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Myositis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
While muscle biopsies have been useful in subcategorizing IIM into different types (DM, PM, IMNM, IBM), we still do not have a clear picture of the underlying immunopathology that leads to the initiation and progression of disease. There are indications that the underlying pathology is diverse based on the MSA, so this subcategorization will perhaps give us a better chance to delve deeply into the pathogenesis in each different patient group. As an example, the seasonality of anti-MDA5+ DM implies that there might be an association with a viral trigger. In addition, the fact that anti-MDA5+ DM is more severe in Asian populations might allow for discovery of a specific genetic background that favors the development of an anti-MDA5 autoimmune response.
Connective Tissue Disorders
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Laura Atzori, Caterina Ferreli, Franco Rongioletti
Blood chemistry and myositis autoantibodies that not only are highly disease-specific but also associated with distinct clinical features are reported in Table 12.7. Anti-MDA5 should be checked since this has been linked to rapidly progressing interstitial lung disease, which is typically fatal.
Inflammatory Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Anti-MDA5 antibody (melanoma differentiation-associated protein 5) was first identified as CADM-140 antigen. It is a cytoplasmic RNA-specific helicase that belongs to a family of retinoic acid-inducible gene (RIG) I-like receptors. It is associated with amyopathic DM or DM/PM spectrum (non-ARS). These patients are clinically asymptomatic with minimal skin features. There is no perifascicular pathology, but MHC class-I may show either widespread or perifascicular expression. The majority of these cases have high prevalence of rapid progressive interstitial lung disease leading to early death.
Functional significance of the rare rs35667974 IFIH1 gene polymorphism, associated with multiple autoimmune diseases, using a structural biological approach
Published in Autoimmunity, 2022
Maria I. Zervou, Athena C. Andreou, Elias E. Eliopoulos, George N. Goulielmos
Interferon-induced with helicase C domain 1 (IFIH1) gene encodes a cytoplasmic RNA helicase MDA5 (otherwise known as MDA5) that recognizes viral RNA and mediates an immune response on viral infection [2]. MDA5 activates the type I interferon signalling pathway upon detection of long viral dsRNA generated during replication of picornaviruses. Upon binding to dsRNA, MDA5 forms a filamentous assembly along the length of dsRNA and utilizes ATP-dependent filament dynamics to discriminate between self vs. non-self on the basis of dsRNA length [3]. It has been shown that mutations of filament-forming residues result in loss of filament formation and MDA5-dependent signalling, with the exception of a pair of mutations, which moderately enhance signalling [4]. In a clinical setting, increased interferon signalling from mutations that stabilize the filament-forming interfaces may be pathogenic. Indeed, many gain-of-function mutations in MDA5 cause severe autoimmune disease [5]. However, mutation positivity and positivity for an interferon signature are not necessarily sufficient to develop an overt clinical phenotype. It has been shown that IFIH1 and PTPN2 contribute to the pathogenesis of diabetes by modifying pancreatic β-cell responses to the viral by-product double-stranded RNA through the regulation of inflammatory signals such as type I-IFNs cytokines [6]. The group of monogenic diseases in which a constitutive upregulation of type I IFN production is considered directly relevant to pathogenesis are clustered under the term “type I interferonopathies” introduced by Crow in 2010 [7].
Association of Elongation Factor Tu GTP-binding Domain-containing 2 Gene (EFTUD2) Polymorphism with the Risk of Hepatitis B Virus Infection
Published in Immunological Investigations, 2022
Anran Tian, Yuwen Li, Haozhi Fan, Pingping Hu, Ruirui Xu, Hui Yuan, Jinyuan Cai, Wen Zhang, Ming Yue, Jun Li, Chen Dong, Chuanlong Zhu
EFTUD2, an extremely conserved spliceosomal GTPase, encodes U5-116 kDa, which comprises a GTP-binding domain (Lines et al. 2012). The downregulation of Snu114p expression reduces the accumulation of unspliced pre-U3 RNAs, demonstrating that Snu114p is an essential factor involved in the splicing of pre-mRNA into mature RNA (Fabrizio et al. 1997). The early inhibitory effect of HBV on the innate immunity of hepatocytes is accomplished via TLR3 and retinoic acid-inducible gene 1 (RIG-1)/MDA5 signaling pathways (Luangsay et al. 2015). MDA5 and RIG-1 are sensors of microbial pathogen-associated molecular patterns in viral dsRNA (a primary mode of replication for numerous viruses) (Ebrahim et al. 2015). In host cells, RIG-1 and MDA5 detect exogenous viral genetic material, such as some double-stranded DNA viruses (HBV). EFTUD2 regulates RIG-1 and MDA5 expression. RIG-1, an intracellular signal transduction factor, has been shown to effectively activate antiviral responses to HBV infection (Sato et al. 2015; Zhu et al. 2015b). Therefore, we propose a model by which EFTUD2 polymorphisms play an important role in HBV infection susceptibility through the regulation of EFTUD2 expression and affect the production of mature mRNA of downstream of RIG-1 and MDA5.
Early initiation of plasma exchange therapy for a patient with anti-MDA5 autoantibody-positive dermatomyositis developing rapidly progressive interstitial lung disease
Published in Modern Rheumatology Case Reports, 2021
Noriko Sasaki, Akira Ishii, Takayoshi Kurabayashi, Mai Sugiyama, Yuto Izumi, Yoko Nakagome, Kazuki Hirano, Sho Sasaki, Yasushi Kondo, Shinichi Nogi, Ayumi Nishikawa, Yuji Hosono, Chiho Yamada, Shinji Sato
The pathogenesis of anti-MDA5 positive RP-ILD and DM remains unclear. Previous studies have reported that the titre of anti-MDA5 antibody measured by ELISA closely tracks RP-ILD disease activity [13,17], and also, that the titre before the treatment is a useful predictor of prognosis [13,17]. Recently, the elevation of anti-MDA5 antibody titre at the time of relapse has been described [40]. These results suggested that anti-MDA5 antibody or MDA5 itself might be involved in the pathogenesis of this condition. Thus, early PE therapy might retard the progression of anti-MDA5 antibody-positive RP-ILD by depleting MDA5, MDA5 fragments or complexes with viruses or MDA5/anti-MDA5 antibody complexes from the serum. Therefore, the early initiation of PE therapy together with intensive immunosuppressive therapy to inhibit production of the causative proteins might be expected to synergize. Indeed, we saw that the anti-MDA5 antibody titre decreased just after the start of PE therapy and the decrease of titre is also consistent with an effect of PE in the case reported here.