Clonal Evolution of Autoreactive Germinal Centers

Søren Egedal Degn, Cees E. van der Poel, Daniel J. Firl, Burcu Ayoglu, Fahd A. Al Qureshah, Goran Bajic, Luka Mesin, Claude-Agnès Reynaud, Jean-Claude Weill, Paul J. Utz, Gabriel D. Victora, Michael C. Carroll

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Germinal centers (GCs) are the primary sites of clonal B cell expansion and affinity maturation, directing the production of high-affinity antibodies. This response is a central driver of pathogenesis in autoimmune diseases, such as systemic lupus erythematosus (SLE), but the natural history of autoreactive GCs remains unclear. Here, we present a novel mouse model where the presence of a single autoreactive B cell clone drives the TLR7-dependent activation, expansion, and differentiation of other autoreactive B cells in spontaneous GCs. Once tolerance was broken for one self-antigen, autoreactive GCs generated B cells targeting other self-antigens. GCs became independent of the initial clone and evolved toward dominance of individual clonal lineages, indicating affinity maturation. This process produced serum autoantibodies to a breadth of self-antigens, leading to antibody deposition in the kidneys. Our data provide insight into the maturation of the self-reactive B cell response, contextualizing the epitope spreading observed in autoimmune disease.

Original languageEnglish
JournalCell
Volume170
Issue5
Pages (from-to)913-926
Number of pages14
ISSN0092-8674
DOIs
Publication statusPublished - 24 Aug 2017

Keywords

  • B-lymphocytes
  • autoantibodies
  • autoantigens
  • autoimmune diseases
  • autoimmunity
  • autoreactive B cells
  • epitope spreading
  • germinal center
  • self-tolerance
  • systemic lupus erythematosus

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