Clonal Evolution of Autoreactive Germinal Centers

Cell. 2017 Aug 24;170(5):913-926.e19. doi: 10.1016/j.cell.2017.07.026.


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.

Keywords: B-lymphocytes; autoantibodies; autoantigens; autoimmune diseases; autoimmunity; autoreactive B cells; epitope spreading; germinal center; self-tolerance; systemic lupus erythematosus.

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • Autoimmune Diseases / immunology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Chimera / immunology
  • Clonal Evolution*
  • Epitopes / immunology
  • Germinal Center / cytology*
  • Germinal Center / immunology*
  • Immune Tolerance*
  • Kidney / immunology
  • Mice
  • Mice, Inbred C57BL


  • Autoantibodies
  • Autoantigens
  • Epitopes