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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

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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 4

Peripheral tolerance removes B cell specificities to many antigen types.

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Peripheral tolerance removes B cell specificities to many antigen types....
Ab binding results of transitional and mature B cells in healthy donors (A and C) and SLE patients (B and D) for individual self-antigens (A and B): Sm (filled square), Hep-2NA (open circle), insulin (filled circle), centromere B (open inverted triangle), histone (+), SSB (open diamond), SSA (filled inverted triangle), Jo-1 (filled diamond), Scl-70 (open square), RNP (filled triangle), dsDNA (×), KYNU (filled hexagon)]; and foreign antigens (C and D): gp41 (+), JR-FL (open square), KLH (×), HAs (open circle), rPA (filled triangle), SA (filled circle), OVA (open triangle), and NP-BSA (filled square). For each antigen, we calculated the frequency of antigen-binding Abs, and ratios of the frequencies of antigen-binding Abs (relative to Abs expressed by transitional B cells) within healthy donors (n = 1083 IgG Abs; see legend of Figure 1) and SLE patients (n = 1248 IgG Abs, see legend of Figure 3 and Supplemental Figure 2) are shown. We tested subsets (n = 358 and n = 416 for healthy donors and SLE patients, respectively) of culture supernatant IgGs for binding to HAs. In each panel, connected lines were not generated when transitional and/or mature B cell cultures did not contain Abs that bound indicated antigens. **P < 0.01; NS: P > 0.05 determined by Wilcoxon’s matched-pairs signed-rank test (2-tailed).

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