02O Characterization of a mouse model for Jo-1, PL-7 and PL-12 associated anti-synthetase syndrome

Abstract

Anti-synthetase syndrome (ASyS) is an autoimmune condition, characterized by the presence of autoantibodies directed against an aminoacyl-tRNA synthetase (anti-ARS). Patients present clinical symptoms such as myositis, interstitial lung disease, Raynaud's phenomenon, and arthritis. Anti-Jo-1, anti-PL-7 and anti-PL-12 are the most frequent anti-ARS. However, their role in ASyS pathogenesis remains incompletely understood. Therefore, robust animal models are essential to gain a detailed insight into the underlying pathophysiology. Aiming to characterize these pathophysiological features, we established and studied a mouse model for Jo-1, PL-7 and PL-12 associated ASyS. ASyS was induced in NOD.Idd 3/5 mice by injection of 200 µg Jo-1, PL-7 or PL-12 recombinant protein emulsified in Complete Freund's Adjuvant (CFA) in combination with OX86. Controls received CFA and Phosphate Buffered Saline only. Muscle strength was assessed by rotarod tests and the effects on the peripheral immune system were investigated by flow cytometry in spleen and lymph nodes. Morphological characteristics of skeletal muscle and lung tissue of immunized mice and the tissue infiltrating immune cells were validated using histology and immunohistochemistry. Immunization of mice led to clinical symptoms including muscle weakness and demonstrated variations in the immune cell response between the ARS subtypes. Histological analysis of skeletal muscle tissues showed infiltration by immune cells in the epimysium, spreading into the adjacent perifascicular area with progressing disease. Analysis of lung specimens by immunohistological staining demonstrated peribronchial accentuated accumulation of lymphocyte aggregates. We present a mouse model, which recapitulates features of the human phenotype of ASyS, to study the molecular pathogenesis and provide new insights into the pathomechanisms.