Prisco, Francesco (2021) New insights into the Pathogenesis of Inflammatory Myopathies in Animals. [Tesi di dottorato]

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Abstract

Inflammatory Myopathies (IMs) are a large and heterogeneous group of acquired disorders of the skeletal muscle characterized by the presence of inflammatory cells directly responsible for initiating and maintaining myofiber injury. IMs are poorly characterized in veterinary medicine. A relatively large body of descriptive knowledge is available, however, many of the factors responsible for disease initiation and perpetuation remain less well-defined and the understanding of these mechanisms is mainly based on biological plausibility from animal models and human medicine. The majority of these disorders are considered to be autoimmune disorders in which skeletal muscle is inappropriately targeted by the immune system. Autoimmune diseases develop as a result of chronic inflammation owing to interactions between genes and the environment. However, the mechanisms by which autoimmune diseases evolve remain poorly understood. Numerous evidences support that the innate immune system (including cytokines and chemokines) and adaptive immune system (including autoantibodies and antigen-specific T cells) are involved in IM pathogenesis. Furthermore, several non-immune-mediated mechanisms contribute to the pathogenesis of these disorders, including cell-stress pathways, free radicals, altered energy metabolism, protein homeostasis and mitochondrial damages. Autoantibodies are present in approximately 60-70% of human patients with IM and often specific autoantibodies are strongly associated with specific forms of IMs. The role of autoantibodies in causing muscle damage and dysfunction is still debated, however, they have proven to be immensely useful biomarkers for the diagnosis, monitoring and prognosis of IMs. Therefore, there is great interest in the identification of myositis-specific autoantibodies. In the present Ph.D. thesis: 1. we have identified novel pathogenetic mechanisms underlying leishmania-associated inflammatory myopathy in dogs. In particular, we identified circulating autoantibodies that recognize the muscle protein sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) as the main antigen, supporting the autoimmune mechanism underlying this myopathy and the antigen mimicry pathogenesis; 2. we morphologically and molecularly characterize the white striping myopathy of the broiler chicken and, based on our results, we hypothesize an associated immune-mediated mechanism; 3. we describe the morphological and molecular findings of the inflammatory myopathy associated with natural Feline Immunodeficiency Virus infection in cats and identify circulating anti-skeletal muscle autoantibodies.

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