IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2

For years, rheumatologists have sought to make sense of autoantibodies that are identified in patients with inflammation following acute infections. Often, it is unclear whether these autoantibodies are directly triggered by infection, and furthermore whether they might be contributing to the patient's immunopathology.

Multisystem inflammatory syndrome in children (MIS-C, also known as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2), is a rare, enigmatic hyperinflammatory disorder triggered by antecedent SARS-CoV-2 infection. MIS-C develops 2–6 weeks after contracting SARS-CoV-2, often after asymptomatic infection, and presents with clinical features resembling Kawasaki disease but with several important distinctions, including predilection for older children (age <5 years in Kawasaki disease vs 8–11 years in MIS-C), presentation with intestinal symptoms, and involvement of the myocardium more often than coronary arteries. Particular observations appear consistent across patients with MIS-C, including innate immune activation, specific expansion of TRBV11-2 T cells, and possibly persistent or recurrent SARS-CoV-2 antigenaemia (all of which are most recently and comprehensively reported by Sacco and colleagues¹). Several patho-aetiological hypotheses have been postulated, including occult intestinal SARS-CoV-2 persistence, virus-derived super-antigens, or the actions of plasmablasts expressing the transcription factor T-bet² (a finding that might be associated with autoimmunity³).

Some pathogens (eg Streptococcus pyogenes or Epstein-Barr virus) are known to trigger autoimmune pathology, but the jury is still out on SARS-CoV-2. Indeed, up to 20% of severe COVID-19 cases might occur as a result of autoimmunity-turned-immunodeficiency due to pre-existing interferon-neutralising autoantibodies.⁴ Although autoantibody arrays have detected the emergence of autoantibodies in adults with COVID-19,⁵ a multinational study in children with MIS-C suggested high titres of autoantibodies were associated with having received intravenous immunoglobulin (IVIG).¹

In a report in The Lancet Rheumatology, Jochen Pfeifer and colleagues identified high-titre autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) in sera from 13 (62%) of 21 children with MIS-C (age 0–18 years; 19 sampled before receiving IVIG).⁶ Anti-IL-1Ra autoantibodies were absent in an array of control participants (healthy children, children with suspected growth retardation [non-inflammatory group], children with mild or asymptomatic COVID-19, children with Kawasaki disease, and children with quiescent systemic juvenile idiopathic arthritis). An unrelated antibody (against Clostridium tetanus toxin) was not elevated in patients with MIS-C versus the control groups, suggesting their findings are not simply the result of non-specific polyclonal stimulation of plasmacytes. In a preprint paper, the same researchers reported anti-IL-1Ra autoantibodies in about 50% of adults with severe or critical COVID-19.⁷

Given the increasing evidence of a link between excess IL-1 and Kawasaki disease-like phenotypes,⁸ we are intrigued by the possibility that such autoantibodies could be contributing to MIS-C. Supporting this hypothesis, free IL-1Ra protein concentrations were lower in patients with MIS-C who were positive for anti-IL-1Ra autoantibodies, versus those who were negative for autoantibodies, or those with Kawasaki disease or quiescent systemic juvenile idiopathic arthritis. Western blots revealed antibody-IL-1Ra complexes, and reporter assays suggested neutralisation of IL-1Ra activity by autoantibody-containing plasma. Decreased autoantibody titres during longitudinal follow-up of two patients with MIS-C suggested that these autoantibodies were transient. The authors also offer a potential mechanism of IL-1Ra-specific autoimmunity: they identified a hyperphosphorylated form of IL-1Ra in the patients with MIS-C who were positive for anti-IL-1Ra autoantibodies, but not in the control groups or autoantibody-negative patients with MIS-C. Similarly, rises and falls in hyperphosphorylated IL-1Ra preceded corresponding rises and falls in anti-IL-1Ra autoantibodies in their adult COVID-19 cohort⁷, and in one of the patients with MIS-C.

These observations are provocative, placing IL-1 signalling downstream of SARS-CoV-2 infection but upstream of hyperinflammation in patients with MIS-C. Yet, this preliminary study has several limitations, including a small number of participants, few longitudinal samples, and incomplete mechanistic evaluation. As such, these findings should neither affect clinical decision making, nor favour an expanded front-line use of anakinra (recombinant IL-1Ra) in patients with MIS-C,⁹ particularly given the complete response of most patients to IVIG and glucocorticoids.

However, if generalisable, these results inspire important questions (panel ). The range and scope of such questions are a testament to the potential novelty and aetiological importance of this study. The apparently unique association of hyperphosphorylated IL-1Ra and neutralising autoantibodies after SARS-CoV-2 infection might launch a new line of study with great translational potential. In the interim, we can thank the unprecedented scientific response to SARS-CoV-2 and its related morbidities for another insight into the host–pathogen autoimmunity problem.

Panel. Questions about interleukin-1 receptor antagonist (IL-1Ra)-specific autoantibodies in multisystem inflammatory syndrome in children (MIS-C).

• •In MIS-C, are there clinical differences at presentation in patients who have anti-IL-1Ra autoantibodies versus those who do not?
• •What signals drive IL-1Ra hyperphosphorylation?
• •Is IL-1Ra hyperphosphorylation unique to SARS-CoV-2 infections?
• •When does IL-1Ra become hyperphosphorylated and when do neutralising autoantibodies develop?
• •Can IL-1Ra hyperphosphorylation or anti-IL-1Ra autoantibody development be used as specific tests to support MIS-C diagnosis?
• •What protects anti-IL-1Ra autoantibody-positive adults with COVID-19 from developing multisystem inflammatory syndrome?
• •Is a parallel mechanism at work in the autoantibody-negative MIS-C patients, or in clinically similar diseases such as Kawasaki disease?
• •What mechanisms give rise to the distinct clinical presentations of MIS-C and deficiency of IL-1Ra?¹⁰

HB has received support from the US National Institutes of Health (grant number R61DH105594) and the Pennsylvania Department of Health for research on MIS-C. SC has received support from the US National Institutes of Health (grant number R01HD098428) for work on hyperinflammation and has consulted for Simcha Therapeutics.