Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8 + T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome

“…Several hypotheses have been presented to explain the systemic inflammatory response and organ involvement in MIS-A/C patients, including antibody enhancement, immune complex-mediated immunopathology, superantigen-mediated immune activation, interferonopathy and others (14,16,17). A recent study performing cytokine profiling in plasma from nine MIS-C patients identified signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28) (15).…”

“…Biologically relevant pathways and functions were chosen based on available literature on MIS-C, given that the MIS-A literature is currently very limited. Dysregulated NK cell, CD8+ T cell, and CD4+ T cell responses have been described in MIS-C, as well as prolonged plasmablast responses and presence of autoantibodies (14,16,21), thus genes related to adaptive and humoral immune responses were investigated. MIS-C is also characterized by hyperinflammation (14,22), prompting examination of genes involved in both inflammatory and anti-inflammatory pathways.…”

“…The pathogenesis underlying MIS-C/A remains enigmatic but may involve aberrant immune responses to SARS-CoV-2, including macrophage hyperactivation, antigen-antibody complex deposition, and formation of autoantibodies (14). Recent studies have identified immunological signatures and features of MIS-C including autoantibodies recognizing endothelial, gastrointestinal, and immune-cells, thus linking autoimmunity to specific tissue pathology (15), as well as specific signatures of alarmins, cytotoxicity, TCR repertoire, and plasmablasts (16) and distinct differences in immune profiles distinguishable between MIS-C as opposed to classical Kawasaki disease (17). However, any genetic basis of this apparent immune dysregulation triggered by SARS-CoV2 infection has not been defined.…”

Virological and immunological features of SARS‐COV‐2 infected children with distinct symptomatology

“… 33 Further, in our cohort either NK cell frequency or CD56+CD16+ distribution was able to discriminate between AS and SY patients. In line with this, Ramaswamy et al 34 found that NK and CD8+ T‐cell phenotype characteristics alone are not sufficient to define the highly symptomatic/severe cases of SARS‐CoV‐2 (eg, MIS‐C), but a deepen study on cytotoxicity genes is required.…”

Children and SARS-CoV-2

“…(2) There appears to be an expansion of a unique TCR repertoire (TRBV11) consistent with a super antigen selection process in patients with MIS-C ( Porritt et al., 2021 ; Ramaswamy et al., 2021 ). (3) A few groups have documented the presence of increased levels of antibodies targeting autoantigens expressed by target organs of MIS-C pathology ( Consiglio et al., 2020 ; Gruber et al., 2020 ; Ramaswamy et al., 2021 ).…”