Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity.

Abstract

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.

• Authors: Kaoru Saegusa, Naozumi Ishimaru, Kumiko Yanagi, Rieko Arakaki, Kouichi Ogawa, Ichiro Saito, Nobuhiko Katunuma, Yoshio Hayashi
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 110 Issue 3 Pg. 361-9 (Aug 2002) ISSN: 0021-9738 [Print] United States
• PMID: 12163455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Autoantigens
• Carrier Proteins
• Histocompatibility Antigens Class II
• Microfilament Proteins
• fodrin
• invariant chain
• Cathepsins
• Cysteine Endopeptidases
• Cathepsin B
• CTSL protein, human
• Cathepsin L
• Ctsl protein, mouse
• cathepsin S

Topics

• Animals
• Antigen Presentation (immunology)
• Antigens, Differentiation, B-Lymphocyte (immunology)
• Autoantigens (immunology)
• Autoimmunity (immunology)
• Carrier Proteins (immunology)
• Cathepsin B (metabolism)
• Cathepsin L
• Cathepsins (antagonists & inhibitors, metabolism)
• Cell Division
• Cysteine Endopeptidases
• Disease Models, Animal
• Histocompatibility Antigens Class II (immunology)
• Mice
• Mice, Inbred C57BL
• Microfilament Proteins (immunology)
• Sjogren's Syndrome (immunology)
• T-Lymphocytes (cytology, immunology)