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

Abstract

Objective To determine the role for APRIL in the development of SLE. 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 ELISA, for glomerular deposition of IgG and C3 by immunofluorescence, for renal histopathology, and for clinical disease (severe proteinuria). Results In comparison to WT mice, NZM.April-/- mice harbored increased spleen B cells, T cells, and plasma cells (PC); increased serum levels of IgG anti-chromatin antibodies; and decreased numbers of bone marrow (BM) PC. In addition, glomerular deposition of IgG and C3 was similar in NZM.April-/- and WT mice; renal histopathology tended to be more severe in NZM.April-/- mice than in WT mice; and development of clinical disease was identical in NZM.April-/- and WT mice. BM (but not spleen) PC and serum IgG anti-chromatin and anti-dsDNA antibody levels were lower in NZM.Baff-/-.April-/- mice than in NZM.Baff-/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusions APRIL is dispensable for development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF has no discernable effect on development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PC 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 concomitant increase in therapeutic efficacy.

The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus

“…Constitutive over-expression of APRIL in non-autoimmune-prone mice fails to promote serologic or clinical autoimmune features [29]. Indeed, features of SLE are modestly exaggerated, rather than attenuated, in APRIL-deficient SLE-prone mice [39], and even the modest delay in development of proteinuria and death observed in some SLE-prone mice treated with an anti-APRIL mAb [40] may be related to reductions in circulating BAFF/APRIL heterotrimers and, hence, reductions in circulating BAFF activity rather than reductions in circulating APRIL activity.…”

B-cell-targeted therapies in systemic lupus erythematosus

“…53 In the absence of BAFF, NZM2328 lupusprone mice are protected from overt disease and present less severe proteinuria and reduced mortality; however, high serum Ig, immune complex deposition and proliferative glomerulonephritis are still apparent. 55 Further inactivation of APRIL in these BAFF knockout mice does not improve the renal immunopathology, 56 which suggests that there may be no clinical advantage in blocking both BAFF and APRIL. However, when using adenovirus receptor-Ig fusion proteins as pathway blockers, there are qualitative differences between blocking BAFF alone or BAFF and APRIL together.…”

Could the Cochin risk prediction score be applied in daily practice to predict pulmonary hypertension in systemic sclerosis? Comment on the article by Meune et al

“…In a recent article in Arthritis & Rheumatism, Meune et al (1) proposed a score to estimate the likelihood of precapillary pulmonary hypertension (PH) developing in patients with systemic sclerosis (SSc). It was proposed that age, diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA), and forced vital capacity (FVC) were independent risk factors for developing precapillary PH within 3 years.…”

“…The Cochin RPS may be helpful in clinical practice for close monitoring of high-risk SSc patients. In a recent article published in Arthritis & Rheumatism, Jacob and colleagues further described the role of APRIL in the development of systemic lupus erythematosus (SLE) (1). Their results showed that compared with wildtype (WT) mice, NZM.April -/Ϫ mice exhibited increased numbers of T cells, B cells, and plasma cells (PCs) in the spleen; elevated levels of serum IgG antichromatin antibodies; and a decreased number of bone marrow PCs.…”