title: Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40.
abstract: Mutations in Bruton's tyrosine kinase (Btk) gene, in mice, result in reduced numbers and responses of peripheral B cells. Surface Ig-mediated signaling is defective in Btk mutant B cells as they do not proliferate upon slg cross-linking and lack thymus-independent (TI) type II responses. Signals through sIg and CD40 play a critical role in B cell maturation. To investigate the consequences of the lack of both Btk and CD40 on B cell development and function, mice were generated that were homozygous for targeted mutations in the Btk and the CD40 genes (BtkMCD40M). The CD40 mutation (CD40M) had a synergistic effect on the BtkM defects. In BtkMCD40M mice the number of B cells was reduced 3- to 4-fold compared to BtkM mice and mature B cells (IgMlow/IgDhigh) were virtually absent; serum levels of all Ig isotypes were diminished; and antibody responses to TI-I TI-II and thymus-dependent antigens were impaired. Furthermore, although wild-type BtkM and CD40M mice produced germinal centers in response to TI-I antigen, the BtkMCD40M mice did not. Maturational and functional B cell defects in BtkMCD40M mice may result from a combination of intrinsic B cell defects, lack of CD40L-dependent T cell help and microenvironmental defects. These data suggest that signals through Btk and CD40 are necessary for the production and maintenance of the mature B cell.
authors.affiliation: Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: W N
authors.initials: WN
authors.lastname: Khan
authors.forename: A
authors.initials: A
authors.lastname: Nilsson
authors.forename: E
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: E
authors.initials: E
authors.lastname: Castigli
authors.forename: J
authors.initials: J
authors.lastname: Forsell
authors.forename: A K
authors.initials: AK
authors.lastname: Bhan
authors.forename: R
authors.initials: R
authors.lastname: Geha
authors.forename: P
authors.initials: P
authors.lastname: Sideras
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D005260:Female; D005838:Genotype; D006410:Hematopoiesis; D007114:Immunization; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction
chemical_list: D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse