High Frequency IL-1-Ra Autoantibodies in Children with PIMS / MIS-C

Although infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) usually affects children only slightly, Pediatric Multisystem Inflammatory Syndrome (MIS-C) or Pediatric Multisystem Inflammatory Syndrome ( PIMS) is a serious but rare complication occurring after infection.

PIMS or MIS-C symptoms in affected children

PIMS or MIS-C usually occurs 2-6 weeks after infection with SARS-CoV-2, and the most common symptom in all affected children is persistent fever, while other clinical features such as sharp abdominal pain, muscle pain, diarrhea or vomiting, headache, and fatigue vary among affected children.

Hyperemia and rash, “strawberry tongue”, and swollen hands and feet resembling Kawasaki disease have been observed in a high proportion of PIMS / MIS-C patients.

Cardiovascular problems such as myocardial dysfunction, arterial hypotension or systemic shock have also been regularly observed, while myocarditis, pericarditis and damage to coronary valves and arteries can also develop.

Laboratory tests show intense inflammation with elevated levels of serum C-reactive protein, ferritin, procalcitonin, troponin, and markers of coagulopathy and hematologic abnormalities. Most children affected by PIMS will need intensive care due to multiple organ failure and shock.

Studies have discussed a possible involvement of pathogenically relevant autoantibodies in MIS-C. Scientists recently discovered neutralizing autoantibodies against IL-1 receptor antagonist (IL-1-Ra) and anti-inflammatory progranulin receptor antagonists (PGRN) in adult patients with severe COVID-19.

Study the plasma of children with severe PIMS / MIS-C for the presence of PGRN and IL-1-Ra autoantibodies

In a recent study, researchers analyzed plasma from an index case with severe PIMS / MIS-C for autoantibodies against PGRN and IL-1-Ra. They then extended the study to a series of 12 additional patients. They used ELISA to detect antibodies and Western blot and isoelectric focusing to analyze IL-1-Ra. The functional activity of autoantibodies was studied in vitro using IL-1β reporter assays. The study is published on the medRxiv* preprint server.

The results show that IL-1-Ra antibodies were detected in 10 of 13 patients or 76.9% of patients with PIMS / MIS-C, but not in controls. Compared to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS / MIS-C. The IL-1-Ra antibodies detected belonged exclusively to the IgG1 class.

None of the antibodies detected were directed against PGRN. Western blots and ELISA revealed a concomitant reduction in plasma levels of free IL-1-Ra in the presence of IL-1-Ra antibodies. The antibodies inhibited IL-1-Ra function in IL-1β reporter cell assays.

Notably, an additional atypical, hyperphosphorylated and transient isoform of IL-1-Ra was observed in all patients positive for IL-1-Ra autoantibodies.

“To summarize, autoantibodies against IL-1-Ra as well as an immunogenic IL1-Ra isoform were observed in one PIMS / MIS-C case and subsequently in a high percentage of a series of cases. . “

Antibodies detected are pathogenically relevant and should be further investigated in PIMS / MIS-C cases

This study reported the high prevalence of neutralizing autoantibodies against the anti-inflammatory molecule IL-1-Ra in a case series of pediatric patients with PIMS / MIS-C. In adults with severe COVID-19, IL-1-Ra antibodies have been detected in approximately 50% of patients and autoantibodies against PGRN in approximately 40% of patients.

In conclusion, IL-1-Ra autoantibodies have been detected at high frequency in children with PIMS / MIS-C. These antibodies can be relevant diagnostic and pathophysiological markers for MIS-C. A hyperphosphorylated isoform of IL-1-Ra eventually triggers the generation of these antibodies.

“The relatively small number of cases included in this study, due to the rarity of the disease, is a limitation. Nonetheless, these antibodies suggest that they are pathogenetically relevant and should be studied further in PIMS / MIS-C and other hyperinflammatory diseases.

*Important Notice

medRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.