Dysregulated Antibody Response Implicated in Severe COVID-19 in Adults and Multisystem Inflammatory Syndrome in Children
Key findings
- This study involved comprehensive profiling of the antibody response to SARS-CoV-2 in 60 acutely infected adults, 25 children with mild acute infection and 17 pediatric patients with multisystem inflammatory syndrome in children (MIS-C)
- Severely ill adults exhibited elevated IgA, which may contribute to enhanced inflammation and symptomatic disease
- Children with severe MIS-C had a distinctly different antibody profile: highly inflammatory monocyte-activating IgG antibodies, which might be what drive macrophage or monocyte activation within distant sites such as the heart and kidney
- Better understanding of the immune mechanisms that underlie differential disease severity may lead to new therapies for severe COVID-19 and MIS-C
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One of the most alarming aspects of SARS-CoV-2 infection is its unpredictable presentation. Severe COVID-19 can emerge in adults, and a small number of children and adolescents develop multisystem inflammatory syndrome in children (MIS-C) about three to six weeks after they contract or are exposed to SARS-CoV-2.
Evidence is emerging that the humoral immune response to SARS-CoV-2 can be pathological instead of protective. To explore this possibility, researchers at Massachusetts General Hospital comprehensively profiled the antibody response to SARS-CoV-2 in acutely infected adults and children and found that differences in IgG and IgA responses might underlie differences in disease severity.
Lael M. Yonker, MD, director of the Cystic Fibrosis Center in the Department of Pediatrics and investigator in the Mucosal Immunology and Biology Research Center at MassGeneral Hospital for Children; Galit Alter, PhD, principal investigator at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and Samana Cay MGH Research Scholar; and colleagues report their observations in Nature Medicine.
Overall Comparison of Mild vs. Severe Disease
The researchers first compared:
- 34 adults with mild COVID-19
- 26 adults with severe COVID-19
- 25 children with mild COVID-19
- 6 children with mild MIS-C
- 11 children with severe MIS-C (cardiac complications)
As expected, levels of IgM and IgG were significantly higher in adults with severe COVID-19 than adults—or children—with mild COVID-19. IgA responses were not apparent in either adults or children with mild disease, suggesting IgG alone can control mild SARS-CoV-2 infection.
Antibody profiles of patients with mild COVID-19 overlapped extensively; it did not seem that children had a stronger or more effective humoral immune response. The severity of disease, not age, seemed to be the predominant influence on antibody response.
In severely ill adults, IgA was elevated, which causes neutrophils to release excess cytokines. This potent inflammatory activity of IgA seems to exacerbate COVID-19 in adults.
Children with MIS-C generated IgA responses, but they tended to be lower than those in adults.
Comparison of Mild/Severe MIS-C vs. Mild Disease in Adults
The researchers then compared the 17 pediatric patients with MIS-C to 18 adults recovering from mild COVID-19. Weeks after acute infection, the 11 patients with severe MIS-C and the convalescent adults still exhibited robust humoral immune responses.
However, only the patients with severe MIS-C maintained highly inflammatory monocyte-activating IgG antibodies. It's possible these persisting, overactive antibodies are what drive macrophage or monocyte activation within distant sites such as the heart and kidney.
In most patients with mild MIS-C, antibodies to SARS-CoV-2 were undetectable.
A Way Forward
Understanding the immune mechanisms underlying severe COVID-19 and severe MIS-C is the first step in determining why SARS-CoV-2 has such varied presentations. It should then be possible to develop therapies targeted to these unique populations.
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