The COVID-19 Textbook

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SECTION 3 • Immunology

hundreds of therapeutics in clinical development and testing across disease indications from autoim munity to infectious disease. The coronavirus disease 2019 (COVID-19) pandemic illustrated the critical role of antibodies in the prevention of disease, in the setting of prophylactic vaccination, and as therapeutics for the treatment of disease. Here, we will review the anatomy of antibodies, their origin, their role in vaccination, and the promise of next-generation strategies through the lens of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ANTIBODIES Antibodies are Y- or T-shaped polypeptide proteins, comprised of four peptide chains: two heavy chains and two light chains (Figure 8.1). Together, these four chains form two identical antigen-binding fragments (Fabs) and a crystallizable fragment (Fc), linked by a hinge domain. 11 They are expressed in B cells, acting as B-cell receptors (BCRs), and produced by antibody-secreting cells, including short-lived plasmablasts and long-lived plasma cells. 12 Each B cell has a unique BCR, formed via a random recombination event during B-cell maturation in the bone marrow, resulting in the gener ation of up to 10 12 unique BCRs with distinct antigen recognition capabilities. 13 At the start of the maturation process, one of two light chains ( κ or λ ) is selected to form the antibody Fab. The light chains pair with the heavy chains to form a polypeptide of two light chains and two heavy chains, forming two identical antigen-binding sites. Variation in the antigen-binding sites arises from the recombination of VJ (light chain) and VDJ (heavy chain) segments found in the Ig locus, and the ensuant random repair following end-joining creates random variation that collectively forms the complementarity determining regions (CDRs), 14 which are supported by framework regions found on the end of each of the polypeptide chains. 14,15 The CDRs are responsible for antibody specificity and variation. Typically, B cells encounter and sample antigens with their BCR in dedicated regions of the lymph node called germinal centers (GCs), 16-18 where antigens are arrayed on specialized set of fibroblasts known as follicular dendritic cells (fDCs). 19 When the BCRs productively engage an antigen, B cells rapidly become activated, acquiring signals to proliferate, travel to a newly devel oped dark zone of the GC, and begin hypermutating their BCR. 20 Hypermutation involves the specialized incorporation of additional mutations in the CDRs of the antibody, aimed at randomly allowing for the creation of almost unlimited variability in antigen specificity and affinities. 14 Hy permutated daughter cells then circulate back to the light zone of the GC, resampling the arrayed antigen. Cells that bind the antigen more tightly gain survival and proliferative signals, present the processed antigen to follicular T-helper cells (Tfh), and return to the dark zone for further hyper mutation. Cells that do not gain affinity, and therefore do not receive additional signals, die off. Following several mutational rounds, a subset of B cells differentiates into short-lived plasmablasts primed to populate the system with antibodies. A second subset of high-affinity GC B cells dif ferentiate into plasma cells that take up long-term residence in the bone marrow. Finally, a third subset become memory B cells that circulate widely through the body, providing memory upon pathogen/antigen reencounter. The Fc-domain, which is composed of two polypeptide chains, can also change during the life span of a B cell. In humans, the Ig locus contains nine different potential Fc-domains that can be attached to any Fab. These include the five antibody isotypes, IgD, IgM, IgG, IgA, and IgE, in which IgG and IgA are composed of the subclasses IgG1, IgG2, IgG3, and IgG4, and IgA1 and IgA2, respectively 21,22 (Table 8.1 23 ). Each Fc-domain can bind to isotype-specific Fc-receptors (FcRs) found in different combinations and at different levels across cells of the immune system. 24,25 Specific inflammatory cues and T-helper signals, present at the time of B-cell programming, lead to the selection of a particular Fc-domain able to recruit and drive the most appropriate immunologic functions to clear the pathogen the antibody recognizes, that is, mucosal pathogens tend to drive IgA Fc-selection, known to play a critical role at mucosal barriers, whereas systemic viral infections tend to elicit IgG1/IgG3 responses that have high affinity for FcRs present on systemic immune cells. 22,24 Together, the pairing of the optimal Fab and Fc results in the generation of bifunctional molecules able to fully leverage the immune system to fight disease.

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