Distribution of anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses in MDA5+ dermatomyositis

Chen, M.; Zhao, Qi; Diao, Licheng; Xue, Ke; Ruan, Yeping; Xue, Feng; Li, Jian; Shi, Ruihan; Pan, Meng; Zheng, Jie; Cao, Hua

doi:10.1093/rheumatology/keab268

Cited by 11 publications

(13 citation statements)

References 49 publications

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“…Interestingly, anti-MDA5 IgG1 were associated with higher serum ferritin levels, severe interstitial pneumonia, and a higher mortality rate. The combined positivity for anti-MDA5 IgG1 and anti-MDA5 IgG4 was predictive of poor prognosis ( 145 ). IgG1 are potent activators of the complement pathway, and as a result, anti-MDA5 IgG1 could be the main subclass involved in the pathogenesis of the disease.…”

Section: Pathogenesis Of the Diseasementioning

confidence: 99%

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: Pathogenesis Of the Diseasementioning

confidence: 99%

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

2021

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“…One study showed that DM/CADM patients with anti-MDA5 IgG1 subclasses were correlated to significantly higher occurrence rates of acute interstitial pneumonia, serum levels of lactate dehydrogenase (LDH), and ferritin. Higher mortality rates were detected in patients who were positive for anti-MDA5 IgG1 and IgG4, thus suggesting that these two IgG subtypes might serve as useful biomarkers for predicting mortality in patients with DM-ILD ( 74 ).…”

Section: The Mechanisms Underlying Ifn I Pathway 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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“…A fluorescein isothiocyanate (FITC)-conjugated goat anti-human IgG,A,M antibody (BI2114; Abliance, Compiègne, France) was diluted at 1:300 in PBS and used as a secondary Ab, which was contrary to the ELISA method that uses an anti-IgG only. The choice of using anti-IgG,A,M Abs, rather than anti-IgG Abs as secondary Abs in the IIF test, is justified by the fact that it has previously been reported that different isotypes of anti-MDA5 antibodies are detectable in the serum of patients, including the different subtypes of IgG, IgA, and IgM [ 27 ]. Moreover, the FITC anti-IgG,A,M Abs used in this study did not generate disturbing background noise for reading.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies

Nombel

Fabien

et al. 2022

Biomedicines

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Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease’s activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA.

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Distribution of anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses in MDA5+ dermatomyositis

Cited by 11 publications

References 49 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

Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies

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