Clonal Evolution of Autoreactive Germinal Centers

Søren E. 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 journalArticlepeer-review

64 Scopus citations

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
Pages (from-to)913-926.e19
JournalCell
Volume170
Issue number5
DOIs
StatePublished - 24 Aug 2017
Externally publishedYes

Keywords

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

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