Endoplasmic Reticulum Stress Is Involved Immune-mediated Necrotizing Myopathy And The Study Of Clinicopathologic Mechanism

PART I Endoplasmic reticulum stress is involved in muscular pathogenesis in immune-mediated necrotizing myopathyObjective: Endoplasmic reticulum(ER)stress plays pivotal roles in regulation of skeletal muscle damage and dysfunction in multiple disease conditions.The activation of ER stress in immune-mediated necrotizing myopathy(IMNM)has not been studied.Methods: Thirty-seven patients with IMNM,twenty-one patients with dermatomyositis(DM),six patients with anti-synthetase syndrome(ASS),and ten controls were enrolled.The expression of ER stress-induced autophagy pathway was detected using immunohistochemistry staining,Western Blot,and real-time quantitative Polymerase Chain Reaction.In vitro study,tunicamycin(TM)or thapsigargin(TG)was used to induced ER stress in human myoblast.Then the ER stress-induced autophagy related ptoreins and major histocompatibility complex I(MHC-I)were evaluated.Cytokines,chemokines,myofier regeneration and atrophagy associated genes were also measured.Results: 1.The ER stress-induced autophagy pathway was activated in biopsied specimens of patients with IMNM,DM,and ASS.2.The ER chaperone protein,glucose-regulated protein 78(GRP78)/immuoglobulin heavy chain binding protein(Bi P)expression in skeletal muscle positively correlated with autophagy,myofiber atrophy,myonecrosis,myoregeneration,and disease activity in IMNM.3.In DM,Bi P expression was significantly associated with myofiber autophagy,atrophy,myonecrosis and myoregeneration.4.In ASS,Bi P expression correlated with myofiber autophagy.5.ER stress induced human myoblast autophagy in vitro study.6.ER stress increased the expression of MHC-I,pro-inflammatory cytokines,and chemokines in human myoblast.7.ER stress inhibited myofiber regeneration and atrophgy.Conclusions: ER stress correlates with disease activity in IMNM.ER stress response may be responsible for skeletal muscle damage and repair in idiopathic inflammatory myopathies.PART II The clinicopathological distinction between seronegative and seropositive immune-mediated necrotizing myopathy in ChinaObjective: The present study aimed to compare the clinicopathological features of patients with seronegative immune-mediated necrotizing myopathy(IMNM)and those positive for anti-signal recognition particle(SRP)or anti-3-hydroxy-3-methylglutarylcoenzyme-a reductase(HMGCR)antibodies.Methods: We retrospectively analyzed the data of patients with IMNM treated in the Neurology Department of Tongji Hospital from January 1,2013,to December 31,2019.Results: 1.Among the 117 patients with IMNM,30.8%(36/117)were positive for anti-SRP antibodies,6.0%(7/117)were positive for anti-HMGCR antibodies,and 13.7%(16/117)were seronegative.2.Myalgia at presentation(62.5% vs.23.3%,P = 0.0114)was more commonly observed in patients with seronegative IMNM than in those with seropositive IMNM.3.Subclinical cardiac involvement was more frequently detected in seronegative IMNM than in seropositive IMNM(6/13 vs.5/33,P = 0.0509,echocardiogram;7/7 vs 12/24,P = 0.0261,cardiac MRI).4.Membrane attack complex(MAC)Deposition on the sarcolemma of myofibers in biopsied muscle was less commonly observed in patients with seronegative IMNM than in patients with seropositive IMNM(16.7% vs.68.2%,P = 0.0104).5.The rate of marked improvement following immunotherapy tended to be higher in patients with seronegative IMNM than in those with seropositive IMNM(87.5% vs.61%,P = 0.0641).Conclusions: Patients with seronegative IMNM more frequently present with myalgia at onset,exhibit more subclinical cardiac involvement,uncommon MAC deposition on myofibers,and likely experience better outcomes than those with seropositive IMNM.