Researchers unveil unique autoimmune response to COVID-19 in MIS-C

A unique SARS-CoV-2 nucleocapsid protein domain, which is associated with cross-reactivity to the sorting nexin-8 (SNX8) protein, has been identified as the target of immune responses in multisystem inflammatory syndrome in children (MIS-C). In a recent study published on the medRxiv preprint server, an extensive dataset of patients with MIS-C is examined to determine if their autoantibodies target a different range of host proteins compared to healthier controls.

Bodansky and his team used phage immunoprecipitation and sequencing (PhIP-Seq), a widely employed technique in various diseases to identify novel autoantigens, to profile autoreactive antibodies and antibodies targeting SARS-CoV-2 in cohorts of children with a history of COVID-19 with and without MIS-C. Additionally, they examined a 768,000-element human proteome-wide library that has previously helped to find novel autoimmune illnesses and define biomarkers for a number of diseases. The at-risk cohort consisted of 45 individuals who once had SARS-CoV-2 infection but did not present with MIS-C, whereas the MIS-C cohort consisted of 199 cases. While MIS-C patients underwent additional serology tests, all patients had SARS-CoV-2 infection confirmed by nucleic acid amplification. 

Another study in 2020 revealed that the rare MIS-C associated with COVID-19 is a complication that typically emerges 4-6 weeks after infection, characterized by high fever, organ dysfunction, and significantly elevated inflammatory marker levels. Although the exact pathophysiology remains unknown, shared characteristics with Kawasaki disease suggest vasculitis and a potential autoimmune origin. Experts conducted a systems-level analysis of blood immune cells, cytokines, and autoantibodies in healthy children, children with pre-existing Kawasaki disease, children infected with SARS-CoV-2, and children presenting with MIS-C. This study discovered that the inflammatory response in MIS-C is distinct from the cytokine storm observed in severe acute COVID-19, displaying similarities to Kawasaki disease. However, differences were observed in terms of T cell subsets, interleukin-17A, and biomarkers associated with vascular injury. Furthermore, autoantibody profiling identified several autoantibodies that could potentially contribute to the pathophysiology of MIS-C.

A shared epitope was discovered between the SNX8 protein and the SARS-CoV-2 nucleocapsid protein domain. It is noteworthy that both B and T lymphocytes target this epitope, suggesting the possibility of molecular mimicry, which calls for further research.


  1. Bodansky A, Sabatino Jr JJ, Vazquez S, Chou J, Novak T, Moffitt KL, Miller H, Kung A, Rackaityte E, Zamecnik CR, Rajan JV. A distinct cross-reactive autoimmune response in multisystem inflammatory syndrome in children (MIS-C). medRxiv. 2023:2023-05.
  2. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, Tan Z, Zicari S, Ruggiero A, Pascucci GR, Santilli V. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell. 2020 Nov 12;183(4):968-81.