Recent eBioMedicine Study identifies shared immunopathology between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and melanoma differentiation-associated autoimmunity protein-5 (MDA5).
Study: MDA5-autoimmunity and interstitial pneumonitis concurrent with the COVID-19 pandemic (MIP-C). Image credit: Light Studio Design / Shutterstock.com
Record
Dermatomyositis (DM) is an autoimmune disease characterized by severe inflammation of the skin and muscles. In addition, DM is associated with interstitial lung disease (ILD), which causes progressive pulmonary fibrosis.
Anti-Mi-2, which targets the nuclear antigen Mi-2, is the first autoantibody associated with DM. Over time, multiple myositis-specific and related autoantibodies (MSAs) 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 the retinoic acid-inducible type 1 (RIG-1) receptor family gene, IFIH1, which encodes the MDA5 protein.
A recent study highlighted that MDA5+ cases that preceded the coronavirus disease 2019 (COVID-19) pandemic showed a significant incidence of ILD. However, these patients did not develop the classic heliotropic rash of DM and instead developed skin-based clinical symptoms, including tender palmar papules and skin ulceration.
MDA5 is a RIG-112 helicase 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.
Therefore, it is crucial to identify the factors associated with MDA5+-associated disease to better understand the increase in anti-MDA5 positivity during the COVID-19 pandemic.
About the study
The current study investigated the epidemiologic factors causing MDA5+-related disease. MDA5 autoimmunity with interstitial pneumonitis concurrent with pandemic COVID-19 (MIP-C) was also investigated.
To this end, transcriptomic datasets were used to investigate mechanisms shared between MDA5-associated disease and COVID-19. Transcriptome datasets were also used to compare autoimmune lung disease, COVID-19 acute lung disease, and idiopathic pulmonary fibrosis (IPF) to better understand the origins of the MDA5+ -DM epidemic.
A model was developed that linked a severe antiviral cytokine response to interferon-inducible helicase C domain-containing protein 1 (IFIH1), which is responsible for the unique immunophenotype associated with MSA-associated progressive ILD.
Data on the number of MDA5+ cases each year between January 2018 and December 2022 were collected from Leeds Teaching Hospitals NHS Trust, which serves as the reference immunology laboratory for Yorkshire. Clinical notes for MDA5+ cases showed patterns of symptomatic MDA5 disease, particularly ILD grade, treatment, treatment responses, and survival rates.
Public Health England (PHE) data allowed researchers to quantify monthly rates of positivity for COVID-19 in Yorkshire. Data on the vaccination status of these patients and the severity of pulmonary infection were also obtained.
Study findings
The current study documents the characteristics and outcomes of the increase in MDA5+ myositis or ILD that occurred during the UK COVID-19 pandemic, specifically in 2021.
Six new MDA5+ cases were identified between January 2018 and December 2019, indicating 1.2% and 0.4% immunoblot MSA positivity in the respective years. However, after the second wave of COVID-19, 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 MDA5 positivity rate increased from 1.2% in 2018 to 1.7% in 2022.
About 42% of MDA5+ cases were associated with progressive ILD, with about 33% showing aggressive MDA5+-ILD. Both transcriptomic data analysis and clinical epidemiological observations indicated that the increase in MDA5 autoimmunity and ILD during COVID-19 could be due to shared aberrant IFN responses centered on type 1 but not in IPF.
Considering the findings of the study and similar cases reported internationally, the current study proposed the terms MDA5-autoimmunity and MIP-C. The advantage of this acronym lies in the distinct features that can separate MIP-C from the MDA5+ DM57 adult syndrome. For example, the MIP-C phenotype has similarities to multisystem inflammatory syndrome in children (MIS-C), even in some cases where the patient had no history of COVID-19.
About 42% of new cases were unvaccinated prior to MDA5+ disease and represented milder COVID-19 infection, which could be sufficient to induce MDA5 autoimmunity.
An immune response or autoimmunity against MDA5 upon exposure to SARS-CoV-2 and/or vaccine was assessed. This demonstrated novel immunogenicity in non-immune subjects after RNA interference with MDA5 increased the cytokine response and induced autoimmune disease.
Theoretically, the development of herd immunity and reduced exposure to SARS-CoV-2 contributed to milder symptoms in the MIP-C cohort. Taken together, activation of MDA5 protein through natural infection or vaccination can potentially induce MIP-C.
conclusions
The current transcriptional analysis elucidated the possible causal relationship between the increase in anti-MDA5 positivity, COVID-19 and autoimmune ILD. In the future, these findings need to be validated using multicenter cohorts in different nations.
Journal Reference:
- David, P., Sinha, S., Iqbal, K., et al. (2024) MDA5-autoimmunity and interstitial pneumonitis concurrent with pandemic COVID-19 (MIP-C). eBioMedicine. doi:10.1016/j.ebiom.2024.105136
