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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 5

Mature, naive B cells in lupus patients exhibit distinct reactivity with foreign antigens.

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Mature, naive B cells in lupus patients exhibit distinct reactivity with...
Ab binding results of total 429 and 654 IgG Abs (transitional and mature B cells, respectively) from 9 healthy individuals and 506 and 742 IgG Abs(transitional and mature B cells, respectively) from 14 individuals with lupus were combined, and distributions of the BCR reactivity of mature B cells (A and B) and of transitional B cells (C and D) compared between healthy and lupus individuals. For each antigen, we counted antigen-reactive Abs and added these numbers to set as 100%; then frequencies of antigen-reactive Abs were determined for individual antigens. Ratios of the frequencies of antigen-reactive B cells from individuals with lupus relative to healthy controls for self-antigens (A and C) and foreign antigens (B and D) are shown. Antigens given ratios of ≥2 and ≤0.5 are indicated with red and blue bars, respectively. Statistical significance was determined by χ2 independence test. NA indicates “not applicable,” as we did not recover any KLH-binding cells from transitional B cells among patients with lupus. In A and C, numbers above bars indicate actual values that exceed y axis.

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