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Abstract
IntroductionHigh Mobility Group Box Protein 1 (HMGB1) is a DNA-binding protein that exerts inflammatory or pro-repair effects upon translocation from the nucleus. We postulate aberrant HMGB1 expression in immune-mediated necrotising myopathy (IMNM).MethodsHerein, we compare HMGB1 expression (serological and sarcoplasmic) in patients with IMNM with that of other myositis subtypes using immunohistochemistry and ELISA.ResultsIMNM (n = 62) and inclusion body myositis (IBM, n = 14) patients had increased sarcoplasmic HMGB1 compared with other myositis patients (n = 46). Sarcoplasmic HMGB1 expression correlated with muscle weakness and histological myonecrosis, inflammation, regeneration and autophagy. Serum HMGB1 levels were elevated in patients with IMNM, dermatomyositis and polymositis, and those myositis patients with extramuscular inflammatory features.DiscussionAberrant HMGB1 expression occurs in myositis patients and correlates with weakness. A unique expression profile of elevated sarcoplasmic and serum HMGB1 was detected in IMNM.
Highlights
High Mobility Group Box Protein 1 (HMGB1) is a DNA-binding protein that exerts inflammatory or pro-repair effects upon translocation from the nucleus
Understanding the molecular events underpinning idiopathic inflammatory myopathy (IIM) pathophysiology and how this differs between subtypes is critical in the pursuit of developing targeted therapies, which is increasingly the goal in rheumatological practice
We have shown HMGB1 to be associated with multiple processes in the muscle microenvironment ranging from physiological to pathological, damaging to restorative
Summary
High Mobility Group Box Protein 1 (HMGB1) is a DNA-binding protein that exerts inflammatory or pro-repair effects upon translocation from the nucleus. The term encompasses dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune-mediated necrotising myopathy (IMNM; called necrotising autoimmune myopathy, NAM). The etiology of these conditions remains obscure and the pathogenic mechanisms likely differ between the subtypes, given their distinct histopathological and immunological features. HMGB1 is rapidly passively released from necrotic cells, following nuclear membrane breakdown (Scaffidi et al, 2002) This protein is implicated in a broad range of conditions, including sepsis, malignancy and autoimmune diseases (Harris and Raucci, 2006; Diener et al, 2013; Magna and Pisetsky, 2014). Myocytes or myofibres exposed to recombinant HMGB1 demonstrate intracellular protein aggregation, increased cell death (Muth et al, 2015), aberrant MHC-I expression (Grundtman et al, 2010; Muth et al, 2015) and impaired calcium release during repeated tetanic stimulation, suggesting enhanced muscle fatigue (Grundtman et al, 2010; Zong et al, 2013)
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