Article Text

PDF
Extended report
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
  1. Khader Valli Rupanagudi1,
  2. Onkar P Kulkarni1,
  3. Julia Lichtnekert1,
  4. Murthy Narayana Darisipudi1,
  5. Shrikant R Mulay1,
  6. Brigitte Schott2,
  7. Sabine Gruner2,
  8. Wolfgang Haap2,
  9. Guido Hartmann2,
  10. Hans-Joachim Anders1
  1. 1Medizinische Klinik and Poliklinik IV, Renal Division, Klinikum der Universität München, München, Germany
  2. 2CV & Metabolism DTA, Pharma Research and Early Development, Hoffmann La Roche, Basel, Switzerland
  1. Correspondence to H-J Anders, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München-LMU, Ziemssenstr. 1, Munich 80336, Germany; hjanders{at}med.uni-muenchen.de

Abstract

Objectives 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.

  • Autoimmune Diseases
  • Autoantibodies
  • Systemic Lupus Erythematosus
  • T Cells
  • Treatment

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.