Tracing Self-Reactive B Cells in Normal Mice.
| Autor: | Nojima T; Department of Immunology, Duke University, Durham, NC 27710., Reynolds AE; Department of Immunology, Duke University, Durham, NC 27710., Kitamura D; Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan; and., Kelsoe G; Department of Immunology, Duke University, Durham, NC 27710.; Duke Human Vaccine Institute, Duke University, Durham, NC 27710., Kuraoka M; Department of Immunology, Duke University, Durham, NC 27710; masayuki.kuraoka@duke.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2020 Jul 01; Vol. 205 (1), pp. 90-101. Date of Electronic Publication: 2020 May 15. |
| DOI: | 10.4049/jimmunol.1901015 |
| Abstrakt: | BCR transgenic mice dominate studies of B cell tolerance; consequently, tolerance in normal mice expressing diverse sets of autoreactive B cells is poorly characterized. We have used single B cell cultures to trace self-reactivity in BCR repertoires across the first and second tolerance checkpoints and in tolerized B cell compartments of normal mice. This approach reveals affinity "setpoints" that define each checkpoint and a subset of tolerized, autoreactive B cells that is long-lived. In normal mice, the numbers of B cells avidly specific for DNA fall significantly as small pre-B become immature and transitional-1 B cells, revealing the first tolerance checkpoint. By contrast, DNA reactivity does not significantly change when immature and transitional-1 B cells become mature follicular B cells, showing that the second checkpoint does not reduce DNA reactivity. In the spleen, autoreactivity was high in transitional-3 (T3) B cells, CD93 + IgM -/lo IgD hi anergic B cells, and a CD93 - anergic subset. Whereas splenic T3 and CD93 + anergic B cells are short-lived, CD93 - IgM -/lo IgD hi B cells have half-lives comparable to mature follicular B cells. B cell-specific deletion of proapoptotic genes, Bak and Bax , resulted in increased CD93 - IgM -/lo IgD hi B cell numbers but not T3 B cell numbers, suggesting that apoptosis regulates differently persistent and ephemeral autoreactive B cells. The self-reactivity and longevity of CD93 - IgM -/lo IgD hi B cells and their capacity to proliferate and differentiate into plasmacytes in response to CD40 activation in vitro lead us to propose that this persistent, self-reactive compartment may be the origin of systemic autoimmunity and a potential target for vaccines to elicit protective Abs cross-reactive with self-antigens. (Copyright © 2020 by The American Association of Immunologists, Inc.) |
| Databáze: | MEDLINE |
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