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Possible role for anti-IL-1Ra autoantibodies in MIS-C

By Eleanor McDermid, medwireNews Reporter

Autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) are present in a large proportion of patients with multisystem inflammatory syndrome in children (MIS-C), say researchers.

The study, which is published in The Lancet Rheumatology, involved 21 patients with MIS-C who were treated in hospitals in Germany and Spain.

“Although the small number of patients with MIS-C enrolled in this study might pose a limitation, the high numbers of controls (both inflammatory and non-inflammatory) highlight our findings as unique rather than an epiphenomenon”, say Lorenz Thurner (Saarland University, Homburg, Germany) and study co-authors.

The team detected anti-IL-1Ra antibodies in 62% of the MIS-C patients, but in none of 33 children with a suspected growth disorder, 24 with Kawasaki disease, 10 with inactive systemic juvenile idiopathic arthritis (JIA), 146 with mild or asymptomatic COVID-19, or 462 healthy children.

The finding of anti-IL-1Ra antibodies in the MIS-C patients is “in accordance with those in our preprint paper on adults with critical COVID-19, in whom anti-IL-1Ra antibodies were detected in a high proportion of patients (about 50%)”, say the researchers.

Antibody titres in the children ranged from 1 in 200 to 1 in 800 and all but one patient had exclusively immunoglobulin (Ig)G antibodies; the other also had IgM antibodies.

The team previously detected progranulin antibodies in a high proportion of adults with critical COVID-19, but these appeared in just one of the MIS-C patients.

In line with the presence of the autoantibodies, plasma levels of free IL-1Ra were significantly lower in patients with autoantibodies than in those without, at an average of 279.4 versus 1746.0 pg/mL. Their levels were also significantly lower than in two tested control groups (Kawasaki disease and JIA) and this remained the case after excluding two MIS-C patients who had received intravenous Ig prior to having blood samples taken.

Of note, the researchers identified a hyperphosphorylated version of IL-1Ra in all the MIS-C patients with autoantibodies but none in those without or in any of the tested controls.

And in two MIS-C patients with follow-up blood samples, “we observed the disappearance of hyperphosphorylated IL-1Ra, which preceded the disappearance of anti-IL-1Ra antibodies”, say Thurner and team.

They conclude: “Collectively, data from both COVID-19 and MIS-C suggest that atypical post-translational modifications are associated with SARS-CoV-2-infection itself or the resulting inflammatory environment, and that these modifications are likely to be immunogenic.”

Writing in a linked commentary, Hamid Bassiri and Scott Canna, both from The Children’s Hospital of Philadelphia in Pennsylvania, USA, say: “These observations are provocative, placing IL-1 signalling downstream of SARS-CoV-2 infection but upstream of hyperinflammation in patients with MIS-C.”

They highlight remaining questions, including what triggers IL-1Ra hyperphosphorylation, why adults with anti-IL-1Ra autoantibodies do not develop MIS-C, and what mechanisms account for MIS-C in patients without these autoantibodies.

“The range and scope of such questions are a testament to the potential novelty and aetiological importance of this study”, they conclude.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00064-9

Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00090-X