doi: 10.1371/journal.ppat.1011223. eCollection 2023 Mar.
Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?
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- PMID:36996026
- PMCID: PMC10062565
- DOI: 10.1371/journal.ppat.1011223
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Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?
Andrew Teo et al. PLoS Pathog..
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- Correction: Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?Teo A, Tan HD, Loy T, Chia PY, Chua CLL.Teo A, et al.PLoS Pathog. 2023 Oct 18;19(10):e1011736. doi: 10.1371/journal.ppat.1011736. eCollection 2023 Oct.PLoS Pathog. 2023.PMID:37851611Free PMC article.
No abstract available
Conflict of interest statement
The authors have declared that no competing interest exist.
Figures
(A) Anti-DENV IgGs can bind to DENV antigens including PrM and E proteins, which promotes interaction with FcγRs, such as FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), expressed by phagocytes. When these antibodies are insufficient to neutralise the DENV, this may then result in enhanced immature virion uptake into the phagocytes (extrinsic pathway). In the phagocytes, the suppression of a pro-inflammatory response and induction of a Th2-type immune response can further enhance viral replication (intrinsic pathway), and subsequently cause excessive cytokine production. Together, this process is termed as antibody-dependent enhancement. On the other hand, in the absence of IgG, DENV is taken into the phagocytes less efficiently through canonical receptor-mediated endocytosis and is unlikely to contribute to ADE. When neutralising anti-DENV IgGs are present at high levels, DENV is fully neutralised and severe pathology can be prevented. (B) IgG is often depicted as a “Y-shaped” molecule consisting of two identical light chains and two identical heavy chains. The antigen-binding site recognises specific antigens, while the Fc region can engage with FcγR expressed by immune cells, leading to activation of effector mechanisms. A posttranslational modification in the Fc region results in the catalysation of a fucose moiety at the asparagine 297 site via FUT8. Afucosylated IgGs lack the fucose structure and have increased binding affinity towards FcγRIII. So far, only afucosylated IgG1s have been reported in dengue patients. The stimuli that trigger IgG1 afucosylation in dengue are not well understood, but DENV surface antigens and microRNAs may play a role in the process by modulating FUT8 expression. ADE, antibody-dependent enhancement; DENV, dengue virus; E, envelope; FcγR, Fcγ receptor; FUT8, fucosyltransferase 8; IgG, immunoglobulin G; PrM, premembrane.
(A) NK cells highly express FcγRIIIa (CD16a) and may recognise afucosylated IgG1–DENV immune complex. This may then promote antibody-dependent cell-mediated cytotoxicity, leading to direct killing of DENV-infected cells and DENV, contributing to protection from symptomatic dengue. (B) Afucosylated IgG1s may promote extrinsic ADE in phagocytes, as the absence of fucose molecule greatly enhances the binding of afucosylated IgG1–DENV immune complex to FcγRIIIa expressed by monocytes/macrophages and dendritic cells. This may lead to immature virion uptake, maturation, and replication, leading to increased viremia and inflammation. Neutrophils express FcγRIIIb, and DENV-activated neutrophil can release potent antimicrobial molecules that are associated with severe dengue. However, whether interaction between afucosylated IgG1–DENV immune complex and FcγRIIIb results in ADE and/or release of potent antimicrobial is unknown. Further investigations are needed to provide evidence on afucosylated lgG1s involvement in the proposed pathways above. ADE, antibody-dependent enhancement; DENV, dengue virus; IgG, immunoglobulin G; NK, natural killer.
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