Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice

Abstract

Objective: To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice.

Methods: 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).

Results: 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.

Conclusion: 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.