Early arrest in B cell development in transgenic mice that express the E41K Bruton's tyrosine kinase mutant under the control of the CD19 promoter region

Bruton's tyrosine kinase (Btk) is a nonreceptor protein kinase that is defe ctive in X-linked agammaglobulinemia in humans and in X-linked immunodefici ency in mice. To study the effect of Btk activation in early B cell develop ment in vivo, we have created transgenic mouse strains expressing Btk under the control of the human CD19 promoter region. The transgenic expression o f; wild-type human Btk corrected all X-linked immunodeficiency features in mice carrying a targeted disruption of the Btk gene. In contrast, expressio n of an activated form of Btk, the E41K mutant, resulted in an almost compl ete arrest of B cell development in the immature IgM(+)IgD(-) B cell stage in the bone marrow, irrespective of the presence of the endogenous intact B tk gene. Immature B cells were arrested at the progression from IgM(low) in to IgM(high) cells, which reflects the first immune tolerance checkpoint at which autoreactive B cells become susceptible to apoptosis. As the constit utive activation of Btk is likely to mimic B cell receptor occupancy by aut oantigens in the bone marrow, our findings are consistent with a role for B tk as a mediator of B cell receptor-induced apoptotic signals in the immatu re B cell stage. Whereas the peripheral mature B cell pool was reduced to < 1% of the normal size, significant numbers of IgM-secreting plasma cells we re present in the spleen. Serum IgM levels were substantial and increased w ith age, but specific Ab responses in vivo were lacking, We conclude that t he residual peripheral B cells were efficiently driven into IgM(+) plasma c ell differentiation, apparently without functional selection.