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Signature antibody determines severity of secondary dengue infection
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Researchers investigating why disease can be more severe during secondary dengue virus infection than primary infection found that patients with more severe disease produced a greater abundance of signature antibodies that enhance Fc receptor IIIA binding than those with mild disease, according to recent study findings.
“Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS),” Jeffrey V. Ravetch, MD, PhD, Theresa and Eugene M. Lang Professor from the Leonard Wagner Laboratory of Molecular Genetics and Immunology at the Rockefeller University, New York, and colleagues wrote in Science. “Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity.”
The researchers reported that less than 15% of DENV infections that occur in the presence of RNNIg progress to severe disease. Severe DENV disease has been linked to certain combinations of virus stereotypes, pre-existing immunity, viral genetic factors and host factors. However, there is a lack of data on how these factors may contribute to ADE of disease.
Researchers hypothesize that RNNIg facilitates increased infectivity of Fc gamma receptor (FcR)–expressing cells, supporting the spread of DENV, according to Ravetch and colleagues. The researchers previously demonstrated that some patients may be inclined to ADE based on their production of IgG antibodies that activate FcRs with higher affinity. For the current study, they characterized RNNIg of patients hospitalized with secondary dengue infection to determine whether those with severe disease had specific IgG Fc domain structures promoting ADE.
Ravetch and colleagues found that patients with severe dengue disease had higher levels of afucosylated IgG1 antibodies, which are known to have higher affinity for the Fc receptor FcgRIIIa, Ravetch told Infectious Disease News.
Additional analyses stratified by clinical diagnosis showed that patients with thrombocytopenia had elevated afucosylated Fc glycoforms (afucFc) IgGs, with afucFc of 10% or more being a significant risk factor for thrombocytopenia (OR = 11.0; 95% CI, 1.64-74.00). The incidence of thrombocytopenia correlated with an increased ratio of IgG subclassess IgG1/IgG2 for the anti-dengue virus envelope protein. Patients with severe thrombocytopenia produced more afucFc IgG1 compared with other patients. The only patient with DSS in the analysis had the greatest abundance of afucFc IgG1.
In addition to thrombocytopenia, elevated afucFc and IgG1/IgG2 ratios were also associated with lower platelet counts. The researchers suggested that when anti-DENV IgGs cross-react with platelet antigens, it might contribute to platelet loss and, subsequently, to ADE of disease.
“We showed that the highly afucosylated anti-dengue IgGs were involved in pathogenesis of disease (they mediated platelet loss) by mechanism(s) involving FcγRIIIA,” Ravetch said. “This basic difference in antibody phenotype begins to explain why only some people become very sick during secondary dengue infections.”
The researchers further noted that there was a significant drop in afucFc and IgG1/IgG2 from early to convalescent phases of disease, indicating that the increase in IgGs with enhanced affinity for FcγRIIIA was triggered by DENV infection.
“The present finding that some individuals respond to DENV infection by producing IgGs with higher affinity for FcγRIIIA indicates a host determinant of susceptibility to severe DENV disease,” they concluded. “Further studies will determine how this patient selectivity may contribute to additional mechanisms underlying ADE of DENV disease.” – by Stephanie Viguers
Disclosures: Ravetch reports no relevant financial disclosures. Please see the study for a full list of authors’ relevant financial disclosures.
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