Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

Multiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS). We characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation. Together, these data argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 expressing T cell activation.

En 2019, les anticorps monoclonaux (Acm) vont représenter un marché mondial annuel de plus de cent milliards de dollars, soit près de 90 milliards d’euros. Outre leur utilisation en clinique, les anticorps monoclonaux sont utilisés également dans de nombreux tests diagnostiques et sont toujours des outils précieux pour la recherche fondamentale et appliquée. Quarante-quatre ans après la publication de Georges Köhler et César Milstein [1], des dizaines de congrès et séminaires de toute nature sur les anticorps monoclonaux se tiennent annuellement à travers le monde. Mais 44 ans plus tard, les travaux scientifiques qui ont amené à cette publication sont peu à peu oubliés et, dans bien des esprits, les anticorps monoclonaux ne sont qu’un business d’un multi-milliard euros/dollars comme un autre, déterminé par les marchés financiers et les résultats des derniers essais cliniques… Il est grand temps de rendre hommage à toute une génération de chercheurs fondamentalistes, à ces fous de science du xx e siècle, à ces chercheurs connus et souvent désormais méconnus, disséminés aux quatre coins du monde, qui ont exploré les frontières de l’inconnu d’alors et qui ont modelé et ciselé un savoir qui a débouché sur une technique d’obtention de molécules qui ont permis l’une des plus grandes révolutions thérapeutiques de ces vingt-cinq dernières années.