Discoveries of myositis-specific antibodies, transcriptomic signatures, and clinicoseropathological correlation support classification of idiopathic inflammatory myopathies (IIM) into four major ...subgroups: dermatomyositis, immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASS), and inclusion body myositis (IBM) whereas leaving polymyositis as a historical nonspecific diagnosis of exclusion. This review summarizes and comments on recent knowledge regarding the major subgroup of IIM.
Type 1 interferon (IFN1) pathway activation is the most prominent in dermatomyositis whereas type 2 interferon (IFN2) pathway activation is high in IBM and ASS; neither pathway is distinct in IMNM. Myxovirus-resistant protein A, IFN1 surrogate marker, is now one of definite dermatomyositis muscle biopsy criteria in the new 2018 European Neuromuscular Centre classification of dermatomyositis; the classification emphasizes on different categorization with and without dermatomyositis-specific antibody result. Novel HLA loci associated with anti-TIF1-γ, anti-Mi-2, and anti-Jo-1 antibodies in Caucasian population are identified. Associations of chaperon-assisted selective autophagy (CASA) and complement-mediated autoimmunity in IMNM as well as highly differentiated T cells in IBM are discovered.
Current IIM classification requires integrated clinicoseropathological approaches. Additional information, such as transcriptomics, HLA haplotyping, and potential biomarkers help tailoring categorization that may have future diagnostic and therapeutic implications.
Inflammatory myopathies are rare diseases. Their diagnosis criteria are historically based on their clinical phenotype (topography of the muscle weakness, presence of skin lesions and/or of ...extra-skin/muscle signs) and the presence of inflammatory infiltrates on muscle biopsy. However, the recent discovery of different myositis-specific antibodies (MSA) or myositis-associated antibodies (MAA) permitted to revisit these old classifications. This review covers recent findings in clinical and pathological phenotypes regarding prognosis, associated cancer and response to the treatment based on MSA/MAA categorization.
Since the mid-1970s, about 20 MSA or MAA were discovered year after year (by immunoprecipitation). Now commercial kits (mainly dot line assays) permit their detection routinely which is clearly a help for the diagnosis but also give some key indications on clinical features, risk of associated cancers and response to the treatments.
Overlap myositis is associated with antisynthetase antibodies (Abs) or those associated with sclerodermia (anti-RNP, Ku and PM-ScL). Dermatomyositis is associated with anti-Mi2, small ubiquitin-like modifier activating enzyme (SAE), nuclear matrix protein-2 (NXP2), TIF-1γ or melanoma differentiation-associated gene 5 (MDA5) Abs. Immune-mediated necrotizing myopathies are associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) Abs. One third of inclusion body myositis' patients also presented anti-cytosolic 5'-nucleotidase 1A (cN1A) Abs. The risk of associated cancers is elevated with anti-TIF-1γ, NXP2 or HMGCR Abs.
Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19.
To study skeletal muscle and myocardial inflammation in patients with ...COVID-19 who had died.
This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19.
Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates.
Forty-three patients with COVID-19 (median interquartile range age, 72 16 years; 31 men 72%) and 11 patients with diseases other than COVID-19 (median interquartile range age, 71 5 years; 7 men 64%) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean SD, 3.4 1.8 vs 1.5 1.0; 95% CI, 0-3; P < .001) and a higher inflammation score (mean SD, 3.5 2.1 vs 1.0 0.6; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median interquartile range, 8 8 vs 3 4 cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy.
In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.
Biomarkers as parameters of pathophysiological conditions can be of outmost relevance for inflammatory myopathies. They are particularly warranted to inform about diagnostic, prognostic, and ...therapeutic questions. As biomarkers become more and more relevant in daily routine, this review focusses on relevant aspects particularly addressing myopathological features. However, the level of evidence to use them in daily routine at presence is low, still since none of them has been validated in large cohorts of patients and rarely in independent biopsy series. Hence, they should be read as mere expert opinions. The evaluation of biomarkers as well as key biological parameters is an ongoing process, and we start learning about relevance of them, as we must recognize that pathophysiology of myositis is biologically incompletely understood. As such this approach should be considered an essay toward expansion of the definition "biomarker" to myositis, an emerging field of interest in biomedical research.
Objective
Immune‐mediated necrotizing myopathies (IMNM) may be associated with either anti–signal recognition protein (SRP) or anti–3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) antibodies (Abs), ...and the titer of these Abs is correlated with disease activity. We investigated whether anti‐SRP and anti‐HMGCR Abs could be involved in muscle damage.
Methods
Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles.
Results
In muscle biopsies of patients with anti‐SRP+ and anti‐HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti‐SRP and anti‐HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)‐6, and reactive oxygen species. In the presence of anti‐SRP or anti‐HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL‐4 and IL‐13. The addition of IL‐4 and/or IL‐13 totally rescued fusion capacity.
Interpretation
These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538–548
Purpose of Review
To review recent advances in immunopathology for idiopathic inflammatory myopathies, focusing on widely available immunohistochemical analyses.
Recent Findings
Sarcoplasmic ...expression of myxovirus resistance protein A (MxA) is specifically observed in all types of dermatomyositis and informs that type I interferons are crucially involved in its pathogenesis. It is a more sensitive diagnostic marker than perifascicular atrophy. Diffuse tiny dots in the sarcoplasm highlighted by p62 immunostaining are characteristically seen in immune-mediated necrotizing myopathy. This feature is linked to a chaperone-assisted selective autophagy pathway. Myofiber invasion by highly differentiated T cells, a marker of which is KLRG1, is specific to inclusion body myositis and has a crucial role in its pathogenesis.
Summary
The recent advances in immunopathology contribute to increased diagnostic accuracy and a better understanding of the underlying pathophysiology in different types of idiopathic inflammatory myopathies.
Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing ...mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)+ and CD105+ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ+ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.
Idiopathic inflammatory myopathies can be classified as polymyositis, dermatomyositis, immune-mediated necrotizing myopathy, sporadic inclusion body myositis or non-specific myositis. Anti-Jo-1 ...antibody-positive patients are assigned to either polymyositis or dermatomyositis suggesting overlapping pathological features. We aimed to determine if anti-Jo-1 antibody-positive myopathy has a specific morphological phenotype. In a series of 53 muscle biopsies of anti-Jo-1 antibody-positive patients, relevant descriptive criteria defining a characteristic morphological pattern were identified. They were tested in a second series of anti-Jo-1 antibody-positive patients and compared to 63 biopsies from patients suffering from other idiopathic inflammatory myopathies. In anti-Jo-1 antibody-positive patients, necrotic fibres, which strongly clustered in perifascicular regions, were frequently observed. Sarcolemmal complement deposition was detected specifically in perifascicular areas. Inflammation was mainly located in the perimysium and around vessels in 90.6%. Perimysial fragmentation was observed in 90% of cases. Major histocompatibility complex class I staining was diffusely positive, with a perifascicular reinforcement. Multivariate analysis showed that criteria defining perifascicular pathology: perifascicular necrosis, atrophy, and perimysial fragmentation allow the distinction of anti-Jo-1 antibody-positive patients, among patients suffering from other idiopathic inflammatory myopathies. Anti-Jo-1 antibody-positive patients displayed perifascicular necrosis, whereas dermatomyositis patients exhibited perifascicular atrophy.
While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth ...and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma‐associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H‐non‐mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high‐grade astrocytomas by CD11b‐based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT‐PCR and bioinformatic analyses. A higher amount of CD68‐, CD163‐ and CD206‐positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro‐inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti‐inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2‐like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H‐non‐mutant GBMs.
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