Virobay

About Cathepsin S and Autoimmune Diseases

Autoimmune disease is characterized by an overactive immune response, presumably against endogenous antigens presented by the immune system. Autoimmune diseases include organ-specific diseases such as rheumatoid arthritis, psoriasis and psoriatic arthritis, multiple sclerosis, type I diabetes, inflammatory bowel disease (IBD), and non-specific disorders such as lupus (SLE). All of these diseases show aberrant immunological tolerance toward self antigens. Such immune-mediated diseases affect several millions of people worldwide and result in high medical and social costs.

Cathepsin S is expressed in professional antigen presenting cells (APCs) but can also be found in non-professional APCs, such as keratinocytes, synoviocytes, and intestinal epithelial cells, particularly under conditions of immune activation and inflammation. In autoimmune diseases, cathepsin S is implicated in the major histocompatibilitiy complex (MHC) Class II-dependent presentation of self-antigens to autoreactive CD4+ T cells.

A chaperone-like protein called invariant chain binds to the peptide-binding groove of the MHC Class II molecule. Invariant chain serves to temporarily occupy the peptide-binding groove of MHC Class II as well as target the receptor to the appropriate cellular compartment for antigenic peptide loading. Cleavage of the invariant chain occurs through proteolysis to a 10 kilodalton intermediate (Iip10), followed by cleavage to form the key 24-amino acid fragment Class II associated invariant chain peptide (CLIP). While a number of proteases have been implicated in cleaving the invariant chain, in key antigen presenting cells including B cells and dendritic cells cathepsin S appears to be the single critical enzyme in the final step of invariant chain processing. Once CLIP is formed, an MHC-like molecule HLA-DM replaces the MHC Class II-bound CLIP peptide with an antigenic peptide. The resulting antigen-loaded MHC Class II molecule is transported to the cell surface where the complex is presented to compatible CD4+ T cells that then become activated.

Cathepsin S inhibitors should have efficacy in diseases in which CD4+ T cells are activated via MHC Class II-antigen presentation such as rheumatoid arthritis, psoriasis, Crohn’s disease/IBD, multiple sclerosis, type I diabetes, etc.

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