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 α-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.

Aod1Controlling Day 3 Thymectomy-Induced Autoimmune Ovarian Dysgenesis in Mice Encompasses Two Linked Quantitative Trait Loci with Opposing Allelic Effects on Disease Susceptibility

“…Stfa1, Stfa2, and Stfa3 (stefin A1, A2, and A3) at 22.85 cM are inhibitors of cysteine endo-and exopeptidases (58) such as cathepsin L and S that are involved in Ag processing (59,60). Most importantly, cathepsin S inhibitors have been shown to prevent autoantigen presentation in vitro, while in vivo treatment blocks lymphocytic infiltration into the salivary and lacrimal glands, abrogates autoantibody production, and promotes the recovery from autoimmune manifestations in D3Tx NFS/sld mice (61). Additionally, stefin A-type inhibitors are markedly overexpressed in bone marrow and spleen cells of me and mev mice compared with normal congenic animals (62).…”

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

“…Moreover, one mouse strain, which is resistant to EAT (BALB͞c), was recently shown to be susceptible to induction of a Graves'-like disease by DNA immunization with the TSH R gene (60). The Tg gene may predispose to AITD by a number of mechanisms; for example: (i) sequence changes in Tg may change its antigenicity making it more immunogenic; (ii) sequence changes in Tg may change its interaction with HLA class II molecules; and (iii) sequence changes in Tg may influence its degradation by cathepsin S in endosomes, a process which has been recently shown to play an important role in development of autoimmunity (61).…”

Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti‐CD4 monoclonal antibody

“…Because SS patients have high titers of autoantibodies, including anti-SSA/Ro and SSB/ La, abnormal T and B cell activation has been considered to cause SS (10,11). We have established and investigated an animal model of SS in NFS/sld-mutant mice thymectomized 3 days after birth and found that the 120-kd ␣-fodrin protein is a critical autoantigen in the development of SS in this mouse model (12)(13)(14). Furthermore, we and other investigators (12,15) have found that patients with SS have high titers of serum anti-␣-fodrin antibody, suggesting that ␣-fodrin is a critical autoantigen for the onset or progression of human SS.…”