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

• Published in: The Journal of experimental medicine Vol. 212; no. 10; pp. 1663 - 1677
• Main Authors: Kolhatkar, Nikita S., Brahmandam, Archana, Thouvenel, Christopher D., Becker-Herman, Shirly, Jacobs, Holly M., Schwartz, Marc A., Allenspach, Eric J., Khim, Socheath, Panigrahi, Anil K., Luning Prak, Eline T., Thrasher, Adrian J., Notarangelo, Luigi D., Candotti, Fabio, Torgerson, Troy R., Sanz, Ignacio, Rawlings, David J.
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 21.09.2015
• Subjects: Adolescent; Adult; Animals; B-Cell Activating Factor - blood; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Case-Control Studies; Child; Child, Preschool; Cytoprotection; High-Throughput Nucleotide Sequencing; Humans; Infant; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Differentiation Factor 88 - metabolism; Receptors, Antigen, B-Cell - metabolism; Toll-Like Receptors - metabolism; Wiskott-Aldrich Syndrome - immunology; Wiskott-Aldrich Syndrome - metabolism; Wiskott-Aldrich Syndrome - pathology; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - metabolism; Young Adult
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20150585

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.