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 language | English |
|---|---|
| Journal | Cell |
| Volume | 170 |
| Issue | 5 |
| Pages (from-to) | 913-926 |
| Number of pages | 14 |
| ISSN | 0092-8674 |
| DOIs | |
| Publication status | Published - 24 Aug 2017 |
Keywords
- B-lymphocytes
- autoantibodies
- autoantigens
- autoimmune diseases
- autoimmunity
- autoreactive B cells
- epitope spreading
- germinal center
- self-tolerance
- systemic lupus erythematosus