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J Exp Med. 2015 Sep 21;212(10):1663-77. doi: 10.1084/jem.20150585. Epub 2015 Sep 14.

Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome.

Author information

1
Department of Immunology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195.
2
Department of Immunology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195 Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
4
Molecular Immunology Unit, Section of Molecular and Cellular Immunology, Centre for Immunodeficiency, University College London Institute of Child Health, London WC1N 1EH, England, UK.
5
Department of Immunology, Children's Hospital Boston, Boston, MA 09210.
6
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
7
Lowance Center for Human Immunology and Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322 Lowance Center for Human Immunology and Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322.
8
Department of Immunology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195 Department of Immunology and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195 Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101 drawling@u.washington.edu.

Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)-deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell-intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.

PMID:
26371186
PMCID:
PMC4577851
DOI:
10.1084/jem.20150585
[Indexed for MEDLINE]
Free PMC Article

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