Thymic-Specific Serine Protease Limits Central Tolerance and Exacerbates Experimental Autoimmune Encephalomyelitis

Area of Science:

• Immunology
• Neuroimmunology
• Genetics

Background:

• Genetic predisposition to multiple sclerosis (MS) is strongly linked to MHC class II haplotypes.
• The role of antigen-processing enzymes in MS susceptibility by editing peptide repertoires remains unclear.
• Thymus-specific serine protease (TSSP) is expressed in the thymus and edits peptides presented by MHC class II molecules.

Purpose of the Study:

• To investigate the role of TSSP in experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To determine if TSSP influences central tolerance to myelin oligodendrocyte glycoprotein (MOG).
• To assess the impact of TSSP expression levels on MS susceptibility in relation to MHC class II alleles.

Main Methods:

• Utilized mouse models (NOD and C57BL/6) to study EAE severity.
• Assessed the effect of TSSP deficiency on EAE development and MOG tolerance.
• Analyzed TSSP expression levels in human thymic dendritic cells (DCs).

Main Results:

• TSSP deficiency conferred protection against EAE in NOD mice but not in C57BL/6 mice, indicating an MHC class II allele-dependent effect.
• TSSP was found to limit central tolerance to MOG, thereby increasing EAE severity.
• Human thymic DCs exhibit variable TSSP expression levels, with a 10-fold difference between high and low expressers.

Conclusions:

• TSSP plays a significant role in regulating autoimmune responses, specifically in the context of MS pathogenesis.
• The level of TSSP expression in thymic DCs could be a crucial factor modulating MS risk associated with certain MHC class II haplotypes.
• Targeting TSSP or modulating its expression may offer novel therapeutic strategies for MS.