Clonal Evolution of Autoreactive Germinal Centers

TY - JOUR

T1 - Clonal Evolution of Autoreactive Germinal Centers

AU - Degn, Søren Egedal

AU - van der Poel, Cees E.

AU - Firl, Daniel J.

AU - Ayoglu, Burcu

AU - Al Qureshah, Fahd A.

AU - Bajic, Goran

AU - Mesin, Luka

AU - Reynaud, Claude-Agnès

AU - Weill, Jean-Claude

AU - Utz, Paul J.

AU - Victora, Gabriel D.

AU - Carroll, Michael C.

PY - 2017/8/24

Y1 - 2017/8/24

N2 - 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.

AB - 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.

KW - B-lymphocytes

KW - autoantibodies

KW - autoantigens

KW - autoimmune diseases

KW - autoimmunity

KW - autoreactive B cells

KW - epitope spreading

KW - germinal center

KW - self-tolerance

KW - systemic lupus erythematosus

UR - http://www.scopus.com/inward/record.url?scp=85028421530&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.07.026

DO - 10.1016/j.cell.2017.07.026

M3 - Journal article

C2 - 28841417

SN - 0092-8674

VL - 170

SP - 913

EP - 926

JO - Cell

JF - Cell

IS - 5

ER -