Distinct autoimmune response to COVID-19 unveiled

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In a recent study published on the preprint server medRxiv*, researchers examine a large dataset of patients with multisystem inflammatory syndrome in children (MIS-C) to determine whether their autoantibodies target a different set of host proteins. compared to healthier controls.

Study: A distinct cross-reactive autoimmune response in multisystem inflammatory syndrome in children (MIS-C). Image Credit: Meletios Verras / Shutterstock.com

*Important Notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guiding clinical practice/health-related behaviors, or treated as established information.

Background

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to long-term dysregulation of the immune system and a wide range of secondary infections and illnesses, including post-acute sequelae of coronavirus disease 2019 (COVID-19) in adults. In children, while COVID-19 findings are generally mild, rare cases progress to MIS-C.

Symptoms of MIS-C, such as systemic infection, prolonged fever, conjunctivitis, rash, and in some cases coronary artery aneurysms and myocarditis, are similar to those reported in severe cases of Kawasaki disease. However, MIS-C after SARS-CoV-2 infection also presents as cardiac dysfunction, gastrointestinal problems, hematological complications such as lymphopenia and thrombocytopenia, and various other multi-organ complications.

Autoimmunity and alterations in adaptive and innate immune responses in MIS-C have also been linked to distinct inflammatory and cytokine signatures, with autoantibody cross-reactivity also implicated in MIS-C.

About the study

In the current study, researchers used cohorts of children with a history of COVID-19 with and without MIS-C to profile autoreactive antibodies and antibodies targeting SARS-CoV-2 using immunoprecipitation and sequencing. of phages (PhIP-Seq), which has been widely used in various diseases to identify new autoantigens. A human proteome-wide library composed of 768,000 elements, which has already been instrumental in defining biomarkers for various diseases and identifying new autoimmune conditions, was also analyzed.

The MIS-C cohort included 199 cases, while the at-risk cohort included 45 people who had previously been infected with SARS-CoV-2 but did not have MIS-C. All patients had SARS-CoV-2 infection confirmed by nucleic acid amplification, while MIS-C patients had additional serologic testing.

Fractional luciferase binding assays were used for deoxyribonucleic acid (DNA) coding of peptides of interest. Specific DNA expression plasmids were used for radioligand binding assays.

Logistic regression machine learning was used to identify the presence of differentially enriched peptides that distinguish MIS-C samples from risk control samples. The Kolmogorov-Smirnov test was used to identify statistically enriched autoreactivity. The validity of the results was confirmed using an independent cohort including MIS-C patients and children severely affected by acute SARS-CoV-2 infection.

PhIP-Seq results were normalized against healthy controls to determine if specific peptides were differentially enriched by the at-risk control or MIS-C samples. Additionally, based on the prediction of preferential peptide display in MIS-C-associated human leukocyte antigen (HLA) types, researchers assessed the presence of MIS-C-specific cross-reactive T cells. using peripheral blood mononuclear cells (PBMC) isolated from MIS-C patients and at-risk controls.

Single-cell PBMC sequences obtained from individuals with asymptomatic, mild or severe SARS-CoV-2 or influenza infections, as well as healthy controls, were used to analyze T- and B-cell autoimmunity against SNX8, which is a key regulator of the antiviral pathway of MIS-C pathogenesis.

Study results

The antibody response in MIS-C patients was differentially responsive to SNX8 and a specific domain of the SARS-CoV-2 nucleocapsid protein compared to the antibody response of at-risk controls. Moreover, the SNX8 protein and this region of the viral nucleocapsid showed remarkable biochemical similarities.

MIS-C patients with autoantibodies against SNX8 also had T cells that cross-reacted with the SNX8 protein and the SARS-CoV-2 viral nucleocapsid region. These cross-reactive T cells are likely to contribute to immune dysregulation by expanding SNX8-expressing immune cell lines.

Fine epitope matching also identified the regular expression epitope [ML]Q[ML]PQG, which was similar in SNX8 and the viral core protein domain. This epitope also appears to be shared by B and T cells in MIS-C patients.

The SNX8 protein is functionally linked to the mitochondrial antiviral signaling pathway (MAVS), and MIS-C is thought to be associated with an increased autoimmune response of SNX8 against tissues with high expression of the MAVS pathway. The researchers believe these findings indicate similarities to other diseases, such as paraneoplastic autoimmune disease, where exposure to a novel antigen results in autoimmunity.

conclusion

MIS-C patients show immune responses against a distinct protein domain of the SARS-CoV-2 nucleocapsid, which is associated with cross-reactivity with the SNX8 protein.

The SNX8 protein and the SARS-CoV-2 core protein domain were found to share an epitope. Notably, the targeting of this epitope by B and T cells suggests the involvement of molecular mimicry, which needs to be explored further.

*Important Notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guiding clinical practice/health-related behaviors, or treated as established information.

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