title: Btk dosage determines sensitivity to B cell antigen receptor cross-linking.
abstract: Mutations in Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Btk is a critical component of signaling pathways regulating B cell development and function. We used a genetic approach to determine whether Btk is also limiting for these processes. One allele of a murine Btk transgene expressed a dosage of Btk (25% of endogenous levels in splenic B cells) sufficient to restore normal numbers of phenotypically mature conventional B cells in xid mice. 2,4,6-trinitrophenyl-Ficoll response, anti-IgM-induced proliferation, B1 cell development, and serum IgM and IgG3 levels remained significantly impaired in these animals. B cells from Btk -/- transgenic mice also responded poorly to anti-IgM, indicating that the xid mutation does not create a dominant negative form of Btk. Response to 2,4,6-trinitrophenyl-Ficoll and B cell receptor cross-linking were increased 3- to 4-fold in xid mice homozygous for the transgene. These results demonstrate that Btk is a limiting component of B cell antigen receptor signaling pathways and suggest that B cell development and response to antigen may require different levels of Btk activity.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Satterthwaite
authors.forename: H
authors.initials: H
authors.lastname: Cheroutre
authors.forename: W N
authors.initials: WN
authors.lastname: Khan
authors.forename: P
authors.initials: P
authors.lastname: Sideras
authors.forename: O N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D005434:Flow Cytometry; D018628:Gene Dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes
chemical_list: D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse