A Btk transgene restores the antiviral TI-2 antibody responses of xid mice in a dose-dependent fashion.
X-linked agammaglobulinemia in humans and X-linked immunodeficiency (xid) in mice are both caused by mutations in Bruton's tyrosine kinase (Btk). Xid mice lack the early T cell-independent type 2 (TI-2) antibody response to polio 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 cDNA transgene driven by the Ig heavy chain promoter plus enhancer and depended crucially on a sufficient Btk expression level. Introduction of the same transgene into wild-type mice had little to no negative effect. The TI-1 antibody response to VSV and the T cell-dependent response to lymphocytic choriomeningitis virus were comparable in all mice tested. All mice analyzed eventually reached similar primary and memory antibody titers against all viruses independent of the mouse Btk genotype. These studies show that the xid mutation in mice has no dominant negative effect and that a transgene - even when not provided in the natural genetic context - may be able to restore functional defects resulting from genetic mutation.
Pinschewer
D D
DD
Institute of Experimental Immunology Department of Pathology, University Hospital of Zürich, Zürich, Switzerland.
Ochsenbein
A F
AF
Satterthwaite
A B
AB
Witte
O N
ON
Hengartner
H
H
Zinkernagel
R M
RM
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D019076:Transgenes / Q000276:immunology*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D004279:DNA, Viral; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse