Tracing Self-Reactive B Cells in Normal Mice.

Published

Journal Article

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-/loIgDhi anergic B cells, and a CD93- anergic subset. Whereas splenic T3 and CD93+ anergic B cells are short-lived, CD93-IgM-/loIgDhi 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-/loIgDhi 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-/loIgDhi 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.

Full Text

Duke Authors

Cited Authors

  • Nojima, T; Reynolds, AE; Kitamura, D; Kelsoe, G; Kuraoka, M

Published Date

  • July 1, 2020

Published In

Volume / Issue

  • 205 / 1

Start / End Page

  • 90 - 101

PubMed ID

  • 32414809

Pubmed Central ID

  • 32414809

Electronic International Standard Serial Number (EISSN)

  • 1550-6606

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.1901015

Language

  • eng

Conference Location

  • United States