title: Early arrest in B cell development in transgenic mice that express the E41K Bruton's tyrosine kinase mutant under the control of the CD19 promoter region.
abstract: Bruton's tyrosine kinase (Btk) is a nonreceptor protein kinase that is defective in X-linked agammaglobulinemia in humans and in X-linked immunodeficiency in mice. To study the effect of Btk activation in early B cell development in vivo, we have created transgenic mouse strains expressing Btk under the control of the human CD19 promoter region. The transgenic expression of wild-type human Btk corrected all X-linked immunodeficiency features in mice carrying a targeted disruption of the Btk gene. In contrast, expression of an activated form of Btk, the E41K mutant, resulted in an almost complete arrest of B cell development in the immature IgM+IgD- B cell stage in the bone marrow, irrespective of the presence of the endogenous intact Btk gene. Immature B cells were arrested at the progression from IgMlow into IgMhigh cells, which reflects the first immune tolerance checkpoint at which autoreactive B cells become susceptible to apoptosis. As the constitutive activation of Btk is likely to mimic B cell receptor occupancy by autoantigens in the bone marrow, our findings are consistent with a role for Btk as a mediator of B cell receptor-induced apoptotic signals in the immature B cell stage. Whereas the peripheral mature B cell pool was reduced to <1% of the normal size, significant numbers of IgM-secreting plasma cells were present in the spleen. Serum IgM levels were substantial and increased with age, but specific Ab responses in vivo were lacking. We conclude that the residual peripheral B cells were efficiently driven into IgM+ plasma cell differentiation, apparently without functional selection.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Maas
authors.forename: G M
authors.initials: GM
authors.lastname: Dingjan
authors.forename: F
authors.initials: F
authors.lastname: Grosveld
authors.forename: R W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000097:blood / Q000235:genetics; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D016130:Immunophenotyping; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008239:Lysine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000473:pathology; D017354:Point Mutation / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D019076:Transgenes / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018698:Glutamic Acid; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D008239:Lysine