Hierarchical cluster analysis of cytokine profiles reveals a cutaneous vasculitis-associated subgroup in dermatomyositis

Bai, Jingjing; Wu, Caimei; Zhong, Danli; Xu, Dong; Wang, Qian; Zeng, Xiaofeng

doi:10.1007/s10067-020-05339-2

Cited by 20 publications

(13 citation statements)

References 31 publications

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“…Moreover, according to the MSAs classification, we found that the expression of CTACK, Eotaxin, IL1Rα, IL7, IL18, IP10, MCP1, MCP3, MCSF, MIG and SCGFβ were differentially expressed in anti-ARS positive, anti-MDA5 positive, anti-TIF1γ positive IIMs compared with HC groups. These results were partially consistent with those of previous reports ( Gono et al, 2010 ; Gono et al, 2014 ; Zou et al, 2016 ; Chen et al, 2018 ; Bai et al, 2020 ; Sugimoto et al, 2021 ). In addition, serum SCGFβ and CTACK were first found to be increased in IIMs and anti-MDA5 positive patients, respectively.…”

Section: Discussionsupporting

confidence: 93%

The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies

Zhou

Zhao

et al. 2022

Front. Pharmacol.

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Background: Cytokines play a vital role in the pathogenesis of idiopathic inflammatory myopathies (IIMs). Here, we investigated the expression of serum cytokine profiles in untreated IIMs and their correlations with clinical indicators, and further studied the expression of related cytokines receptors in IIMs.Methods: The Human 48-Plex Luminex assay for cytokines was performed in the serum of IIMs, including 93 untreated and 18 follow-up (39 samples) patients, and 32 healthy controls (HC). Mann-Whitney U test with bonferroni adjusted was used to identify the differentially expressed cytokines among groups. Celltalker software was used to identify the receptors of differentially expressed cytokines. The expression of receptors was further validated by published GEO datasets (muscle, blood and skin), RT-qPCR, western blot and flow cytometry.Results: The serum levels of Eotaxin, IL7, IL18, IP10, MCP1, MCSF, MIG and SCGFβ were elevated in the 93 untreated patients. Except for IL7, all other cytokines were decreased after treatment and their levels were positively correlated with clinical indices such as LDH, ESR, CRP, ALT, IgA, AST and IgG while negatively correlated with albumin and MMT8. According to the serum myositis-specific antibodies (MSAs), patients were classified into three groups: anti-ARS (Jo-1, OJ, EJ, PL7, PL12), anti-MDA5 positive, and anti-TIF1γ positive. Compared with HC, the levels of IP10 and MIG were increased in three groups. Moreover, IL18 and MSCF were increased in anti-ARS patients, and CTACK, Eotaxin, IL1Rα, IL7, IL18, MCP1, MCP3, MCSF and SCGFβ were elevated in anti-MDA5 patients. Twenty receptors of the 8 differentially expressed cytokines were matched by celltalker software, among them, IL18R1 and CCR1 were up-regulated in blood, muscle and skin of IIMs from the analysis of GEO published datasets. RT-qPCR and western blot further validated IL18R1 was upregulated in the muscle tissues of dermatomyositis. The number of IL18R1+CD4+ cells was increased while IL18R1+CD8+ cells was decreased in peripheral blood of anti-MDA5 patients.Conclusion: This study showed that cytokine profiles were significantly changed in IIMs, and different MSA groups had unique cytokine expression patterns. The levels of some cytokine were correlated with clinical indices. The IL18 receptor IL18R1 might play important roles in IIMs.

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Section: Discussionsupporting

confidence: 93%

The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies

Zhou

Zhao

et al. 2022

Front. Pharmacol.

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“…Downstream chemokines and cytokines of IFN I system are known to be upregulated in MDA5 + DM patients with ILD. In a hierarchical cluster analysis of cytokine profiles, levels of IFN-related cytokines (IFNγ, IFNα, and IP-10, an IFN-induced proteins) were significantly higher in the anti-MDA5 antibody-positive subgroup patients than in the anti-TIF1γ antibody-positive subgroup patients ( 48 ). Elevated levels of CX3CL1 were found in ILD patients associated with MDA5 + DM and were correlated with the titers of the anti-MDA5 antibodies ( 49 , 50 ).…”

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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“…The cytokine profile in patients with anti-MDA5 DM further supports an upregulated interferon axis (IFN-γ, IFN-α, and IFN-induced protein, IP-10) alongside other proinflammatory cytokines [39,40]. A hierarchical cluster analysis of the cytokine profiles in DM revealed two distinct clusters, with predominance of IFN-related cytokines in cluster one, 75% of which was constituted by anti-MDA5 DM and strong correlation with cutaneous vasculitis [39]. It seems plausible that cytokine mediated microvascular injury may contribute to the unique cutaneous lesions in DM and, possibly, lung involvement.…”

Section: Environmentalmentioning

confidence: 71%

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry

2021

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Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a recently identified subtype of myositis characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and unique cutaneous features. We reviewed PubMed, SCOPUS and Web of Science databases and selected 87 relevant articles after screening 1485 search results, aiming to gain a better understanding of the pathophysiology, clinical features, diagnosis, and treatment approaches of anti-MDA-5 DM described in the literature. The etiopathogenesis is speculatively linked to an unidentified viral trigger on the background of genetic predisposition culminating in an acquired type I interferonopathy. The clinical phenotype is highly varied in different ethnicities, with new clinical features having been recently described, expanding the spectrum of cases that should raise the suspicion of anti-MDA-5 DM. Unfortunately, the diagnosis is frequently missed despite excessive mortality, calling for wider awareness of suspect symptoms. RP ILD is the major determinant of survival, treatment being largely based on observational studies with recent insights into aggressive combined immunosuppression at the outset.

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Hierarchical cluster analysis of cytokine profiles reveals a cutaneous vasculitis-associated subgroup in dermatomyositis

Cited by 20 publications

References 31 publications

The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies

The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies

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

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry

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