title: Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming.
abstract: OBJECTIVE
  Major histocompatibility complex (MHC) class II-mediated priming of T and B lymphocytes is a central element of autoimmunity in systemic lupus erythematosus (SLE) and lupus nephritis. The cysteine protease cathepsin S degrades the invariant peptide chain during MHC II assembly with antigenic peptide in antigen-presenting cells; therefore, we hypothesised that cathepsin S inhibition would be therapeutic in SLE.
  
  
  METHODS
  We developed a highly specific small molecule, orally available, cathepsin S antagonist, RO5461111, with suitable pharmacodynamic and pharmacokinetic properties that efficiently suppressed antigen-specific T cell and B cell priming in vitro and in vivo.
  
  
  RESULTS
  When given to MRL-Fas(lpr) mice with SLE and lupus nephritis, RO5461111 significantly reduced the activation of spleen dendritic cells and the subsequent expansion and activation of CD4 T cells and CD4/CD8 double-negative T cells. Cathepsin S inhibition impaired the spatial organisation of germinal centres, suppressed follicular B cell maturation to plasma cells and Ig class switch. This reversed hypergammaglobulinemia and significantly suppressed the plasma levels of numerous IgG (but not IgM) autoantibodies below baseline, including anti-dsDNA. This effect was associated with less glomerular IgG deposits, which protected kidneys from lupus nephritis.
  
  
  CONCLUSIONS
  Together, cathepsin S promotes SLE by driving MHC class II-mediated T and B cell priming, germinal centre formation and B cell maturation towards plasma cells. These afferent immune pathways can be specifically reversed with the cathepsin S antagonist RO5461111, which prevents lupus nephritis progression even when given after disease onset. This novel therapeutic strategy could correct a common pathomechanism of SLE and other immune complex-related autoimmune diseases.
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Khader Valli
authors.initials: KV
authors.lastname: Rupanagudi
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Lichtnekert
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Murthy Narayana
authors.initials: MN
authors.lastname: Darisipudi
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.affiliation: CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schott
authors.affiliation: CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gruner
authors.affiliation: CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Haap
authors.affiliation: CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; C000596028:RO5461111; D011392:Proline; D002403:Cathepsins; C028217:cathepsin S
keywords: Autoantibodies; Autoimmune Diseases; Systemic Lupus Erythematosus; T Cells; Treatment