Pattern Recognition Receptors Detect Nonself
Pattern recognition receptors (PRRs) raisethe alarm
To identify potentially dangerous microbial agents, our immune systems need to be able to discriminate between “non-infectious self and infectious nonself” as Janeway elegantly put it. Recognition of nonself entities is achieved by means of an array of pattern recognition receptors and proteins (collectively called pattern recognition molecules) that have evolved to detect conserved (i.e., not prone to mutation) components of microbes that are not normally present in the body (i.e., PAMPs).
In practice, PAMPs can be anything from carbohydrates that are not normally exposed in vertebrates, proteins only found in bacteria, such as flagellin (a component of the bacterial flagellum that is used for swimming), double‐stranded RNA that is typical of RNA viruses, as well as many other molecules that betray the presence of microbial agents. The cardinal rule is that a PAMP is not normally found in the body but is a common and invariant feature of many frequently encountered microbes. Pattern recognition molecules also appear to be involved in the recognition of DAMPs released from necrotic cells.
Upon engagement of one or more of these pattern recognition molecules with an appropriate PAMP or DAMP, an immune response ensues (Figure 1.2). Fortunately, we have many ways in which an impending infection can be dealt with, and indeed it is a testament to the efficiency of our immune systems that the majority of us spend most of our lives relatively untroubled by infectious disease.
A variety of responses can occur downstream of pattern recognition
One way of dealing with unwelcome intruders involves the binding of soluble (humoral) pattern recognition molecules, such as complement (an enzyme cascade we will deal with later in this chapter), mannose‐binding lectin, C‐reactive protein, or lysozyme, to the infectious agent. The binding of soluble pattern recognition molecules to a pathogen has a number of outcomes (Figure 1.2).
First, this can lead directly to killing of the pathogen through destruction of microbial cell wall constituents and breaching of the plasma membrane because of the actions of such proteins. Second, humoral factors are also adept at coating microorganisms (a process called opsonization) and this greatly enhances their uptake through phagocytosis and subsequent destruction by phagocytic cells.
Other PRRs are cell associated and engagement of such receptors can also lead to phagocytosis of the microorganism followed by its destruction within phagocytic vesicles. Just as importantly, cellular PRR engagement also results in the activation of signal transduction pathways that greatly enhance the effector functions of cells bearing these receptors (such as increasing their propensity for phagocytosis or the production of antimicrobial proteins) and also culminate in the release of soluble messenger proteins (cytokines, chemokines, and other molecules) that mobilize other components of the immune sys- tem. PRR engagement on effector cells can also result in differentiation of such cells to a more mature state that endows specialized functions on such cells. Later we will deal with a very important example of this when we discuss the issue of dendritic cell maturation, which is initiated as a consequence of engagement of PRR receptors on these cells by microbial PAMPs. Therefore, pattern recognition of a pathogen by soluble or cell‐associated PRRs can lead to:
▪ Direct lysis of the pathogen
▪ Opsonization followed by phagocytosis
▪ Direct phagocytosis via a cell‐associated prr
▪ Enhancement of phagocytic cell functions
▪ Production of antimicrobial proteins
▪ Production of cytokines and chemokines
▪ Differentiation of effector cells to a more active state.
There are several classes of pattern recognition receptor
As we shall see later in this chapter, there are a number of different classes of cell‐associated PRRs (Toll‐like receptors [TLRs], C‐type lectin receptors [CTLRs], NOD‐like receptors [NLRs], RIG‐I‐like receptors [RLRs], among others) and it is the engagement of one or more of these different categories of receptors that not only enables the detection of infection, but also conveys information concerning the type of infection (whether yeast, bacterial, or viral in origin) and its location (whether extracellular, endosomal, or cytoplasmic). In practise, most pathogens are likely to engage several of these receptors simultaneously, which adds another level of complexity to the signaling outputs that can be generated through engagement of these receptors. This, in turn, enables the tailoring of the subsequent immune response towards the particular vulnerabilities of the pathogen that raised the alarm.
Cells of the immune system release messenger proteins that shape and amplify immune responses
An important feature of the immune system is the ability of its constituent cells to communicate with each other upon encountering a pathogen to initiate the most appropriate response. As we shall see shortly, there are quite a number of different “ranks” among our immune forces, each with their own particular arsenal of weapons, and it is critical that a measured and appropriate response is deployed in response to a specific threat. This is because, as we have already alluded to, many of the weapons that are brought into play during an immune response are destructive and have the potential to cause collateral damage. Furthermore, initiation and escalation of an immune response carries a significant metabolic cost to the organism (due to the necessity to make numerous new proteins and cells). Thus, communication among the different immune battalions is essential for the initiation of the correct and proportional response to the particular agent that triggered it. Although cells of the immune system are capable of releasing numerous biologically active molecules with diverse functions, two major categories of proteins – cytokines and chemokines – have particularly important roles in shaping and escalating immune responses.
Cytokines are a diverse group of proteins that have pleiotropic effects, including the ability to activate other cells, induce differentiation to particular effector cell subsets and enhance microbicidal activity (Figure 1.4). Cytokines are commonly released by cells of the immune system in response to PAMPs and DAMPs, and this has the effect of altering the activation state and behavior of other cells to galvanize them into joining the fight. Chemokines are also released upon encountering PAMPs/DAMPs and typically serve as chemotactic factors, helping to lay a trail that guides other cells of the immune system to the site of infection or tissue damage. Both types of messenger proteins act by diffusing away from the cells secreting them and binding to cells equipped with the appropriate plasma membrane receptors to receive such signals.
The interleukins are an important class of cytokines
A particularly important group of cytokines in the context of immune signaling is the interleukin (IL) family, which has over 40 members at present, numbered in the order of their discovery. Thus, we have IL‐1, IL‐2, IL‐3, IL‐4, etc. Interleukins, by definition, are cytokines that signal between members of the leukocyte (i.e., white blood cell) family. However, these molecules often have effects on other tissues that the immune sys- tem needs to engage in the course of initiating immune responses. So, although interleukins are heavily involved in communication between immune cells, these cytokines also have profound effects on endothelial cells lining blood capillaries, hepatocytes in the liver, epithelial cells, bone marrow stem cells, fibroblasts, and even neurons within the central nervous system. It is also important to note that the same interleukin can trigger different functional outcomes depending on the cell type that it makes contact with; these are simply “switch” molecules that can turn different functions on or off in the cells they encounter. The function that is switched on, or off, will depend on the target cell and the other cytokine signals that this cell is receiving in tandem. Thus, just as we integrate lots of different sources of information (e.g., from colleagues, friends, family, newspapers, TV, radio, books, websites, social media, etc.) in our daily lives that can all influence the decisions we make, cells also integrate multiple sources of cytokine information to make decisions on whether to divide, initiate phagocytosis, express new gene products, differentiate, migrate, and even die. We will discuss cytokines, chemokines, and their respective receptors at length in Chapter 8.