Defective B cell development and function in Btk-deficient mice

Wasif N. Khan, Frederick W. Alt, Rachel M. Gerstein, Barbara A. Malynn, Irene Larsson, Gary Rathbun, Laurie Davidson, Sussane Müller, Aaron B. Kantor, Leonora A. Herzenberg, Fred S. Rosen, Paschalis Sideras

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Abstract

Mutations in the Bruton's tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammaglobulinemia (XLA), and to milder B cell activation deficiencies in murine X-linked immune deficiency (Xid). To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin homology or kinase domains, and assayed their effects by RAG2-deficient blastocyst complementation or introduction into the germline. Both mutations block expression of Btk protein and lead to reduced numbers of mature conventional B cells, severe B1 cell deficiency, serum IgM and IgG3 deficiency, and defective responses in vitro to various B cell activators and in vivo to immunization with thymus-independent type II antigens. These results prove that lack of Btk function results in an Xid phenotype and further suggest a differential requirement for Btk during the early stages of murine versus human B lymphocyte development.

Original languageEnglish (US)
Pages (from-to)283-299
Number of pages17
JournalImmunity
Volume3
Issue number3
DOIs
StatePublished - Sep 1995
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Khan, W. N., Alt, F. W., Gerstein, R. M., Malynn, B. A., Larsson, I., Rathbun, G., Davidson, L., Müller, S., Kantor, A. B., Herzenberg, L. A., Rosen, F. S., & Sideras, P. (1995). Defective B cell development and function in Btk-deficient mice. Immunity, 3(3), 283-299. https://doi.org/10.1016/1074-7613(95)90114-0