title: TACI-dependent APRIL signaling maintains autoreactive B cells in a mouse model of systemic lupus erythematosus.
abstract: Autoantibodies contribute to the development of systemic lupus erythematosus (SLE). APRIL (a proliferation-inducing ligand), a member of the TNF superfamily, regulates plasma-cell survival and binds to TACI (transmembrane activator CAML interactor) and BCMA (B-cell maturation antigen). We previously showed that APRIL blockade delayed disease onset in lupus-prone mice. In order to evaluate the role of APRIL receptors in the development of SLE, APRIL, TACI, BCMA, or double TACI.BCMA null mutations were introduced into the Nba2.Yaa (Y-linked autoimmune acceleration) spontaneous lupus mouse model. Mortality as a consequence of glomerulonephritis (GN) was reduced in Nba2.APRIL-/-.Yaa, Nba2.TACI-/-.Yaa and double-KO mice compared with Nba2.Yaa mice and correlated with lower levels of circulating antibodies, while splenic populations remained unchanged. In contrast, the appearance of symptoms was accelerated in BCMA-deficient mice, in which TACI signaling was increased. Finally, lupus-prone mice deficient for the APRIL-TACI axis produced less pathogenic antibodies and developed less GN. Disease reduction was attributed to impaired T-independent type 2 responses when the APRIL-TACI signaling axis was disrupted. Collectively, our results have identified and confirmed APRIL as a new target involved in B-cell activation, in the maintenance of plasma cell survival and subsequent increased autoantibody production that sustains lupus development in mice.
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Ngoc Lan
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Santiago-Raber
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000235:genetics; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D053301:B-Cell Maturation Antigen; C486361:Tnfrsf13b protein, mouse; C490176:Tnfrsf17 protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: APRIL; B-cell maturation antigen (BCMA); Systemic lupus erythematosus (SLE); TACI; mouse model