Drs. C. O. Jacob and Guo contributed equally to this work.
Systemic Lupus Erythematosus
Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice
Version of Record online: 26 APR 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 5, pages 1610–1619, May 2012
How to Cite
Jacob, C. O., Guo, S., Jacob, N., Pawar, R. D., Putterman, C., Quinn, W. J., Cancro, M. P., Migone, T.-S. and Stohl, W. (2012), Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis & Rheumatism, 64: 1610–1619. doi: 10.1002/art.33458
- Issue online: 26 APR 2012
- Version of Record online: 26 APR 2012
- Accepted manuscript online: 29 NOV 2011 03:57PM EST
- Manuscript Accepted: 27 OCT 2011
- Manuscript Received: 16 JUN 2011
- NIH. Grant Numbers: R01-AR-048692, T32-AI-055428, R01-AI-073939, R01-AR-050193
- American College of Rheumatology Research and Education Foundation (Abbott Medical Student Clinical Preceptorship award)
- Arthritis Foundation (Postdoctoral Fellowship)
- Arthritis Foundation Southern California Chapter
To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice.
Wild-type (WT) NZM 2328, NZM. April–/–, NZM.Baff–/–, and NZM.Baff–/–.April–/– mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria).
In comparison to WT mice, NZM.April–/– mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April–/– mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April–/– mice than in WT mice, and development of clinical disease was identical in NZM.April–/– mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti–double-stranded DNA antibody levels were lower in NZM.Baff–/–.April–/– mice than in NZM.Baff–/– mice, whereas renal immunopathology in each cohort was equally mild.
APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.