immunogenic. Rather, the induction of strong immune responses against purified proteins required the inclusion of microbial constituents, such as killed bacteria or bacterial extracts, famously called the immunologist’s ‘dirty little secret’ by Charles Janeway (see Appendix I, Sections A-1–A-4). This additional material was termed an adjuvant, because it helped intensify the response to the immunizing antigen (adjuvare is Latin for ‘to help’). We know now that adjuvants are needed, at least in part, to activate innate receptors on various types of sensor cells to help activate T cells in the absence of an infection.
Macrophages, neutrophils, and dendritic cells are important classes of sensor cells that detect infection and initiate immune responses by producing inflammatory mediators, although other cells, even cells of the adaptive immune system, can serve in this function. As mentioned in Section 1-3, these cells express a limited number of invariant innate recognition receptors as a means of detecting pathogens or the damage induced by them. Also called pattern recognition receptors (PRRs), they recognize simple molecules and regular patterns of molecular structure known as pathogen-associated molecular patterns (PAMPs) that are part of many microorganisms but not of the host body’s own cells. Such structures include mannose-rich oligosaccharides, peptidoglycans, and lipopolysaccharides of the bacterial cell wall, as well as unmethylated CpG DNA common to many pathogens. All of these microbial elements have been conserved during evolution, making them excellent targets for recognition because they do not change (Fig. 1.9). Some PRRs are transmembrane proteins, such as the Toll-like receptors (TLRs) that detect PAMPs derived from extracellular bacteria or bacteria taken into vesicular pathways by phagocytosis. The role of the Toll receptor in immunity was discovered first in Drosophila melanogaster by Jules Hoffman, and later extended to homologous TLRs in mice by Janeway and Bruce Beutler. Hoffman and Beutler shared the remaining half of the 2011 Nobel Prize (see Section 1-4) for their work in the activation of innate immunity. Other PRRs are cytoplasmic proteins, such as the NOD-like receptors (NLRs) that sense intracellular bacterial invasion. Yet other cytoplasmic receptors detect viral infection based on differences in the structures and locations of the host mRNA and virally derived RNA species, and between host and microbial DNA. Some receptors expressed by sensor cells detect cellular damage induced by pathogens, rather than the pathogens themselves. Much of our knowledge of innate recognition has emerged only within the past 15 years and is still an active area of discovery. We describe these innate recognition systems further in Chapter 3, and how adjuvants are used as a component of vaccines in Chapter 16.
1-6 Sensor cells induce an inflammatory response by producing mediators such as chemokines and cytokines.
Activation of PRRs on sensor cells such as macrophages and neutrophils can directly induce effector functions in these cells, such as the phagocytosis and degradation of bacteria they encounter. But sensor cells serve to amplify the immune response by the production of inflammatory mediators. Two important categories of inflammatory mediators are the secreted proteins called cytokines and chemokines, which act in a manner similar to hormones to convey important signals to other immune cells.
‘Cytokine’ is a term for any protein secreted by immune cells that affects the behavior of nearby cells bearing appropriate receptors. There are more than 60 different cytokines; some are produced by many different cell types; others, by only a few specific cell types. Some cytokines influence many types of cells, while others influence only a few, through the expression pattern of each cytokine’s specific receptor. The response that a cytokine induces in a target cell is typically related to amplifying an effector mechanism of the target cell, as illustrated in the next section.