In a recent study published on the preprint server medRxiv, researchers analyzed a large dataset of children with multisystem inflammatory syndrome (MIS-C) to determine whether their autoantibodies target a different set of host proteins than healthy controls. The researchers aimed to determine whether fine epitope matching between SARS-CoV-2 and the SNX8 protein is associated with the development of MIS-C in children.
While the outcomes of COVID-19 in children are generally mild, rare cases progress to MIS-C. This syndrome is characterized by systemic infection, prolonged fever, conjunctivitis, rash, coronary artery aneurysms, and myocarditis. MIS-C is a result of SARS-CoV-2 infection and presents with cardiac dysfunction, GI 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 cytokine and inflammatory signatures, with cross-reactivity of autoantibodies also implicated in MIS-C.
The researchers used cohorts of children with a history of COVID-19 with and without MIS-C to profile the autoreactive and SARS-CoV-2 antibodies. The researchers used the phage immunoprecipitation and sequencing (PhIP-Seq) which has been instrumental in defining biomarkers for various diseases and identifying novel autoimmune conditions. Additionally, a human proteome-wide library consisting of 768,000 elements was analyzed.
The study included 199 cases of MIS-C and 45 cases of individuals with SARS-CoV-2 infection but without MIS-C. All patients were confirmed to have SARS-CoV-2 infection by nucleic acid amplification. The researchers then used logistic regression machine learning to identify differentially enriched peptides that distinguish MIS-C samples from at-risk control samples.
The results showed that the antibody response in MIS-C patients was differentially reactive to SNX8 and a specific domain of the nucleocapsid protein of SARS-CoV-2 as compared to the antibody response of the at-risk controls. Furthermore, the SNX8 protein and this viral nucleocapsid region had remarkable biochemical similarities. MIS-C patients with autoantibodies against SNX8 also had cross-reactive T-cells to the SNX8 protein and viral SARS-CoV-2 nucleocapsid region.
The researchers identified the regular expression epitope [ML]Q[ML]PQG, which was similar in SNX8 and the viral nucleocapsid protein domain. This epitope also appeared to be shared by the B- and T-cells in MIS-C patients. The researchers believe these results indicate similarities with other diseases, such as paraneoplastic autoimmune disease, where exposure to a novel antigen results in autoimmunity.
In conclusion, the study found that MIS-C patients exhibit immune responses against a distinct SARS-CoV-2 nucleocapsid protein domain, which is associated with cross-reactivity to the SNX8 protein. The SNX8 protein and SARS-CoV-2 nucleocapsid protein domain were found to share an epitope. Notably, targeting this epitope by both B- and T-cells suggests the involvement of molecular mimicry, which needs to be explored further. These results provide further understanding and insights for the treatment and prevention of MIS-C in children.
