Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity.
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.
Saegusa
Kaoru
K
Department of Pathology, Tokushima University School of Dentistry, Tokushima, Japan.
Ishimaru
Naozumi
N
Yanagi
Kumiko
K
Arakaki
Rieko
R
Ogawa
Kouichi
K
Saito
Ichiro
I
Katunuma
Nobuhiko
N
Hayashi
Yoshio
Y
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000276:immunology*; D012859:Sjogren's Syndrome / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013049:Spectrin
D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; D002352:Carrier Proteins; D002401:Cathepsin B; D056668:Cathepsin L; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D000949:Histocompatibility Antigens Class II; D008840:Microfilament Proteins; D013049:Spectrin; C045084:invariant chain; C534281:CTSL protein, human; C534278:Ctsl protein, mouse; C028217:cathepsin S