The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080611
The Journal of Experimental Medicine, Vol. 206, No. 1, 139-151
The Rockefeller University Press, 0022-1007 $30.00
© Duty et al.
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ARTICLE

 Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors

J. Andrew Duty1,3, Peter Szodoray1, Nai-Ying Zheng5, Kristi A. Koelsch1,4, Qingzhao Zhang1,4, Mike Swiatkowski5, Melissa Mathias1, Lori Garman1, Christina Helms1, Britt Nakken1, Kenneth Smith1, A. Darise Farris2,3,4, and Patrick C. Wilson5,6

1 Immunobiology and Cancer and 2 Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
3 Department of Microbiology and Immunology and 4 Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
5 Section of Rheumatology, Department of Medicine and 6 Committee on Immunology, University of Chicago, Chicago, IL 60637

CORRESPONDENCE Patrick C. Wilson: wilsonp{at}uchicago.edu

Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD+IgM– B cells [BND]). These BND cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single BND cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, BND cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes BND cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.

Abbreviations used: ANA, antinuclear antibody; BCR, B cell receptor; dsDNA, double-stranded DNA; HEL, hen egg lysozyme; MTG, MitoTracker Green; pTyr, phosphorylated tyrosine; SLE; systemic lupus erythematosus; ssDNA, single-stranded DNA; T3, transitional 3.

© 2009 Duty et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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