Characterization of the Role of Bruton`s Tyrosine Kinase (BTK) for Myeloid Cell Function in Mouse and Man

Bruton‘s Tyroine Kinase(BTK)基因突变导致人类X连锁无丙种球蛋白血症(XLA)，其特征是血液中几乎完全没有成熟的B细胞，伴随着免疫球蛋白的缺乏，因此对反复细菌感染具有很高的易感性。最近的一项研究表明，201名患有XLA的患者中，只有26%的人年龄在21岁或以上。然而，BTK不仅在B细胞中表达，而且在包括髓系细胞在内的其他造血细胞中也表达，但BTK对XLA髓系细胞功能的影响仍存在争议。最近，我们发现BTK缺陷的中性粒细胞在小鼠体内发生了严重的成熟和功能缺陷。为了更深入地了解BTK在髓系间室中的作用，我们建议采用新的尝试和方法。利用一线主要依赖髓系细胞作用的体内实验小鼠模型，如实验性自身免疫性脑脊髓炎(EAE)或创伤愈合模型，或BTK表达或功能下调的人髓系细胞，以及呈现BTK表达下调的人造血细胞的“人源化小鼠”，我们期待的结果将包含我们对BTK/BTK在小鼠和人的髓系细胞发育和功能中所起作用的了解。最后，这些结果可能会改变我们对XLA发病机制的理解，以及对受影响患者的治疗方法。

Mutations within the gene coding for Bruton’s Tyrosine Kinase (BTK) cause X-linked agammaglobulinemia (XLA) in man, which is characterized by the almost complete absence of mature B cells within the circulation accompanied by the lack of immunoglobulins and therefore by a high susceptibility to recurrent bacterial infections. A recent study revealed that only 26% of 201 patients suffering from XLA were aged 21 years or older. However, BTK is expressed not exclusively in B cells but also in other hematopoietic cells including cells of the myeloid lineage but the impact of BTK to the function of XLA myeloid cells is discussed controversial. Recently, we have shown a profound maturation and functional defect of Btk-deficient neutrophilic granulocytes in mice. To get more insight into the role of BTK for the myeloid compartment we suggest here new attempts and approaches. Using in vivo experimental mouse models depending in a first line mainly on the action of myeloid cells, like the experimental autoimmune encephalomyelitis (EAE) or wound healing models, or human myeloid cells in which BTK expression or function will be down-modulated, and also “humanized mice” presenting human hematopoietic cells in which BTK expression will be knocked-down, we expect results that engross our knowledge about the role of Btk/BTK for myeloid cell development and function in mouse and man. Finally, these results may alter our understanding about the pathogenesis of XLA as well as therapy approaches for treatment of affected patients.