Pathogenic role of anti–signal recognition protein and anti–3‐Hydroxy‐3‐methylglutaryl‐<scp>C</scp>o<scp>A</scp> reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies

Arouche-Delaperche, Louiza; Allenbach, Yves; Amelin, D.; Preuße, Corinna; Mouly, Vincent; Mauhin, Wladimir; Tchoupou, Gaelle Dzangue; Drouot, Laurent; Boyer, Olivier; Stenzel, Werner; Butler-Browne, Gillian; Benveniste, Olivier

doi:10.1002/ana.24902

Cited by 113 publications

(92 citation statements)

References 50 publications

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“…Such an analysis would be impractical using immunoblotting techniques to quantify protein expression levels. Further, we and others have previously shown that Mi‐2, TIF1γ, Jo‐1, HMGCR, and SRP proteins are upregulated in regenerating cells of myositis muscle , validating a correlation between RNA levels and protein levels for these autoantigens.…”

Section: Discussionsupporting

confidence: 73%

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity

Pinal‐Fernandez¹,

Amici

Parks

et al. 2019

Arthritis & Rheumatology

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Objective Although more than a dozen myositis‐specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis. Methods In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA‐positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells. Results Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl‐coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo‐1 (n = 18), nuclear matrix protein 2 (n = 12), Mi‐2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation–associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells. Conclusion Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.

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Section: Discussionsupporting

confidence: 73%

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity

Pinal‐Fernandez¹,

Amici

Parks

et al. 2019

Arthritis & Rheumatology

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“…We next questioned how the immune system may recognize “CASA‐tagged” myofibers. Since we had previously shown that MHC class I is upregulated on the sarcolemmal surface (in addition to sarcoplasmic positivity) of IMNM myofibers, and that it confers parts of the immune response in vivo and in vitro , we performed co‐staining of MHC class I and p62, and show that p62 positive fibers were lined by sarcolemmal MHC class I in V+ and V− biopsies of IMNM patients, with MHC class I not beeing exclusively positive on p‐62‐positive fibers (Figure C). MHC class I expression was particularly elevated in V+ IMNM biopsies, (not significant as compared to V−), which is shown by semi‐quantitative evaluation and exemplary immunohistochemistry (Figure A,B,D).…”

Section: Resultsmentioning

confidence: 99%

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

et al. 2019

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Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune‐mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone‐assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB‐crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2‐associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM‐specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.

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“…Both molecules could be exposed on sarcolemma as autoantigens. In addition, it has recently been demonstrated that the IMNM‐specific autoantibodies anti‐SRP and anti‐HMGCR impair muscle regeneration via a decreased production of interleukin (IL) 4 and IL13 from myotubes and bind their cognate autoantigens, ectopically exposed on NCAM + regenerating myofibers from patients with IMNM . Autoantigen levels, such as HMGCR protein, were highest in regenerating myofibers and may perpetuate the immune response.…”

Section: Discussionmentioning

confidence: 99%

Autophagy markers LC3 and p62 accumulate in immune‐mediated necrotizing myopathy

et al. 2019

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Introduction: The molecular mechanism of immune‐mediated necrotizing myopathy (IMNM) remains unknown. Autophagy impairment, described in autoimmune diseases, is a key process in myofiber protein degradation flux and muscle integrity and has not been studied in IMNM. Methods: Muscle biopsies from patients with IMNM (n = 40), dermatomyositis (DM; 24), polymyositis (PM; 8), polymyositis with mitochondrial pathology (4), sporadic inclusion body myositis (8), and controls (6) were compared by immunohistochemistry. Results: The proportions of myofibers containing autophagy markers LC3b and p62 were higher in IMNM than in DM or PM and correlated with creatine kinase levels. In IMNM, compartmentalized LC3b puncta were located in regenerating and degenerating myofibers surrounded by major histocompatibility complex type II+ inflammatory cells. Several IMNM myofibers accumulated ubiquitin and misfolded protein. Discussion: The detection of LC3b+ or p62+ myofibers could be used in differentiating IMNM from PM. The identification of autophagy‐modifying molecules potentially could improve patients’ outcomes. Muscle Nerve, 2019

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Pathogenic role of anti–signal recognition protein and anti–3‐Hydroxy‐3‐methylglutaryl‐CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies

Abstract: 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.

Cited by 113 publications

References 50 publications

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

Autophagy markers LC3 and p62 accumulate in immune‐mediated necrotizing myopathy

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