The COVID-19 Textbook

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SECTION 3 • Immunology

antibodies bind to FcRn with a higher affinity and thus they both persist for longer periods of time and can be transferred more efficiently to tissues. In immune cells, FcRn is involved in driving anti gen processing and presentation for the potent induction of T-cell immune responses. Finally, FcRn also contributes to the delivery of antibody-antigen/pathogen complexes to antigen-presenting cells (APCs) that are involved in T-cell education. 36 ANTIBODY EFFECTOR FUNCTIONS Antibodies act through synergy, typically binding a target as a polyclonal pool of molecules, meaning that antibodies with different affinities, geometries, and Fc-domains bind simultaneously to a target, forming a large complex, also known as an immune complex (IC). Thus, given the multitude of different Fc-domains that may be present within a given IC, antibodies can drive a range of different functional responses. In viral infection, these effector functions include either direct antiviral activity through neutralization or indirect antiviral activity through the recruitment of immune functions via Fc:FcR interactions. Direct neutralization occurs when neutralizing antibodies (nAbs) bind to a pathogen and phys ically prevent the pathogen from infecting a new cell. nAbs often bind to the receptor or close to the receptor used by the pathogen to attach to the host cell, such as the receptor-binding domain (RBD) on SARS-CoV-2, preventing viral binding to the host cell, and thereby preventing entry and thus infec tion. As this is largely driven by the Fab-domain, all isotypes and subclasses of antibodies can be nAbs. However, viruses often evolve rapidly to evade direct nAbs. Thus, the Fab must perpetually evolve to catch-up to pathogen evolution. For example, over the COVID-19 pandemic, several variants emerged that were able to evade the nAbs induced by various vaccines. 37 Although the vaccine-induced immune responses, programmed with the original SARS-CoV-2 Spike antigen, were insufficient to provide pro tection against the new variants, the ensuing humoral immune responses observed in breakthrough vaccine cases evolved to cover the new variants, illustrating the plasticity of the memory B-cell response able to rapidly adapt to an evolving pathogen (see Figure 8.2). F c -MEDIATED EFFECTOR FUNCTIONS ADCC is the antibody-driven killing of target cells by natural killer (NK) cells, lymphocytes that belong to the innate arm of the immune system, and represent the first line of defense against incom ing pathogens. NK cells recognize their targets via an array of receptors that detect transformed or infected cells. 38 Mature NK cells express copious amounts of FcRs, specifically the Fc γ RIIIA recep tor, enabling a pathogen-specific response to antibody-opsonized targets. Upon activation by IgG/ Fc γ RIIIA, NK cells can release cytotoxic granules containing perforin, which creates channels in the cell membrane, and granzyme, which drives apoptosis in the cell. Although NK cells are primarily responsible for ADCC in vivo, multiple other cytotoxic innate effector cells, including neutrophils, monocytes, macrophages, and NK T cells, have been shown to also induce ADCC in vitro. ADCC has been implicated in the control of influenza 39,40 and human immunodeficiency virus (HIV), 41-43 and has also been observed in the setting of SARS-CoV-2 infection. 44-46 Antibody-dependent cellular phagocytosis (ADCP) , or opsonophagocytosis, is the antibody-mediated mechanism whereby antibodies drive pathogen-antibody complex uptake into phagocytic cells, where the complexes are degraded in the lysosomes. Phagocytosis can be induced by a wide range of receptors, including high- and low-affinity receptors, as well as by activating and inhibitory receptors. 47 Monocytes, macrophages, neutrophils, B cells, and dendritic cells (DCs) can all mediate opsonophagocytic uptake of ICs. Depending on the ligated cell type, ADCP can induce cytokine release, neutrophil NETosis (a process in which neutrophils release extracellular webs of chromatin, antimicrobicidal proteins, and oxidant enzymes that kill extracellular pathogens 48,49 ), antigen presentation by DCs to promote more effective T-cell immunity, and/or antiviral mecha nisms. ADCP may play a role in the immune response to HIV, 50,51 adenovirus, 52 West Nile virus, 53 and coxsackieviruses. 54,55 Antibody-mediated complement deposition , also known as complement-dependent cyto toxicity (CDC) , occurs when antibodies activate the classical complement pathway, enabling the

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