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

Abstract

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.

Diagnosis and classification of idiopathic inflammatory myopathies

“…These autoantibodies all target antigens that are ubiquitously expressed in the cytoplasm of all nucleated cells with some variation in expression between different organs that may explain the link e.g. between muscle and lung in the antisynthetase syndrome (7) A new myositis-specific autoantibody has been discovered that targets a muscle specific protein, four and half limb domain 1 (FHL1) (8). This antibody was present in approximately 25% of patients with PM, DM or IBM with the predominate clinical features of severe muscle atrophy and dysphagia but an absence of lung or joint involvement, supporting the hypothesis that different autoantibodies are associated with distinct clinical phenotypes and that different molecular pathways may predominate in different subsets of myositis.…”

Myositis an evolving spectrum of disease

“…This autoantibody was rarely found in other systemic rheumatic diseases and not in neuromuscular disorders suggesting this antibody to be myositis specific. Furthermore, anti-FHL1 antibodies were associated with a severe myopathy, often with clinical muscle atrophy and pronounced histopathological changes with accumulation of fat and connective tissue in muscle biopsies [57]. Patients with anti-FHL1 antibodies also had a worse prognosis with progressive muscle weakness despite immunosuppressive treatment compared to patients with IIM who were anti-FHL1 negative.…”

“…This was the background for a study which started by screening a muscle cDNA library with sera from patients with IIIM to identify muscle specific autoantibodies. Through a serial of experiments FHL1 was identified as a muscle specific antigen that was targeted by autoantibodies in patients with IIM [57]. This autoantibody was rarely found in other systemic rheumatic diseases and not in neuromuscular disorders suggesting this antibody to be myositis specific.…”

Successful use of rituximab in a patient with refractory thrombotic thrombocytopaenic purpura complicated by polymyositis

“…The serum levels of B cell-activating factor are significantly elevated in patients with PM/DM, especially those with anti-Jo-1 antibodies (8). In addition, autoantibodies against four-and-a-half LIM domain 1 (FHL1), which is a muscle-specific protein, are associated with the aggravation of idiopathic inflammatory myopathies (9). Although T cell-mediated cytotoxicity to muscle has been considered a central disease mechanism of PM, B cells and autoantibodies may contribute to the pathogenesis of a subset of PM.…”