title: Defective B cell development and function in Btk-deficient mice.
abstract: Mutations in the Bruton's tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammaglobulinemia (XLA), and to milder B cell activation deficiencies in murine X-linked immune deficiency (Xid). To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocyst complementation or introduction into the germline. Both mutations block expression of Btk protein and lead to reduced numbers of mature conventional B cells, severe B1 cell deficiency, serum IgM and IgG3 deficiency, and defective responses in vitro to various B cell activators and in vivo to immunization with thymus-independent type II antigens. These results prove that lack of Btk function results in an Xid phenotype and further suggest a differential requirement for Btk during the early stages of murine versus human B lymphocyte development.
authors.affiliation: Howard Hughes Medical Institute, Childrens Hospital, Boston, Massachusetts 02115, USA.
authors.forename: W N
authors.initials: WN
authors.lastname: Khan
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
authors.forename: R M
authors.initials: RM
authors.lastname: Gerstein
authors.forename: B A
authors.initials: BA
authors.lastname: Malynn
authors.forename: I
authors.initials: I
authors.lastname: Larsson
authors.forename: G
authors.initials: G
authors.lastname: Rathbun
authors.forename: L
authors.initials: L
authors.lastname: Davidson
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.forename: A B
authors.initials: AB
authors.lastname: Kantor
authors.forename: L A
authors.initials: LA
authors.lastname: Herzenberg
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000502:physiology; D011817:Rabbits
chemical_list: D007136:Immunoglobulins; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse