title: Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.
abstract: On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.
authors.affiliation: Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Kil
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Menno
authors.initials: M
authors.lastname: van Nimwegen
authors.forename: Odilia B J
authors.initials: OB
authors.lastname: Corneth
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Dingjan
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Dianne
authors.initials: D
authors.lastname: Delsing
authors.forename: Pieter Fokko
authors.initials: PF
authors.lastname: van Loo
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D010880:Piperidines; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000225:Adenine