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JCI Insight. 2019 May 16;4(10). pii: 122551. doi: 10.1172/jci.insight.122551. eCollection 2019 May 16.

Self-tolerance curtails the B cell repertoire to microbial epitopes.

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Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Tzu Chi Medical Center, Hualien, Taiwan.
Deparment of Microbiology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Howard Hughes Medical Institute, Boston, Massachusetts, USA.
Duke Human Vaccine Institute and.
Department of Medicine, Duke University, Durham, North Carolina, USA.


Immunological tolerance removes or inactivates self-reactive B cells, including those that also recognize cross-reactive foreign antigens. Whereas a few microbial pathogens exploit these "holes" in the B cell repertoire by mimicking host antigens to evade immune surveillance, the extent to which tolerance reduces the B cell repertoire to foreign antigens is unknown. Here, we use single-cell cultures to determine the repertoires of human B cell antigen receptors (BCRs) before (transitional B cells) and after (mature B cells) the second B cell tolerance checkpoint in both healthy donors and in patients with systemic lupus erythematosus (SLE) . In healthy donors, the majority (~70%) of transitional B cells that recognize foreign antigens also bind human self-antigens (foreign+self), and peripheral tolerance halves the frequency of foreign+self-reactive mature B cells. In contrast, in SLE patients who are defective in the second tolerance checkpoint, frequencies of foreign+self-reactive B cells remain unchanged during maturation of transitional to mature B cells. Patterns of foreign+self-reactivity among mature B cells from healthy donors differ from those of SLE patients. We propose that immune tolerance significantly reduces the scope of the BCR repertoire to microbial pathogens and that cross-reactivity between foreign and self epitopes may be more common than previously appreciated.


B cells; Immunology; Lupus; Tolerance

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