Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice

Lindsey R. Whyburn, Kristina E. Halcomb, Cristina M. Contreras, Clifford A. Lowell, Owen N. Witte, Anne B. Satterthwaite

Research output: Contribution to journalArticle

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Abstract

The development of autoimmunity is correlated with heightened sensitivity of B cells to B cell Ag receptor (BCR) cross-linking. BCR signals are down-regulated by Lyn, which phosphorylates inhibitory receptors. lyn -/- mice have reduced BCR signaling thresholds and develop autoantibodies, glomerulonephritis, splenomegaly due to myeloid hyperplasia, and increased B-1 cell numbers. Bruton's tyrosine kinase (Btk), a critical component of BCR signaling pathways, is required for autoantibody production in lyn-/- mice. It is unclear whether Btk mediates autoimmunity at the level of BCR signal transduction or B cell development, given that lyn -/-Btk-/- mice have a severe reduction in conventional B and B-1 cell numbers. To address this issue, we crossed a transgene expressing a low dosage of Btk (Btklow) in B cells to lyn-/-Btk -/- mice. Conventional B cell populations were restored to levels similar to those in lyn-/- mice. These cells were as hypersensitive to BCR cross-linking as lyn-/- B cells as measured by proliferation, Ca2+ flux, and activation of extracellular signal-regulated kinase and Akt. However, lyn-/-Btklow mice did not produce anti-ssDNA, anti-dsDNA, anti-histone, or anti-histone/DNA IgM or IgG. They also lacked B-1 cells and did not exhibit splenomegaly. Thus, B cell hyperresponsiveness is insufficient for autoimmunity in lyn-/- mice. These studies implicate B-1 and/or myeloid cells as key contributors to the lyn-/- autoimmune phenotype.

Original languageEnglish (US)
Pages (from-to)1850-1858
Number of pages9
JournalJournal of Immunology
Volume171
Issue number4
StatePublished - Aug 15 2003

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Autoimmunity
B-Lymphocytes
Splenomegaly
Autoantibodies
Histones
Agammaglobulinaemia tyrosine kinase
Cell Count
Extracellular Signal-Regulated MAP Kinases
Myeloid Cells
Glomerulonephritis
Transgenes
Hyperplasia
Immunoglobulin M
Signal Transduction
Immunoglobulin G
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Whyburn, L. R., Halcomb, K. E., Contreras, C. M., Lowell, C. A., Witte, O. N., & Satterthwaite, A. B. (2003). Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. Journal of Immunology, 171(4), 1850-1858.

Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. / Whyburn, Lindsey R.; Halcomb, Kristina E.; Contreras, Cristina M.; Lowell, Clifford A.; Witte, Owen N.; Satterthwaite, Anne B.

In: Journal of Immunology, Vol. 171, No. 4, 15.08.2003, p. 1850-1858.

Research output: Contribution to journalArticle

Whyburn, LR, Halcomb, KE, Contreras, CM, Lowell, CA, Witte, ON & Satterthwaite, AB 2003, 'Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice', Journal of Immunology, vol. 171, no. 4, pp. 1850-1858.
Whyburn, Lindsey R. ; Halcomb, Kristina E. ; Contreras, Cristina M. ; Lowell, Clifford A. ; Witte, Owen N. ; Satterthwaite, Anne B. / Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. In: Journal of Immunology. 2003 ; Vol. 171, No. 4. pp. 1850-1858.
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