Understanding the pathogenesis of anti-PL-7 and anti-PL-12 associated antisynthetase syndromes

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Idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of entities, which can occur in children and adults, and lead to potentially severe disabilities. IIMs affect the skeletal muscles and several other organ systems in a characteristic way defining specific syndromes. The antisynthetase syndrome (ASS) is clinically characterized by a combination of autoimmune muscle inflammation, interstitial lung disease (ILD), Raynaud phenomenon, fever, seronegative arthritis and mechanics hands. Recently, we were able to demonstrate that ASS-associated myositis represents anindependent entity among the IIMs. Specific autoantibodies directed against different t-RNA synthetases define the different ASS and seem to play an essential role in their pathogenesis. However, the precise mechanisms of both innate and adaptive immune responses resulting in affection of skeletal muscle, lung, joints and skin remain unclear.In the present proposal we intend to expand our previous results on patientswith antibodies directed to the tRNA-synthetase Jo-1 to ASS associated with PL-7 and PL-12. We will study the immune response in human blood and skeletal muscle in-depth and define the overall morphology as well as phenotypic and functional alterations in the immune system. We aim to identify similarities and discrepancies between the different types of ASS to develop a deeper understanding of the pathogenesis and to identify potential therapeutic targets. Finally, we will generate a mouse model recapitulating thehuman disease by immunizing congenic mice with Jo-1, PL-7 and PL-12 proteins. We will characterize the pathogenic consequences in skeletal muscle, lung and immune system and compare them to the human diseases. The models could then be used to study and model diverse mechanisms of the disease and to test new therapeutic approaches.