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Abstract Number: 1032

Aberrant Sarcoplasmic Expression of the Alarmin ‘High Mobility Group Box Protein 1” (HMGB1) in Patients with Idiopathic Inflammatory Myopathy

Jessica Day1, Sophia Otto2, Kathy Cash3, Preethi Eldi4, Pravin Hissaria5, Susanna Proudman6, John Hayball4 and Vidya Limaye7, 1Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia, 2Pathology, Royal Adelaide Hospital, Adelaide, Australia, 3Muscle and Nerve Laboratory, SA Pathology, Adelaide, Australia, 4Experimental Therapeutics Laboratory, University of South Australia, Adelaide, Australia, 5Immunology, Royal Adelaide Hospital, Adelaide, Australia, 6Royal Adelaide Hospital, Rheumatology Unit and University of Adelaide, Discipline of Medicine, Adelaide, Australia, 7Rheumatology, The Royal Adelaide Hospital, Adelaide, Australia

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: cytokines and myositis, Idiopathic Inflammatory Myopathies (IIM)

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Session Information

Date: Monday, October 22, 2018

Session Title: Innate Immunity Poster

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Components of the innate immune system, such a High Mobility Group Box Protein 1 (HMGB1), may contribute to the initiation, perpetuation and resolution of the idiopathic inflammatory myopathies (IIMs). HMGB1 is a ubiquitous nuclear DNA-binding protein that can translocate to the cytoplasm and extracellular space, where it exerts pro-inflammatory or pro-repair effects depending on its molecular state and the surrounding cytokine milieu. Given HMGB1 undergoes rapid, passive release from necrotic cells, we postulate a key role for this protein in the aetiopathogenesis of necrotising myopathy (NM). Herein, we evaluate sarcoplasmic expression of HMGB1 in different forms of IIM and correlate it with clinical, serological and histological parameters.

Methods:

Consecutive muscle sections were stained for HMGB1, CD68 (macrophages), CD45 (lymphocytes), neonatal myosin heavy chain (nMHC, regenerating myofibres) and LC3 (an autophagic protein) using immunohistochemistry. Standard H&E stains were performed to assess the degree of necrosis. Slides were independently graded by a muscle pathologist. Clinical and demographic data were prospectively collected. Dermatomyositis (DM) and polymyositis (PM) patients satisfied EULAR/ACR criteria. Inclusion Body Myositis (IBM) patients satisfied European Neuromuscular Centre Criteria. The diagnosis of necrotising myopathy (NM) was made where necrotic muscle fibres were the predominant abnormal histological feature and macrophage infiltration exceeded lymphocyte infiltration.

Results:

Samples from 132 IIM patients with NM (n = 59), DM (n = 17), PM (n = 19), IBM (n = 22) and non-specific IIM (NSIIM, n = 15) were analysed, in addition to 18 control samples. Sarcoplasmic HMGB1 was significantly elevated in all IIM subtypes compared with controls (p < 0.001). Levels correlated positively with creatine kinase (Rs 0.31, p = 0.002) and physician’s global assessments of disease activity (Rs 0.89, p = 0.001), negatively with manual assessments of muscle strength (MMT8, Rs -0.77, p = 0.009) and negatively with cumulative prednisolone dose (Rs -0.24, p = 0.03). Patients with NM and IBM had significantly increased sarcoplasmic HMGB1 compared with DM, PM and NSIIM. In NM patients, HMGB1 grades were highly correlated with the degree of necrosis (Rs 0.74, p < 0.001) and inflammatory infiltration (CD68: Rs 0.66, p < 0.001; CD45: Rs 0.62, p < 0.001). In IBM, HMGB1 grades were highly correlated with regenerating myofibers (Rs 0.81, p < 0.001) and autophagic proteins (Rs 0.85, p = 0.002).

Conclusion:

Sarcoplasmic levels of HMGB1 are significantly elevated in NM and IBM compared with other IIM subtypes. The mechanisms underpinning aberrant sarcoplasmic expression in these subtypes are likely to be distinct and may reflect differing roles for this protein in these particular subtypes. Our finding of a negative association with cumulative prednisolone exposure supports earlier work demonstrating a reduction in tissue HMGB1 with treatment. Understanding the role of HMGB1 in the pathogenesis of these complex conditions may lead to novel diagnostic paradigms and therapeutic interventions.


Disclosure: J. Day, None; S. Otto, None; K. Cash, None; P. Eldi, None; P. Hissaria, None; S. Proudman, None; J. Hayball, None; V. Limaye, None.

To cite this abstract in AMA style:

Day J, Otto S, Cash K, Eldi P, Hissaria P, Proudman S, Hayball J, Limaye V. Aberrant Sarcoplasmic Expression of the Alarmin ‘High Mobility Group Box Protein 1” (HMGB1) in Patients with Idiopathic Inflammatory Myopathy [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/aberrant-sarcoplasmic-expression-of-the-alarmin-high-mobility-group-box-protein-1-hmgb1-in-patients-with-idiopathic-inflammatory-myopathy/. Accessed January 31, 2023.
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