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 July 16, 2019; First 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 1

Peripheral tolerance removes self-reactive mature B cells in healthy donors.

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Peripheral tolerance removes self-reactive mature B cells in healthy don...
Reactivity of clonal Abs in culture supernatants of individual single B cell cultures (n = 429 from transitional B cell cultures and n = 654 from mature B cell cultures) from healthy individuals were tested against 4 positive and negative controls (anti-IgG, anti-Igκ, anti-Igλ, and BSA) and a panel of self- and foreign antigens by Luminex multiplex assays. (A and B) Representative diagrams for transitional B cells (A) and mature B cells (B) from healthy donors. Each dot represents an individual test for each antigen. Figures represent n = 82 and n = 92 for transitional B and mature B cells, respectively. Blue bars indicate the threshold median fluorescence intensities (MFI) for each antigen (average + 6SD of B cell–negative, mock-treated samples). Number of positive reactions is indicated for each antigen above each panel. We tested subsets (n = 145 and n = 213 for transitional and mature B cells, respectively) of culture supernatant IgGs for binding to HAs. (C and D) Frequency of self-reactive B cells in transitional and mature B cells (n = 9). (C) Boxes extend from the 25th to 75th percentile, and lines in the boxes represent medians. Error bars represent minimum to maximum values. (D) Each dot represents an individual subject. For each individual, frequencies of self-reactive B cells were normalized with those of transitional B cells, and transitional and mature B cells are connected with lines.**P < 0.01 determined by Wilcoxon’s matched-pairs signed-rank test.