Mitochondrial morphology and MAVS‐IFN1 signaling pathway in muscles of anti‐MDA5 dermatomyositis

Jiang, Yanyan; Liu, Yilin; Zhao, Yawen; Zheng, Yiming; Yu, Meng; Deng, Jianwen; Hao, Hongjun; Zhang, Wei; Wang, Zhaoxia; Yuan, Yun

doi:10.1002/acn3.51311

Cited by 11 publications

(11 citation statements)

References 27 publications

(65 reference statements)

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“…Complement membrane attack complex deposition is rarely observed. Furthermore, IFN signature in skeletal muscles of patients with anti-MDA5 DM is up-regulated, compared with healthy subjects but lower than patients with anti-MDA5 negative DM ( 21 , 22 ). These observations are consistent with the mild muscle phenotype frequently associated with anti-MDA5 DM.…”

Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 87%

“…When present, muscle damage mainly affects proximal muscles ( 2 , 12 ). Several histological features of muscle biopsies are shared by different forms of DM, and include perifascicular fiber atrophy, perivascular inflammation, infiltrates of T and B cells, diffuse class I major histocompatibility complex (MHC-I) expression and deposition of complement attack complex ( 21 , 22 ). In contrast, muscle biopsies of patients with anti-MDA5 DM are often normal or highlight only rare anomalies.…”

Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 99%

“…Ferritin levels correlate with the severity of the disease and ILD ( 6 , 7 , 51 , 52 ). Liver dysfunction is also recurrently observed in anti-MDA5 DM, as evidenced by elevated levels of alanine transaminase or gamma-glutamyl transferase, without elevated creatine kinase ( 6 , 7 , 21 , 53 ). Liver biopsies show steatosis and hepatocyte ballooning ( 53 ).…”

Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 99%

“…Several pieces of evidence point toward a central role of vascular injury in the pathogenesis of anti-MDA5 DM: (i) Patients frequently show typical cutaneous features such as skin ulcers due to severe vasculopathy; (ii) Histopathology of palmar papules, as well as lung tissues highlights vasculopathy ( 12 , 15 , 105 ); (iii) Biomarkers of endothelial dysfunctions have been identified in the sera of patients ( 106 , 107 ); (iv) Patients exhibited a strong IFN-I signature distributed in the vasculature of the skin ( 108 , 109 ). It is important to emphasize that these particular features are observed in the skin and the lungs of patients with anti-MDA5 DM but that there is no or few signs of vasculopathy nor of an enhanced IFN-I signature, compared to other DM, in muscle tissue of anti-MDA5 DM patients ( 21 , 22 ).…”

Section: Pathogenesis Of the Diseasementioning

confidence: 99%

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Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies

2021

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Anti-MDA5 dermatomyositis is a rare systemic autoimmune disease, historically described in Japanese patients with clinically amyopathic dermatomyositis and life-threatening rapidly progressive interstitial lung disease. Subsequently, the complete clinical spectrum of the disease was enriched by skin, articular and vascular manifestations. Depending on the predominance of these symptoms, three distinct clinical phenotypes with different prognosis are now defined. To date, the only known molecular component shared by the three entities are specific antibodies targeting MDA5, a cytosolic protein essential for antiviral host immune responses. Several biological tools have emerged to detect these antibodies, with drawbacks and limitations for each of them. However, the identification of this highly specific serological marker of the disease raises the question of its role in the pathogenesis. Although current knowledge on the pathogenic mechanisms that take place in the disease are still in their enfancy, several lines of evidence support a central role of interferon-mediated vasculopathy in the development of skin and lung lesions, as well as a possible pathogenic involvement of anti-MDA5 antibodies. Here, we review the clinical and biological evidences in favor of these hypothesis, and we discuss the contribution of emerging therapies that shed some light on the pathogenesis of the disease.

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Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 87%

Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 99%

Section: Clinical Spectrum In Adults Of the Dermatomyositis With Anti-mda5 Antibodiesmentioning

confidence: 99%

Section: Pathogenesis Of the Diseasementioning

confidence: 99%

See 2 more Smart Citations

Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies

2021

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“…Although the IFN signature was up-regulated in groups of patients with MDA5 + DM and classic DM when compared with normal muscle, the up-regulation of ISGs was less significantly in MDA5 + DM patients than that in classic DM patients ( 41 ). A study from China investigated the mitochondrial changes and MAVS-type I IFN signaling pathways in the muscles of MDA5 + DM patients ( 42 ). These authors found that the IFN-I inducible proteins (MDA5, MAVS, IRF7, and ISG15) were overexpressed in the muscles of MDA5 + DM patients, suggesting that the MAVS-type I IFN pathway is broadly involved in the muscle pathology of MDA5 + DM.…”

Section: Footprints Of Ifn I System In Organs Involved In Mda5 + Dmmentioning

confidence: 99%

Pathogenesis of Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis: A Concise Review With an Emphasis on Type I Interferon System

Yang

Liu

et al. 2022

Front. Med.

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Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5+ DM) is typically characterized by cutaneous manifestations, amyopathic or hypomyopathic muscle involvement, and a high incidence of rapid progressive interstitial lung disease (RP-ILD). However, the exact etiology and pathogenesis of this condition has yet to be fully elucidated. Melanoma differentiation-associated gene 5 (MDA5), as the autoantigen target, is a member of the retinoic acid-inducible gene-I (RIG-I) family. The MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN). Therefore, it was presumed that viruses might trigger the overproduction of type I IFN, thus contributing to the development of MDA5+ DM. Emerging evidence provides further support to this hypothesis: the increased serum IFNα level was detected in the patients with MDA5+ DM, and the type I IFN gene signature was upregulated in both the peripheral blood mononuclear cells (PBMCs) and the skin tissues from these patients. In particular, RNA sequencing revealed the over-expression of the type I IFN genes in blood vessels from MDA5+ DM patients. In addition, Janus kinase (JAK) inhibitors achieved the promising therapeutic effects in cases with interstitial lung disease (ILD) associated with MDA5+ DM. In this review, we discuss the role of the type I IFN system in the pathogenesis of MDA5+ DM.

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Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

Wang,

Zhao,

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAnti‐mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell‐free mitochondrial DNA (ccf‐mtDNA), and circulating cell‐free nuclear DNA (ccf‐nDNA) in AMA‐associated IIMs.MethodsMedical records of 37 IIMs patients with AMAs were reviewed. Circulating cell‐free mtDNA and ccf‐nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty‐eight immune‐mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti‐synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed.ResultsLimb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf‐mtDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p < 0.001), but no significant differences between AMA‐associated IIMs and IMNM, DM, or ASS. Serum ccf‐nDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p = 0.02), and significantly lower than those in DM (p = 0.02). Serum ccf‐nDNA levels correlated negatively with MMT8 total scores (rs = −0.458, p = 0.037) and positively with mRS scores (rs = 0.486, p = 0.025). Serum ccf‐nDNA levels were significantly higher in the non‐remission group (p < 0.01).InterpretationAMA‐associated IIMs exhibit distinct clinicopathological features. Serum ccf‐nDNA may serve as a potential marker for disease severity and prognosis in AMA‐associated IIMs.

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Mitochondrial morphology and MAVS‐IFN1 signaling pathway in muscles of anti‐MDA5 dermatomyositis

Cited by 11 publications

References 27 publications

Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies

Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies

Pathogenesis of Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis: A Concise Review With an Emphasis on Type I Interferon System

Clinicopathological and circulating cell‐free DNA profile in myositis associated with anti‐mitochondrial antibody

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