Antibody Fc: Linking Adaptive and Innate Immunity

The book opens with a section devoted to three Fc-dependent mechanisms that are crucial to immunity: (1) antibody-dependent cellular cytotoxicity (ADCC); (2) antibody-dependent cellular phagocytosis (ADCP); and (3) complement-dependent cytotoxicity (CDC). Victor Raúl Gómez Román, Joseph C. Murray and Louis M. Weiner discuss ADCC, and set the stage for subsequent chapters, by first introducing two crucial elements of the immune system, effector cells and the Fcγ receptors (FcγR) expressed on them. The authors then explain in detail the sequential steps of ADCC, including crosslinking of target and effector cells, downstream signaling in the effector cell and killing of the target cell, which can be achieved via various pathways. The roles of ADCC in cancer therapy (e.g., rituximab, cetuximab, trastuzumab, panitumumab treatment), and in protection from infectious disease are considered. The authors note that enhancement of ADCC mediated by monoclonal antibodies (mAbs) can be achieved via glycoor protein-engineering of the Fc region, but a wide variety of other mechanisms of action can also be utilized by mAb therapeutics. ADCP and its impact on pathogen control are examined by Stefan S. Weber and Annette Oxenius. The process of phagocytosis involves the active uptake and endocytosis of particles larger than 0.5 μm (e.g., antibody-containing immune complexes) into FcγR-expressing cells such as monocytes, macrophages, neutrophils and dendritic cells. The FcγRs are differentially expressed on the cells in a dynamic fashion that is regulated by the cytokine milieu. With this as introduction, the authors then discuss the role of FcγR-mediated phagocytosis for the uptake, cellular localization and control of pathogens, including bacteria, viruses, parasites and fungi. Evasion strategies developed by pathogens and the phenomenon of antibody-dependent enhancement (ADE) of infection are also presented. The complex interactions between the complement system and FcγRs are explored by Margaret A. Lindorfer, Jörg Köhl and Ronald P. Taylor. They first describe the CDC process, which involves complement activation by immune complex, opsonization, immobilization of the complex via complement receptor 1 (CR1; cognate ligand is C3b) on erythrocytes and, finally, transfer to acceptor cells (e.g., monocytes, macrophages) via their FcγRs. Interestingly, B cells can engage in a similar process, although immobilization of the complex occurs via CR2 (cognate ligand is C3d) expressed on B cells. The authors present the different processing reactions of immune complexes in the context of infection by human immunodeficiency virus (HIV), emphasizing that a possible outcome is infection of the acceptor cell. Cooperation/synergy between FcγRs and CRs, in particular FcγRIII and CR3, on effector cells and cross-talk between the C5a receptor and FcγR on effector cells are discussed in detail. The authors conclude by remarking on the challenges of developing therapeutics that appropriately regulate the two effector systems. Section 2 focuses on three types of cells that are crucial to the immune system, natural killer (NK) cells, phagocytes and B cells. Andreas Diefenbach presents the role of NK cells in the innate immune response and emphasizes the complex interplay of inhibitory input (e.g., from killer cell immunoglobulin-like receptors) and activating input (e.g., from FcγRIIIa, NKG2D) that regulates their activity. The author also highlights recent work that has identified adaptive features of NK cells, such as priming and memory. The interactions of phagocytes and immunoglobulins are examined by Luisa Martinez-Pomares. Correspondence to: Janice M Reichert; Email: [email protected] Submitted: 03/18/14; Accepted: 03/18/14; Published Online: 03/21/2014 http://dx.doi.org/10.4161/mabs.28617 Antibody Fc: Linking Adaptive and Innate Immunity Editors Margaret E. Ackerman, Falk Nimmerjahn