title: Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers.
abstract: B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia. Electronic address: Fabienne.Mackay@monash.edu.au.
authors.forename: William A
authors.initials: WA
authors.lastname: Figgett
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia.
authors.forename: Devy
authors.initials: D
authors.lastname: Deliyanti
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia; The Walter and Eliza Hall Institute of Medical Research, Molecular Medicine Division, 1G Royal Parade, Parkville 3052, Australia; Department of Experimental Medicine, University of Melbourne, Parkville 3052, Australia.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Fairfax
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia.
authors.forename: Pin Shie
authors.initials: PS
authors.lastname: Quah
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne 3004, Australia.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C486361:Tnfrsf13b protein, mouse; C505720:Tnfsf13b protein, mouse; D051199:Toll-Like Receptor 7; D053303:Transmembrane Activator and CAML Interactor Protein
keywords: Autoantibodies; BAFF; Lupus nephritis; Systemic lupus erythematosus; TACI; TLR7