Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 44, Issue 10, Pages 3093-3108Publisher
WILEY
DOI: 10.1002/eji.201344282
Keywords
AID; Pathogenic autoantibodies; Receptor editing; Systemic lupus erythemathosus
Categories
Funding
- National Institutes of Health [R01AI45104, R01AI076409A, T32 AI007077-26A2]
- Lupus Research Institute [R25 GM066567]
- German Science Foundation [EXC294, TRR130]
- Eshe Fund
- Keck Foundation
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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG antinuclear antibodies. Pathogenic IgG autoantibody production requires B-cell activation, leading to the production of activation-induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG antinucleic acid Abs. We have generated 564Igi mice that conditionally express an activation-induced cytidine deaminase transgene (Aicda(tg)), either in all B cells or only in mature B cells. Here, we show that class-switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early-developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early-developing B cells also results in increased production of self-reactive IgM, indicating that AID, through somatic hypermutation, contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early-developing B cells.
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