Beyond binding: antibody effector functions in infectious diseases

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.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1 |. Antibody isotypes and subclasses.

The basic structure of a human antibody consists of two functional domains linked by a hinge region. The domains include an antigen-binding fragment (Fab) domain that binds to antigens and a crystallizable fragment (Fc) domain that binds to host sensors that deploy effector functions. Each antibody molecule is composed of four chains with two identical heavy chains (blue) and two identical light chains (red). These are further divided into variable (VH or VL) domains and constant (CH or CL) domains, which form the Fab and the Fc domains. Fc domain diversity is generated during an immune response via the selection of different antibody isotypes, subclasses and post-translational glycosylation profiles. Five isotypes (IgM, IgD, IgG, IgA and IgE) and six subclasses (IgG1–4, IgA1 and IgA2) exist in humans. Each isotype or subclass exists as monomers and/or multimers, linked by disulfide bridges, polypeptide J chains or the secretory component, which is a proteolytic cleavage product of the polymeric immunoglobulin that remains associated with secreted dimeric IgA. Three structural features influence their flexibility and/or conformation and hence impact antibody–receptor and even antigen binding; these features include hinge length and flexibility, the number and location of disulfide bridges and O-linked or N-linked glycosylation. Together, changes in isotype or subclass and glycosylation influence the capacity of any antibody to interact with innate immune receptors and thereby deploy distinct innate immune effector functions.

Figure 2 |. Antigen, antibody and Fc receptor stoichiometry in effector function.

Antibodies collaboratively generate immune complexes that drive innate immune effector function. Antigen–antibody complex quality is influenced by both the crystallizable fragment (Fc domain) characteristics of the antibody (how strongly it will bind to Fc receptors) and the ratio of antigen to antibody, which will greatly affect the size and shape of immune complexes. The size and shape of the immune complex likely influences both the number and conformation of Fc domain sensors that may be engaged on the surface of innate effector cells. Immune complex stability is driven by multiple bonds that enhance the binding between Fc domains and Fc domain sensors. In a state of antigen excess (and antibody scarcity, left side) or antibody excess (and antigen scarcity, right side), immune complex quality shifts towards small complexes that cluster fewer Fc domain sensors on the surface of innate immune cells. Conversely, at an optimal antibody:antigen ratio (centre), larger, more stable immune complexes are generated that are able to cluster a larger number of Fc domain sensors, thereby driving optimal innate immune effector activation. FcR, Fc receptor.

Figure 3 |. Antibody effector functions.

Antibodies are able to deploy a plethora of effector functions over the course of an infection. These include but are not limited to the following: a | The direct neutralization of toxins or microorganisms. b | The neutralization of microbial virulence factors, such as those involved in quorum sensing and biofilm formation. c | The trapping of pathogens in mucins. d | The activation of complement to drive phagocytic clearance or destruction, generate chemoattractants or anaphylatoxins such as C3a and C5a or complement fragment opsonins such as C3b or induce lysis through the membrane attack complex. e | The activation of neutrophil opsonophagocytosis, oxidative bursts, production of lytic enzymes and chemoattractants, or the formation of neutrophil extracellular traps (NETs) of chromatin and antimicrobial proteins. f | The induction of macrophage opsonophagocytosis, oxidative bursts or antimicrobial peptide release. g | The activation of natural killer (NK) cell degranulation to kill infected cells. h | The enhancement of antigen uptake, processing and presentation by dendritic cells (DCs) to T cells. i | The presentation of antigens by follicular dendritic cells (FDCs) to B cells. j | The degranulation of mast cells, basophils and eosinophils to release vasoactive substances, chemoattractants and T helper 2 (TH2)-type cytokines in the setting of allergens or parasitic infections. Fc, crystallizable fragment; MBL, mannose-binding lectin; pMHC, peptide–MHC complex.

Figure 4 |. Factors influencing humoral activity in response to infection.

Microbial life cycles, including tissue tropism and disease pathogenesis, can dynamically impact humoral immunity over the course of an infection. Factors that include the spectrum of antigens recognized by the host over the course of infection, the inflammatory profiles driven by the pathogen and the physiological compartment or compartments where infection occurs may alter the landscape of humoral immune responses that may provide protection. These infection profile features in turn influence the quality of the humoral immune response, such that antibody specificity and antibody function are rapidly customized to effectively target the pathogen. Thus, based on the inflammatory profile and tissue compartment, the humoral immune response rapidly explores the combinatorial diversity of different isotypes, subclasses and crystallizable fragment (Fc domain) glycovariants to selectively recruit the Fc domain sensors available on innate immune cells at the site of infection. In the context of antibody glycosylation in the figure, G refers to galactose, S refers to sialic acid, F refers to fucose and B refers to bisecting N-acetylglucosamine. DC, dendritic cell; DC-SIGN, dendritic cell-specific ICAM3-grabbing non-integrin; GPI, glycosyl phosphatidylinositol; MBL, mannose-binding lectin; NK, natural killer; pIgR, polymeric immunoglobulin receptor; TH2, T helper 2.