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Clonal Evolution of Autoreactive Germinal Centers.

Cell | 2017

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.

Pubmed ID: 28841417 RIS Download

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Associated grants

  • Agency: NIAID NIH HHS, United States
    Id: R21 AI117737
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI039246
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI125197
  • Agency: NIAID NIH HHS, United States
    Id: R37 AI054636
  • Agency: NIAID NIH HHS, United States
    Id: U19 AI110491
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI130307
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI119006

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