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Beyond binding: antibody effector functions in infectious diseases

Key Points

  • Beyond direct neutralization, antibodies induce, through their crystallizable fragment (Fc) domain, innate and adaptive immune responses critical to a successful host immune response against infection.

  • The constant Fc domain of the antibody is remarkably diverse, with a repertoire of isotype, subclass and post-translational modifications, such as glycosylation, that modulate binding to Fc domain sensors on host cells that changes dynamically over the course of infection.

  • The antigen-binding fragment (Fab) and Fc domains of an antibody distinctly influence each other and collaboratively drive function.

  • Stoichiometry between antigen and antibody influence immune complex formation and subsequent engagement with Fc domain sensors on host cells and thus effector functions.

  • Antibodies can both provide protection and enhance disease in infections.

  • Emerging tools that systematically probe antibody specificity, affinity, function, glycosylation, isotypes and subclasses to track protective or pathologic phenotypes during infection may provide novel insight into the rational design of monoclonal therapeutics and next-generation vaccines.

Abstract

Antibodies play an essential role in host defence against pathogens by recognizing microorganisms or infected cells. Although preventing pathogen entry is one potential mechanism of protection, antibodies can control and eradicate infections through a variety of other mechanisms. In addition to binding and directly neutralizing pathogens, antibodies drive the clearance of bacteria, viruses, fungi and parasites via their interaction with the innate and adaptive immune systems, leveraging a remarkable diversity of antimicrobial processes locked within our immune system. Specifically, antibodies collaboratively form immune complexes that drive sequestration and uptake of pathogens, clear toxins, eliminate infected cells, increase antigen presentation and regulate inflammation. The diverse effector functions that are deployed by antibodies are dynamically regulated via differential modification of the antibody constant domain, which provides specific instructions to the immune system. Here, we review mechanisms by which antibody effector functions contribute to the balance between microbial clearance and pathology and discuss tractable lessons that may guide rational vaccine and therapeutic design to target gaps in our infectious disease armamentarium.

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Figure 1: Antibody isotypes and subclasses.
Figure 2: Antigen, antibody and Fc receptor stoichiometry in effector function.
Figure 3: Antibody effector functions.
Figure 4: Factors influencing humoral activity in response to infection.

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Acknowledgements

This work was supported by the US National Institutes of Health (R01AI10266, AI080289, R33AI110165, K08AI130357), DARPA and the Ragon Institute of MGH, MIT and Harvard.

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L.L.L., T.J.S., S.M.F. and G.A. all contributed to researching data for the article, discussing the content and writing, reviewing and editing the manuscript before submission.

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Correspondence to Galit Alter.

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PowerPoint slides

Glossary

Monoclonal therapeutics

Treatments utilizing immunoglobulins that are engineered with a single antigenic specificity. Current monoclonal therapeutics approved by the US Food and Drug Administration (FDA) involve a range of immune targets, which are important in cancer and autoimmune diseases, as well as three infectious disease targets.

Affinity

The strength of the interaction between an antigen and antibody. Ka, the affinity constant, is influenced by pH, temperature and buffer and ranges from below 105 mol−1 to above 1012 mol−1. Affinity and Kd, the equilibrium dissociation constant, are inversely related.

Avidity

The overall strength of the antibody–antigen complex. It is dependent on affinity, valency of the antibody and antigen, and structural arrangements of the interacting parts.

Complement

A system that consists of a large number of plasma proteins that follow a cascade of reactions, which induce antimicrobial and inflammatory responses.

Immune complex

An aggregate complex formed from the binding of several antibodies to an antigen that can exist as a solitary unit and/or further multimerize to induce antibody effector function.

Glycoforms

Isoforms of glycans that can exist on proteins in a set of specific states. For example, 36 distinct glycoforms can theoretically be attached at a single conserved residue (asparagine 297) on the crystallizable fragment (Fc) domain of an IgG1 antibody.

Antibody-dependent enhancement

A phenomenon where pre-existing cross-reactive antibodies bind to cells and enhance host cell entry of a pathogen, its replication and the host inflammatory response to infection, thus exacerbating pathogenesis and disease.

Direct neutralization

Inhibition of a pathogen or microbial component by direct binding of antibody to the antigen in the absence of a target host cell. By contrast, non-neutralizing antibody functions involve additional host immune factors to generate antimicrobial functions.

Biofilms

Collections of microorganisms that adhere to each other and produce an extracellular matrix on living or non-living surfaces. Biofilms can be found in the natural and humanized environment, with uniquely resilient growth phenotypes not observed in single cells.

Membrane attack complex

A complex formed by terminal complement components that create transmembrane channels directly on the surface of bacteria or an infected host cell, which disrupt the cell membrane, leading to membrane destabilization and death.

Metalloproteinases

Protease enzymes that contain a catalytic metal ion in their active site and that cleave and inactivate proteins. Matrix metalloproteinases can degrade extracellular matrix proteins and act on pro-inflammatory cytokines, chemokines and other proteins to modulate inflammation and immunity.

Neutrophil extracellular traps

(NETs). Extracellular chromatin studded with granular and selected cytoplasmic proteins that bind to pathogens. NETs are produced through a process called NETosis in neutrophils, which is induced in response to microbial components, antibodies and reactive oxygen species.

Leishmania amastigotes

Leishmaniasis is a vector-borne disease caused by an obligate intracellular protozoa of the genus Leishmania. Sandfly-to-human transmission occurs at the promastigote stage; the promastigotes then transform into amastigotes that replicate in human cells, to be taken up by the sandfly and complete the life cycle.

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Lu, L., Suscovich, T., Fortune, S. et al. Beyond binding: antibody effector functions in infectious diseases. Nat Rev Immunol 18, 46–61 (2018). https://doi.org/10.1038/nri.2017.106

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