Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity

• Published in: The Journal of clinical investigation Vol. 110; no. 3; pp. 361 - 369
• Main Authors: Saegusa, Kaoru, Ishimaru, Naozumi, Yanagi, Kumiko, Arakaki, Rieko, Ogawa, Kouichi, Saito, Ichiro, Katunuma, Nobuhiko, Hayashi, Yoshio
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2002
• Subjects: Animals; Antigen Presentation - immunology; Antigens; Antigens, Differentiation, B-Lymphocyte - immunology; Apoptosis; Autoantigens - immunology; Autoimmune diseases; Autoimmunity - immunology; Biomedical research; Carrier Proteins - immunology; Cathepsin B - metabolism; Cathepsin L; Cathepsins - antagonists & inhibitors; Cathepsins - metabolism; Cell Division; Cysteine Endopeptidases; Disease Models, Animal; Exocrine glands; Histocompatibility Antigens Class II - immunology; Mice; Mice, Inbred C57BL; Microfilament Proteins - immunology; Peptides; Sjogren's Syndrome - immunology; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Japan
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI0214682

The cysteine endoprotease cathepsin S mediates degradation of the MHC class II invariant chain Ii in human and mouse antigen-presenting cells. Studies described here examine the functional significance of cathepsin S inhibition on autoantigen presentation and organ-specific autoimmune diseases in a murine model for Sjögren syndrome. Specific inhibitor of cathepsin S (Clik60) in vitro markedly impaired presentation of an organ-specific autoantigen, 120-kDa alpha-fodrin, by interfering with MHC class II-peptide binding. Autoantigen-specific T cell responses were significantly and dose-dependently inhibited by incubation with Clik60, but not with inhibitor s of cathepsin B or L. Clik60 treatment of mouse salivary gland cells selectively inhibited autopeptide-bound class II molecules. Moreover, the treatment with Clik60 in vivo profoundly blocked lymphocytic infiltration into the salivary and lacrimal glands, abrogated a rise in serum autoantibody production, and led to recovery from autoimmune manifestations. Thus, inhibition of cathepsin S in vivo alters autoantigen presentation and development of organ-specific autoimmunity. These data identify selective inhibition of cysteine protease cathepsin S as a potential therapeutic strategy for autoimmune disease processes.