Btk dosage determines sensitivity to B cell antigen receptor cross- linking

A. B. Satterthwaite, H. Cheroutre, Wasif Khan, P. Sideras, O. N. Witte

Research output: Contribution to journalArticle

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Abstract

Mutations in Btk result in the B cell immunodeficiencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Btk is a critical component of signaling pathways regulating B cell development and function. We used a genetic approach to determine whether Btk is also limiting for these processes. One allele of a murine Btk transgene expressed a dosage of Btk (25% of endogenous levels in splenic B cells) sufficient to restore normal numbers of phenotypically mature conventional B cells in xid mice. 2,4,6-trinitrophenyl-Ficoll response, anti-IgM-induced proliferation, B1 cell development, and serum IgM and IgG3 levels remained significantly impaired in these animals. B cells from Btk -/- transgenic mice also responded poorly to anti-IgM, indicating that the xid mutation does not create a dominant negative form of Btk. Response to 2,4,6-trinitrophenyl- Ficoll and B cell receptor cross-linking were increased 3- to 4-fold in xid mice homozygous for the transgene. These results demonstrate that Btk is a limiting component of B cell antigen receptor signaling pathways and suggest that B cell development and response to antigen may require different levels of Btk activity.

Original languageEnglish
Pages (from-to)13152-13157
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number24
DOIs
StatePublished - Dec 16 1997
Externally publishedYes

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B-Cell Antigen Receptors
B-Lymphocytes
Ficoll
Transgenes
Mutation
Transgenic Mice
Immunoglobulin M
Immunoglobulin G
Alleles
Cell Proliferation
Antigens
Serum

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Btk dosage determines sensitivity to B cell antigen receptor cross- linking. / Satterthwaite, A. B.; Cheroutre, H.; Khan, Wasif; Sideras, P.; Witte, O. N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 24, 16.12.1997, p. 13152-13157.

Research output: Contribution to journalArticle

Satterthwaite, A. B. ; Cheroutre, H. ; Khan, Wasif ; Sideras, P. ; Witte, O. N. / Btk dosage determines sensitivity to B cell antigen receptor cross- linking. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 24. pp. 13152-13157.
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