Background/Purpose:

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare systemic autoimmune diseases collectively called myositis causing progressive muscle weakness. Interestingly, myositis-specific autoantibodies described in different subsets of IIM are directed against ubiquitously expressed, intracellular proteins and show a lack of muscle specificity. Here we show for the first time that patients with IIM develop autoimmunity to the muscle-specific protein Four-and-a-half-LIM-domain 1 (FHL1). Strikingly, FHL1 is the causative factor for several X-linked hereditary myopathies, collectively called FHL1-related myopathies.

Methods:

Sera from IIM patients (n=141), followed at the Rheumatology Unit, Karolinska University Hospital, were compared to gender- and age-matched healthy controls (n=126) as well as patients diagnosed with other autoimmune disorders (n=186) and patients with non-inflammatory neuromuscular diseases (n=9) by ELISA and immunoblot. For 132/141 patients detailed clinical and laboratory data from patient records were available and the significance of differences between anti-FHL⁺ and anti-FHL^– patients was calculated by the Wilcoxon’s rank-sum test for continuous variables, and by Pearson’s Chi-square test or by the Fischer’s exact test for categorical variables. Expression pattern of FHL1 in muscle tissue of affected patients was analysed by confocal microscopy. Functional aspects of an anti-FHL1 autoimmune response was investigated in IIM-susptible MHC class I-overexpressing HT mice.

Results:

Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases including rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) or non-inflammatory neuromuscular diseases were largely anti-FHL1-negative. A comprehensive analysis of clinical data on muscular and extra-muscular involvement as well as biopsy characteristics revealed that anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage characterized by necrosis and connective tissue/fat replacement of muscle tissue, and vasculitis. The targeted autoantigen FHL1 showed an altered expression pattern with focal accumulation in muscle fibers of autoantibody-positive patients compared to a homogeneous expression in anti-FHL1-negative patients and healthy controls. By addressing the question how FHL1-autoimmunity might be initiated, we found that FHL1 is a target of granzyme B. To investigate if FHL1-autoimmunity contributes to muscle damage, we immunized myositis-prone mice with FHL1 and found aggravated muscle weakness, pronounced muscle damage, evidence for T cell infiltrates and increased mortality.

Conclusion:

Our findings provide the first evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, detection of anti-FHL1 autoantibodies in peripheral blood represents a potential biomarker able to identify a subset of severe IIM characterized by a progressive, therapy-resistant disease and poor prognosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-four-and-a-half-lim-domain-1-fhl1-as-a-new-autoantibody-target-in-idiopathic-inflammatory-myopathies/