Genetic interaction between Lyn, Ets1, and Btk in the control of antibody levels

Jessica Mayeux, Brian Skaug, Wei Luo, Lisa M. Russell, Shinu John, Prontip Saelee, Hansaa Abbasi, Quan Zhen Li, Lee Ann Garrett-Sinha, Anne B. Satterthwaite

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The Ets1 transcription factor acts in B cells to prevent PC differentiation. Ets1<sup>-/-</sup> mice accumulate PCs and produce autoantibodies. Ets1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, Ets1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoantibodies, and an autoimmune phenotype similar to that of Ets1<sup>-/-</sup> mice. Defects in inhibitory signaling molecules, including Lyn and Ets1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. In this study, we explore the effect of partial disruption of the Lyn/Ets1 pathway on B cell tolerance and find that Lyn<sup>+/-</sup>Ets1<sup>+/-</sup> mice demonstrate greater and earlier production of IgM, but not IgG, autoantibodies compared with Lyn<sup>+/-</sup> or Ets1<sup>+/-</sup> mice.We also show that Btk-dependent downregulation of Ets1 is important for normal PC homeostasis when inhibitory signaling is intact. Ets1 deficiency restores the decrease in steady state PCs and Ab levels observed in Btk<sup>-/-</sup> mice. Thus, depending on the balance of activating and inhibitory signals to Ets1, there is a continuum of effects on autoantibody production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of Ets1-maintaining signals to reduced PC and Ab levels with impaired Ets1 down-regulation.

Original languageEnglish (US)
Pages (from-to)1955-1963
Number of pages9
JournalJournal of Immunology
Volume195
Issue number5
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Immunology

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    Mayeux, J., Skaug, B., Luo, W., Russell, L. M., John, S., Saelee, P., Abbasi, H., Li, Q. Z., Garrett-Sinha, L. A., & Satterthwaite, A. B. (2015). Genetic interaction between Lyn, Ets1, and Btk in the control of antibody levels. Journal of Immunology, 195(5), 1955-1963. https://doi.org/10.4049/jimmunol.1500165