Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40

Wasif Khan, Anna Nilsson, Emiko Mizoguchi, Emanuella Castigli, Johan Forsell, Atul K. Bhan, Raif Geha, Paschalis Sideras, Frederick W. Alt

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Abstract

Mutations in Bruton's tyrosine kinase (Btk) gene, in mice, result in reduced numbers and responses of peripheral B cells. Surface Ig-mediated signaling is defective in Btk mutant B cells as they do not proliferate upon sIg cross-linking and lack thymus-independent (TI) type II responses. Signals through sIg and CD40 play a critical role in B cell maturation, To investigate the consequences of the lack of both Btk and CD40 on a cell development and function, mice were generated that were homozygous for targeted mutations in the Btk and the CD40 genes (Btk(M)CD40(M)). The CD40 mutation (CD40(M)) had a synergistic effect on the Btk(M) defects. In Btk(M)CD40(M) mice the number of a cells was reduced 3- to 4-fold compared to Btk(M) mice and mature B cells (IgM(low)/IgD(high)) were virtually absent; serum levels of all Ig isotypes were diminished; and antibody responses to TI-I, TI-II and thymus-dependent antigens were impaired. Furthermore, although wild-type Btk(M) and CD40(M) mice produced germinal centers in response to TI-I antigen, the Btk(M)CD40(M) mice did not. Maturational and functional B cell defects in Btk(M)CD40(M) mice may result from a combination of intrinsic B cell defects, lack of CD40L-dependent T cell help and microenvironmental defects. These data suggest that signals through Btk and CD40 are necessary for the production and maintenance of the mature B cell.

Original languageEnglish
Pages (from-to)395-405
Number of pages11
JournalInternational Immunology
Volume9
Issue number3
DOIs
StatePublished - Mar 22 1997
Externally publishedYes

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Keywords

  • CD40
  • CD40L (gp39)
  • Germinal center
  • Immature B cells
  • Immune response
  • Mature B cells
  • Surface Ig
  • Thymus dependent
  • Thymus independent
  • X-linked agammaglobulinemia
  • X-linked immunodeficiency

ASJC Scopus subject areas

  • Immunology

Cite this

Khan, W., Nilsson, A., Mizoguchi, E., Castigli, E., Forsell, J., Bhan, A. K., Geha, R., Sideras, P., & Alt, F. W. (1997). Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40. International Immunology, 9(3), 395-405. https://doi.org/10.1093/intimm/9.3.395