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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 6

Self-reactive Abs exhibit long HCDR3s with frequent JH6 usage.

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Self-reactive Abs exhibit long HCDR3s with frequent JH6 usage.
VHDJH rea...
VHDJH rearrangements were recovered from transitional and mature B cells after single B cell culture. Based on the reactivity of the culture supernatant Abs, samples were grouped as follows: S-only-reactive (filled circles, n = 42); F+S-reactive (filled triangles, n = 49); F-only-reactive (open circles, n = 72); and unknown (open triangles, n = 67). Self-reactive Abs in this experiment represent Abs that reacted with RNP and/or Sm protein. (A) HCDR3 lengths are shown. Each symbol represents an individual sample. ***P < 0.001, NS: P > 0.05 determined by Mann-Whitney U test. (B) VH, D, and JH gene usages are shown. (C) The JH6 usage was compared between self-reactive (S-only-reactive plus F+S, n = 91) and non-self (F-only-reactive plus unknown, n = 139) groups. **P < 0.01 determined by χ2 test.

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