title: Cathepsin S is not crucial to TSHR processing and presentation in a murine model of Graves' disease.
abstract: By regulating invariant (Ii) chain processing and MHC class II peptide loading, the endosomal protease cathepsin S (Cat S) has a potential role in autoimmune susceptibility. Indeed, Cat S null mice are resistant to I-Ab-restricted experimental myasthenia gravis due to inadequate peptide presentation. To explore the role of Cat S in a Graves' disease model, I-Ad-restricted wild-type (WT) and Cat S(-/-) mice were immunized with adenovirus encoding the A subunit of thyroid stimulating hormone receptor (TSHR). TSHR adenovirus immunized mice develop Th1 T cells, TSHR antibodies, and a proportion become overtly hyperthyroid. Although TSHR presentation in vitro was initially impaired in Cat S(-/-) mice, subsequent TSHR presentation in vitro and disease development were similar in both groups but with higher antibody responses in Cat S null mice. WT and Cat S(-/-) mice recognized similar T cell epitopes from a panel of overlapping TSHR peptides. TSHR responses were found to be I-Ad-restricted and Cat S(-/-) I-Ad B cells had marked defects in Ii processing. These data imply that loading of TSHR peptides critical to TSHR antibody responses becomes Ii-independent. Contrasting findings among organ-specific murine autoimmune models imply that potential uses of Cat S inhibitors to ameliorate autoimmunity must be determined empirically.
authors.affiliation: Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, 93143, USA.
authors.forename: Mrinalini
authors.initials: M
authors.lastname: Kala
authors.forename: Chun-Rong
authors.initials: CR
authors.lastname: Chen
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
authors.forename: Basil
authors.initials: B
authors.lastname: Rapoport
authors.forename: Holly
authors.initials: H
authors.lastname: Aliesky
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D002403:Cathepsins / Q000276:immunology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D006111:Graves Disease / Q000276:immunology* / Q000503:physiopathology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D013961:Thyroid Gland / Q000503:physiopathology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D011989:Receptors, Thyrotropin; C045084:invariant chain; D002403:Cathepsins; C028217:cathepsin S