Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus.
Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE.
Cappione
Amedeo
A
Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Anolik
Jennifer H
JH
Pugh-Bernard
Aimee
A
Barnard
Jennifer
J
Dutcher
Paul
P
Silverman
Gregg
G
Sanz
Iñaki
I
D001172:Arthritis, Rheumatoid / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002675:Child, Preschool; D017635:Clonal Anergy / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000502:physiology; D007075:Immunoglobulin M / Q000096:biosynthesis; D007156:Immunologic Memory / Q000502:physiology; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M