Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies

作者：Albrecht Inka^*; Wick Cecilia; Hallgren Asa; Tjarnlund Anna; Nagaraju Kanneboyina; Andrade Felipe; Thompson Kathryn; Coley William; Phadke Aditi; Diaz Gallo Lina Marcela; Bottai Matteo; Nennesmo Inger; Chemin Karine; Herrath Jessica; Johansson Karin; Wikberg Anders; Ytterberg A Jimmy; Zubarev Roman A; Danielsson Olof; Krystufkova Olga; Vencovsky Jiri; Landegren Nils; Wahren Herlenius Marie; Padyukov Leonid; Kampe Olle; Lundberg Ingrid E

来源：Journal of Clinical Investigation, 2015, 125(12): 4612-4624.

DOI：10.1172/JCI81031

Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

• 出版日期2015-12