Evolution of autoantibody responses via somatic hypermutation outside of germinal centers.
Somatically mutated high-affinity autoantibodies are a hallmark of some autoimmune diseases, including systemic lupus erythematosus. It has long been presumed that germinal centers (GCs) are critical in autoantibody production, because they are the only sites currently believed to sustain a high rate of somatic hypermutation. Contrary to this idea, we found that splenic autoreactive B cells in autoimmune MRL.Fas(lpr) mice proliferated and underwent active somatic hypermutation at the T zone-red pulp border rather than in GCs. Our results implicate this region as an important site for hypermutation and the loss of B cell self-tolerance.
William
Jacqueline
J
Department of Laboratory Medicine, Section of Immunobiology, Yale University School of Medicine, Box 208035, New Haven, CT 06520-8035, USA.
Euler
Chad
C
Christensen
Sean
S
Shlomchik
Mark J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D020566:Dendritic Cells, Follicular / Q000276:immunology; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012217:Rheumatoid Factor / Q000096:biosynthesis*; D017634:Self Tolerance; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D007135:Immunoglobulin Variable Region; D012217:Rheumatoid Factor