLA. The results obtained here are as follows :1) Employing Btk expression in monocytes, we showed th … More at a flow cytometric analysis using anti-Btk monoclonal antibody could detect easily and rapidly XLA and its carrier.2) By the use of both flow cytometric and genetic analyses, we newly identified 65 cases with XLA, resulting in our confirmation of totally 100 families with XLA in Japan.3) Atypical cases with XLA, who showed the normal range of serum IgG or the adult onset, were discovered.4) Investigation of Japanese Immunodeficiency Registry presented the possibility that a number of XLA cases without family history often misdiagnosed as CVID.5) Examination of bone marrow from XLA using anti-VpreB monoclonal antibody for the first time demonstrated that the genetic defect in XLA might impede the maturational evolution of pro-B cells into the later stage of pre-B cells in B cell differentiation pathway.6) It was demonstrated that neutropenia was occasionally associated with XLA, and Btk was possibly involved for the essential function of monocytes/macrophages in neutropoiesis through production of some cytokines. Less