Self-tolerance curtails the B cell repertoire to microbial epitopes
Akiko Watanabe, … , E. William St. Clair, Garnett Kelsoe
Akiko Watanabe, … , E. William St. Clair, Garnett Kelsoe
Published May 16, 2019
Citation Information: JCI Insight. 2019;4(10):e122551. https://doi.org/10.1172/jci.insight.122551.
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Research Article Immunology

Self-tolerance curtails the B cell repertoire to microbial epitopes

Abstract

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.

Authors

Akiko Watanabe, Kuei-Ying Su, Masayuki Kuraoka, Guang Yang, Alexander E. Reynolds, Aaron G. Schmidt, Stephen C. Harrison, Barton F. Haynes, E. William St. Clair, Garnett Kelsoe

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Figure 2

Peripheral tolerance removes F+S-reactive B cells.

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Peripheral tolerance removes F+S-reactive B cells. Frequencies of clonal...
Frequencies of clonal Abs that react with one or more foreign antigens in transitional and mature B cell cultures (see legend of Figure 1). Foreign antigen–reactive Abs in C were divided by their reactivity with self-antigens, and the frequencies of F+S-reactive Abs (A) and F-only-reactive Abs (B) are shown. In A–C, each dot represents an individual subject. For each individual, frequencies of self-reactive Abs were normalized with those of transitional B cells, and transitional and mature B cells are connected with lines. In B, connected lines were not generated for those individuals whose transitional and/or mature B cell cultures did not contain F-only-reactive Abs. *P < 0.05, **P < 0.01, NS P > 0.05 determined by Wilcoxon’s matched-pairs signed-rank test (2-tailed). (D) Frequency of F-reactive (open circles), F+S-reactive (filled circles), and F-only-reactive (filled squares) B cells in transitional and mature B cells are connected with lines. For each group, frequencies of individual samples were normalized to the average frequency of antigen-binding B cells among transitional B cells. *P < 0.05 determined by Wilcoxon’s matched-pairs signed-rank test (2-tailed) to compare antigen-reactive B cells in transitional B cells and mature B cells for each group.