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

Clonal Evolution of Autoreactive Germinal Centers.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: sdegn@biomed.au.dk.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Department of Medicine, Stanford University, Stanford, CA 94305, USA.
5
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
6
Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
8
Institut Necker Enfants Malades, INSERM U1151/CNRS UMS 8253, Université Paris Descartes, Sorbonne Paris Cité, 75993 Paris Cedex 14, France.
9
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.carroll@childrens.harvard.edu.

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.

KEYWORDS:

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

PMID:
28841417
PMCID:
PMC5784431
DOI:
10.1016/j.cell.2017.07.026
[Indexed for MEDLINE]
Free PMC Article

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