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Mechanisms of antibody-dependent enhancement of infectious disease

Nature Reviews Immunology volume 25, pages 6–21 (2025)Cite this article

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Abstract

Antibody-dependent enhancement (ADE) of infectious disease is a phenomenon whereby host antibodies increase the severity of an infection. It is well established in viral infections but ADE also has an underappreciated role during bacterial, fungal and parasitic infections. ADE can occur during both primary infections and re-infections with the same or a related pathogen; therefore, understanding the underlying mechanisms of ADE is critical for understanding the pathogenesis and progression of many infectious diseases. Here, we review the four distinct mechanisms by which antibodies increase disease severity during an infection. We discuss the most established mechanistic explanation for ADE, where cross-reactive, disease-enhancing antibodies bound to pathogens interact with Fc receptors, thereby enhancing pathogen entry or replication, ultimately increasing the total pathogen load. Additionally, we explore how some pathogenic antibodies can shield bacteria from complement-dependent killing, thereby enhancing bacterial survival. We interrogate the molecular mechanisms by which antibodies can amplify inflammation to drive severe disease, even in the absence of increased pathogen replication. We also examine emerging roles for autoantibodies in enhancing the pathogenesis of infectious diseases. Finally, we discuss how we can leverage these insights to improve vaccine design and future treatments for infectious diseases.

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Fig. 1: Mechanisms of antibody-dependent enhancement of pathogen uptake and replication.
Fig. 2: Mechanisms of antibody-dependent serum resistance.
Fig. 3: Mechanisms of antibody-dependent enhancement of inflammation.
Fig. 4: Mechanism of anti-cytokine autoantibodies enhancing infection.

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Authors and Affiliations

  1. Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia

    Timothy J. Wells

  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    Tyron Esposito, Ian R. Henderson & Larisa I. Labzin

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T.J.W., I.R.H. and L.I.L. conceptualized the Review; T.J.W., T.E. and L.I.L. drafted the Review and figures; all authors contributed to editing the manuscript.

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Glossary

Alternative NF-κB pathway

(Also known as the non-canonical NF-κB pathway). This pathway controls thymic expression of autoimmune regulator protein (AIRE) and development of mature thymic epithelial cells for effective central tolerance, preventing autoantibody formation.

Antibody-dependent cellular cytotoxicity

A mechanism in which immune cells, particularly natural killer cells, recognize antibodies bound to a membrane-bound antigen on a host cell and target it for destruction.

Antibody-dependent phagocytosis

A mechanism in which immune cells engulf and digest pathogens or target cells coated with specific antibodies.

Autoimmune regulator protein

(AIRE). A key regulator of central tolerance, facilitating the expression of tissue-specific antigens in the thymus to prevent the development of autoimmune diseases.

IgG hexamers

IgG is theorized to recruit the C1 complex and activate the complement cascade through interactions between the crystallizable fragment (Fc) domains of six IgG antibodies to form hexamers.

Opsonization

A process where pathogens or particles are marked for phagocytosis by immune cells through the binding of antibodies or complement, enhancing their recognition and elimination.

Pyroptosis

A form of programmed cell death characterized by inflammatory cell lysis, often triggered by infection or cellular damage.

Shwachman–Kulczycki score

A method that assesses and scoaseverity of cystic fibrosis using clinical and radiological evaluation.

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Wells, T.J., Esposito, T., Henderson, I.R. et al. Mechanisms of antibody-dependent enhancement of infectious disease. Nat Rev Immunol 25, 6–21 (2025). https://doi.org/10.1038/s41577-024-01067-9

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