Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice

• Published in: Blood Vol. 119; no. 16; pp. 3744 - 3756
• Main Authors: Kil, Laurens P., de Bruijn, Marjolein J.W., van Nimwegen, Menno, Corneth, Odilia B.J., van Hamburg, Jan Piet, Dingjan, Gemma M., Thaiss, Friedrich, Rimmelzwaan, Guus F., Elewaut, Dirk, Delsing, Dianne, van Loo, Pieter Fokko, Hendriks, Rudi W.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 19.04.2012; Americain Society of Hematology
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Autoimmunity - immunology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Biological and medical sciences; Cell Lineage - immunology; Gene Expression - immunology; Germinal Center - cytology; Germinal Center - immunology; Hematologic and hematopoietic diseases; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymphocyte Activation - immunology; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells - cytology; Myeloid Cells - immunology; Plasma Cells - cytology; Plasma Cells - immunology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - immunology; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Vertebrata; Bruton tyrosine kinase; Mammalia; Hematology; Mouse; Animal; Rodentia; B-Lymphocyte; Negative selection; Autoreactive cell; Threshold
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-12-397919

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 Ca2+ 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.