A recent eBioMedicine study identifies shared immunopathology between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and melanoma differentiation-associated protein-5 (MDA5) autoimmunity.

Study: MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C). Image Credit: Light Studio Design / Shutterstock.com

Background

Dermatomyositis (DM) is an autoimmune disease that is characterized by severe skin and muscle inflammation. Additionally, DM is associated with interstitial lung disease (ILD), which causes progressive pulmonary fibrosis.

Anti-Mi-2, which targets the Mi-2 nuclear antigen, is the first autoantibody to be associated with DM. Over time, multiple myositis-specific and related autoantibodies (MSA) have been identified for different phenotypic patterns.

Clinically, amyopathic dermatomyositis (CADM) has been significantly associated with DM and leads to progressive ILD. CADM is expressed through retinoic acid-inducible gene 1 (RIG-1)-like receptor family gene, IFIH1, which encodes the MDA5 protein. 

A recent study highlighted that MDA5+ cases predating the coronavirus disease 2019 (COVID-19) pandemic exhibited a significant manifestation of ILD. However, these patients did not develop the classical DM heliotropic rash and instead developed skin-based clinical symptoms, including tender palmar papules and skin ulceration. 

MDA5 is a RIG-1 helicase12 that functions as an RNA sensor and pattern recognition receptor for SARS-CoV-2. A recent study revealed that variants of the IFIH1 gene confer protection against SARS-CoV-2 infections and facilitate favorable outcomes.

Thus, it is vital to identify the factors associated with MDA5+-related disease to better understand the rise in anti-MDA5 positivity during the COVID-19 pandemic.

About the study

The current study investigated the epidemiological factors that cause MDA5+ related disease. MDA5 autoimmunity with interstitial pneumonitis cotemporaneous with the COVID-19 pandemic (MIP-C) was also investigated. 

To this end, transcriptomic datasets were used to explore the mechanisms that are shared between MDA5-associated disease and COVID-19. Transcriptomic datasets were also used to compare autoimmune lung disease, acute COVID-19 lung disease, and idiopathic pulmonary fibrosis (IPF) to better understand the origin of the MDA5+ -DM outbreak. 

A model was developed that connected severe anti-viral cytokine response with interferon-induced helicase C domain-containing protein 1 (IFIH1) stimulation, which is responsible for the unique immunophenotype linked with MSA-associated progressive ILD.

Data on the number of MDA5+ cases each year between January 2018 and December 2022 was collected from the Leeds Teaching Hospitals NHS Trust, which serves as an immunology laboratory reference for Yorkshire. Clinical notes for MDA5+ cases indicated patterns of symptomatic MDA5 disease, particularly the degree of ILD, treatment, therapy responses, and survival rates. 

Public Health England (PHE) data allowed the researchers to quantify monthly COVID-19 positivity rates in Yorkshire. Data on these patients’ vaccination status and severity of lung infection were also obtained. 

Study findings

The current study documents the features and outcomes of the surge in MDA5+ myositis or ILD that occurred during the COVID-19 pandemic in the United Kingdom, especially in 2021.

Six new MDA5+ cases were identified between January 2018 and December 2019, which indicates 1.2% and 0.4% MSA immunoblot positivity in the respective years. However, after the second COVID-19 wave, there was a rapid increase in new MDA5+ cases. More specifically, the number of new cases in 2020, 2021, and 2022 were nine, 35, and 16, respectively; therefore, the rate of MDA5 positivity increased from 1.2% in 2018 to 1.7% in 2022.

Approximately 42% of MDA5+ cases were associated with progressive ILD, with about 33% exhibiting aggressive MDA5+-ILD. Both transcriptomic dataset analysis and clinical epidemiologic observations indicated that the surge in MDA5 autoimmunity and ILD during COVID-19 could be due to shared aberrant type 1-centric IFN responses but not IPF.

Considering the study findings and similar cases reported internationally, the current study proposed the terms MDA5-autoimmunity and MIP-C. The merit of this acronym lies in the distinct features that can separate MIP-C from the syndrome of adult MDA5+ DM57. For example, the MIP-C phenotype has similarities to multisystem inflammatory syndrome in children (MIS-C), even in some cases where the patient did not have a history of COVID-19.

About 42% of new cases were not vaccinated before MDA5+ disease and represented milder COVID-19 infection, which could be sufficient to cause MDA5 autoimmunity. 

An immune reaction or autoimmunity against MDA5 upon SARS-CoV-2 and/or vaccine exposure was assessed. This indicated novel immunogenicity in non-immune subjects upon RNA engagement with MDA5 that increased cytokine response and induced autoimmune disease.

Theoretically, the development of herd immunity and reduced SARS-CoV-2 exposure contributed to milder symptoms in the MIP-C cohort. Taken together, MDA5 protein activation through natural infection or vaccination can potentially induce MIP-C.

Conclusions

The current transcriptomic analysis elucidated the possible causal link between the surge in anti-MDA5-positivity, COVID-19, and autoimmune ILD. In the future, these findings must be validated using multicenter cohorts across nations.