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We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune‐mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP+ and HMGCR+ muscle samples (p < 0.0001 in SRP+ and p = 0.0316 for HMGCR+), with higher values for SRP+ (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll‐like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP+ compared to HMGCR+ patients. Within IMNM group, only IL‐7 was differentially expressed between SRP+ and HMGCR+ patients, with higher values in SRP+ patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL‐7 represent potential immune biomarkers able to differentiate between SRP+ and HMGCR+ patients. [ABSTRACT FROM AUTHOR]

Laminopathies are a heterogeneous group of diseases, caused by mutations in lamin A/C proteins. The most common laminopathy (LMNA-related myopathies, LMNA-RM) affects skeletal and cardiac muscles; muscle histopathology is variable, ranging from mild unspecific changes to dystrophic features, sometimes with inflammatory evidence. Whether the genetic defect might activate innate immune components, leading to chronic inflammation, myofiber necrosis and fibrosis, is still unknown. By qPCR, a significant up-regulation of Toll-like receptor (TLR) 7 and 9 transcripts was found in LMNA-RM compared to other myopathic and non-myopathic muscles. A marked TLR7/9 staining was observed on LMNA-RM blood vessels and muscle fibers and, when present, on infiltrating cells, mainly macrophages, scattered in the tissue or localized close to degenerated muscle fibers and connective tissue. Our results recognize innate immunity as a player in LMNA-RM pathogenesis. Modulation of TLR7/9 signaling pathways and decrease of macrophage-mediated inflammation might be potential therapeutic strategies in LMNA-RM management. Abbreviations: DMD, Duchenne muscular dystrophy; EDMD2, Emery-Dreifuss muscular dystrophy type 2; FSHD, facio-scapulo-humeral muscular dystrophy; LGMD1B, limb-girdle muscular dystrophy type 1B; LMNA-CMD, LMNA-related congenital muscular dystrophy; LMNA-RM, LMNA-related myopathies; sIBM, sporadic inclusion body myositis; TLR, Toll-like receptor [ABSTRACT FROM AUTHOR]

Unlabelled: Mutations in SEPN1 cause selenoprotein N (SEPN)-related myopathy (SEPN-RM) characterized by early-onset axial and neck weakness, spinal rigidity, respiratory failure and histopathological features, ranging from mild dystrophic signs to a congenital myopathy pattern with myofibrillar disorganization. We report on clinical and instrumental features in three patients affected with a congenital myopathy characterized by prevalent neck weakness starting at different ages and mild myopathy, in whom we performed diagnosis of SEPN-RM. The patients presented myopathic signs since their first years of life, but the disease remained unrecognized because of a relatively benign myopathic course. In two cases, myopathic features were stable after 2 years of follow-up, but respiratory involvement worsened. The muscle MRI and muscle biopsy showed a typical pattern of SEPN-RM. Molecular diagnosis revealed two novel homozygous mutations in SEPN1, c.1176delA and c.726_727InsTCC.Conclusion: This report underlines the clinical diagnostic clues of early neck and axial weakness to suspect a SEPN-RM and the usefulness of muscle MRI in conjunction with clinical features to achieve the diagnosis. Our data confirm the slow progression of respiratory involvement in spite of the relatively stable course of myopathy. We report two previously undescribed mutations in SEPN1.What Is Known: • Mutations in SEPN1 cause myopathy characterized by early-onset axial and neck weakness spinal rigidity and respiratory failure. • SEPN-related myopathies have been initially associated with four distinct histopathological entities that however appear more mixed in recently described cases. What is New: • SEPN-related myopathies can remain unrecognized because of the normal early motor development and relatively benign myopathic course of the disease. • Our study adds two novel homozygous mutations to the number of reported pathogenic SEPN1 variants. [ABSTRACT FROM AUTHOR]

Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous ‘danger signal’. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types. [ABSTRACT FROM AUTHOR]