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: Mrinalini Kala, Chun-Rong Chen, Sandra M McLachlan, Basil Rapoport, Holly Aliesky, Harold A Chapman
• Journal: Immunology (Immunology) Vol. 116 Issue 4 Pg. 532-40 (Dec 2005) ISSN: 0019-2805 [Print] England
• PMID: 16313367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Autoantibodies
• Epitopes, T-Lymphocyte
• Histocompatibility Antigens Class II
• Receptors, Thyrotropin
• invariant chain
• Cathepsins
• cathepsin S

Topics

• Adenoviridae (genetics)
• Animals
• Antigen Presentation (immunology)
• Antigens, Differentiation, B-Lymphocyte (immunology)
• Autoantibodies (biosynthesis)
• Cathepsins (immunology)
• Disease Models, Animal
• Epitopes, T-Lymphocyte (immunology)
• Female
• Genetic Vectors
• Graves Disease (immunology, physiopathology)
• Histocompatibility Antigens Class II (immunology)
• Immunization
• Mice
• Mice, Inbred BALB C
• Receptors, Thyrotropin (genetics, immunology)
• Th1 Cells (immunology)
• Thyroid Gland (physiopathology)