A Btk transgene restores the antiviral Tl-2 antibody responses of xid micein a dose-dependent fashion

X-linked agammaglobulinemia in humans and X-linked immunodeficiency (xid) i n mice are both caused by mutations in Bruton's tyrosine kinase (Btk). Xid mice lack the early T cell-independent type 2 (Tl-2) antibody response to p olio virus and to a recombinant vaccinia virus (Vacc-IND-G) expressing the neutralizing determinant of vesicular stomatitis virus (VSV). This response could be restored by introduction of one or two copies of a murine Btk cDN A transgene driven by the Ig heavy chain promoter plus enhancer and depende d crucially on a sufficient Btk expression level. Introduction of the same transgene into wild-type mice had little to no negative effect. The Tl-1 an tibody response to VSV and the T cell-dependent response to lymphocytic cho riomeningitis virus were comparable in all mice tested. All mice analyzed e ventually reached similar primary and memory antibody titers against all vi ruses independent of the mouse Btk genotype. These studies show that the ri d mutation in mice has no dominant negative effect and that a transgene - e ven when not provided in the natural genetic context - may be able to resto re functional defects resulting from genetic mutation.