New Concepts in Antibody-Mediated Immunity

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Abstract
After stimulating the development of immunology in the early 20th century, the study of the functional aspects of anti- body-mediated immunity (AMI) stagnated in the 1960s be- cause the function of antibodies (Abs) was considered under- stood and available Ab preparations were limited to polyclonal immune sera. Abs in polyclonal sera are heterogeneous, and the uniqueness of each preparation with respect to specificity and isotype posed formidable problems in achieving consis- tency, reliability, and reproducibility in Ab experimentation. The limitations inherent in studies of AMI with polyclonal sera, combined with the discovery of T cells, an increased interest in cell-mediated immunity, and later a rediscovery of innate immunity, steered immunology research away from studies of AMI. However, by the late 1980s the development of monoclonal antibody (MAb) technology, the discovery of Fc receptors (FcR), and the generation of mice with defined ge- netic deficiencies made possible studies that rekindled interest in the basic mechanisms of AMI. More than a dozen MAbs are now licensed for clinical use for diverse indications, such as prophylaxis of respiratory syncytial virus disease in neonates, treatment of Crohn's disease, prevention of coronary artery closure after angioplasty, and therapy of refractory rheumatoid arthritis (65). In addition, the fact that the use of passive Abs is currently the only means to provide immediate immunolog- ical protection against biological weapons in immunologically naïve populations has stimulated new interest in AMI (9, 13). The availability of new technologies to study AMI and the need for specific, rapidly acting therapies for new and emerg- ing diseases have led to the discovery of new Ab functions that have broadened the classical views of AMI. This review will focus primarily on insights that have emerged from studies with whole Ab molecules, which are the natural products of B cells. However, many contributions to the field of AMI and promising clinical reagents have also come from studies with Ab fragments and antibody-derived peptides, although to date fewer studies have addressed the mechanisms of efficacy for these reagents. CLASSICAL VIEWS OF AMI Antibody molecules consist of two domains, an antigen bind- ing region composed of variable (V) region elements and a constant (C) region. The C region includes an Fc region, which determines the antibody's isotype and functional characteris- tics, such as its half-life in serum, complement activation, and ability to interact with FcR. The V region binds to antigens by forming hydrophobic, ionic, and van der Waal interactions, while the Fc region binds to cellular receptors and some hu- moral components of the immune system, such as complement. When AMI is ascribed to such receptor-ligand interactions, Ab function can be viewed as bridging the distance between a microbial antigen and the immune system. The classical func- tions of specific Abs include direct Ab activities, such as toxin and virus neutralization, and indirect activities that require other immune system components, such as opsonization and complement activation. Each of these functions was initially described at the end of the 19th or in the early 20th century; however, recent studies of Ab-mediated complement activa- tion have revealed that Ab- and complement-mediated op- sonophagocytosis can be functionally redundant, at least for some microbes (47). Later, Ab-dependent cellular cytotoxicity was recognized as an important mechanism whereby specific Abs could focus cytotoxic effects of certain host effector cells, such as NK cells, against tumors and microbes.