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  • The EMBO Journal (1998) 17, 5309 - 5320
  • doi:10.1093/emboj/17.18.5309

Severe B cell deficiency and disrupted splenic architecture in transgenic mice expressing the E41K mutated form of Bruton's tyrosine kinase

Gemma M. Dingjan1,2, Alex Maas1, Martijn C. Nawijn2, Linda Smit3, Jane S.A. Voerman2, Frank Grosveld1 and Rudolf W. Hendriks1

  1. Department of Cell Biology and Genetics Faculty of Medicine, Erasmus University Rotterdam, Dr Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
  2. Department of Immunology, Faculty of Medicine, Erasmus University Rotterdam, Dr Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
  3. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Correspondence to:

Rudolf W. Hendriks, E-mail: hendriks@ch1.fgg.eur.nl

Received 14 April 1998; Accepted 15 July 1998; Revised 12 June 1998

To identify B-cell signaling pathways activated by Bruton's tyrosine kinase (Btk) in vivo, we generated transgenic mice in which Btk expression is driven by the MHC class II Ea gene locus control region. Btk overexpression did not have significant adverse effects on B cell function, and essentially corrected the X-linked immunodeficiency (xid) phenotype in Btk- mice. In contrast, expression of a constitutively activated form of Btk carrying the E41K gain-of-function mutation resulted in a B cell defect that was more severe than xid. The mice showed a marked reduction of the B cell compartment in spleen, lymph nodes, peripheral blood and peritoneal cavity. The levels in the serum of most immunoglobulin subclasses decreased with age, and B cell responses to both T cell-independent type II and T cell-dependent antigens were essentially absent. Expression of the E41K Btk mutant enhanced blast formation of splenic B cells in vitro in response to anti-IgM stimulation. Furthermore, the mice manifested a disorganization of B cell areas and marginal zones in the spleen. Our findings demonstrate that expression of constitutively activated Btk blocks the development of follicular recirculating B cells.

  • Keywords:

    • B cell antigen receptor,
    • B lymphocytes,
    • Btk,
    • xid,
    • XLA