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J Exp Med. 2016 May 2;213(5):751-69. doi: 10.1084/jem.20150537. Epub 2016 Apr 25.

Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells.

Author information

1
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
2
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
3
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206 John.Cambier@ucdenver.edu.

Abstract

Many autoreactive B cells persist in the periphery in a state of unresponsiveness called anergy. This unresponsiveness is rapidly reversible, requiring continuous BCR interaction with self-antigen and resultant regulatory signaling for its maintenance. Using adoptive transfer of anergic B cells with subsequent acute induction of gene deletion or expression, we demonstrate that the continuous activities of independent inhibitory signaling pathways involving the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain anergy. Acute breach of anergy by compromise of either of these pathways leads to rapid cell activation, proliferation, and generation of short-lived plasma cells that reside in extrafollicular foci. Results are consistent with predicted/observed reduction in the Lyn-SHIP-1-PTEN-SHP-1 axis function in B cells from systemic lupus erythematosus patients.

PMID:
27114609
PMCID:
PMC4854724
DOI:
10.1084/jem.20150537
[Indexed for MEDLINE]
Free PMC Article

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