CORRECTION OF THE X-LINKED IMMUNODEFICIENCY PHENOTYPE BY TRANSGENIC EXPRESSION OF HUMAN BRUTON TYROSINE KINASE UNDER THE CONTROL OF THE CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX EA LOCUS-CONTROL REGION

Bruton tyrosine kinase (Btk) is essential for the development of pre-B cells to mature B cell stages. Btk-deficient mice manifest an X-linke d immunodeficiency (xid) defect characterized by a reduction of periph eral IgM(low) IgD(high) B cells, a lack of peritoneal CD5(+) B cells, low serum levels of IgM and IgG3, and impaired responses to T cell ind ependent type II (TI-II) antigens, We have generated transgenic mice i n which expression of the human Btk gene is driven by the murine class II major histocompatibility complex Ea gene locus control region, whi ch provides gene expression from the pre-B cell stage onwards. When th ese transgenic mice were mated onto a Btk(-) background, correction of the xid B cell defects was observed: B cells differentiated to mature IgM(low)IgD(high) stages, peritoneal CD5(+) B cells were present, and serum Ig levels and in vivo responses to TI-II antigens were in the n ormal ranges. A comparable rescue by transgenic Btk expression was als o observed in heterozygous Btk(+/-) female mice in those B-lineage cel ls that were Btk-deficient as a result of X chromosome inactivation. T hese findings indicate that the Btk(-) phenotype in the mouse can be c orrected by expression of human Btk from the pre-B cell stage onwards.