Innate Versus Adaptive Immunity
Three levels of immune defense
Before we get into the details, we will first summarize how the immune system works in broad brushstrokes. The vertebrate immune system comprises three levels of defense (Figure 1.5). First, there is a physical barrier to infection that is provided by the skin on the outer surfaces of the body, along with the mucous secretions covering the epidermal layers of the inner surfaces of the respiratory, digestive, and reproductive tracts. Any infectious agent attempting to gain entry to the body must first breach these surfaces that are largely impermeable to microorganisms; this is why cuts and scrapes that breach these physical barriers are often followed by infection. The second level of defense is provided by the innate immune system, a relatively broad‐acting but highly effective defense layer that is largely preoccupied with trying to kill infectious agents from the moment they enter the body. The actions of the innate immune system are also responsible for alerting the cells that operate the third level of defense, the adaptive (or acquired) immune system. The latter cells represent the elite troops of the immune system and can launch an attack that has been specifically adapted to the nature of the infectious agent using sophisticated weapons such as antibodies. As we shall see, the innate and adaptive immune systems each have their own particular advantages and disadvantages and therefore act cooperatively to achieve much more effective immune protection than either could achieve in isolation.
Innate immune responses are immediate and relatively broad acting
Upon entry of a foreign entity into the body, the innate immune response occurs almost immediately. Innate immune responses do not improve (at least to a dramatic degree) upon frequent encounter with the same infectious agent. The innate immune system recognizes broadly conserved components of infectious agents, the aforementioned PAMPs, which are not normally present in the body. The molecules and receptors (i.e., PRRs) used by the innate immune system to detect PAMPs are hard‐wired (i.e., germline encoded, which means that such genes are passed in essentially identical form from parent to offspring) and respond to broad categories of foreign molecules that are commonly expressed on microorganisms. The relatively invariant nature of PRRs is a strength, as well as a weakness, of the innate immune system. It is a strength in terms of discriminating self from nonself very reliably (as PRRs have evolved over millions of years to be able to detect nonself, while ignoring self ), but is a weakness in that the specificity of a given PRR towards an individual pathogen is poor as these receptors do not mutate at any appreciable rate. Thus, innate immune responses cannot be uniquely tailored towards a specific pathogen, at least beyond the number of individual PRRs that our innate immune systems possess.
Because the receptors of the innate immune system are encoded by the germline, innate immune responses are there-fore quite similar between individuals of the same species. Upon detecting a PAMP, the innate immune system mounts an immediate attack on anything displaying such molecules by either engulfing such entities or through attacking them with destructive enzymes, such as proteases or membrane‐ attacking proteins (Figure 1.2). The clear intent is to bludgeon the unwanted intruder into submission as quickly as possible. This makes sense when one considers the prodigious rates of proliferation that bacteria can achieve (many bacterial species are capable of dividing every 20 minutes or so), particularly in the nutrient‐rich environment our bodies provide. Key players in the innate immune response include macrophages, neutrophils, and soluble bactericidal (i.e., bacteria killing) proteins such as complement and lysozyme. Although highly effective, innate immune responses are not always sufficient to completely deal with the threat, particularly if the infectious agent is well adapted to avoid the initial attack. In this situation, a more specific immune response is required, tailored towards particular determinants that are present on individual pathogens. This is where the adaptive immune response comes into play.
Adaptive immune responses are delayed but highly specific
Because of the way in which adaptive immune responses are initiated, such responses take longer to achieve functional significance, typically 4–5 days after the innate immune response, but are exquisitely tailored to the nature of the infectious agent. How the pathogen‐detecting receptors of the adaptive immune system (such as antibody) achieve their high specificity will be discussed at length in later chapters, but in brief this involves the shuffling of a relatively small number of receptor precursors that, through the power of random genetic recombination, can produce a truly spectacular number of specific antigen receptors (numbering in the tens of millions). The major downside to this genetic recombination process is that it is prone to producing receptors that recognize self. However, the adaptive immune system has evolved ways of dealing with this problem, as will be discussed in Chapter 10.
Importantly, because the antigen receptors of the adaptive immune system are custom‐built to recognize specific pathogens, such responses improve upon each encounter with a particular infectious agent, a feature called immunological memory, which underpins the concept of vaccination. The adaptive immune response is mediated primarily by T‐ and B‐ lymphocytes and these cells display specific receptors on their plasma membranes that can be tailored to recognize an almost limitless range of structures. By definition, molecules that are recognized by T‐ and B‐lymphocytes are called antigens. Recognition of antigen by a lymphocyte triggers proliferation and differentiation of such cells and this has the effect of greatly increasing the numbers of lymphocytes capable of recognizing the particular antigen that triggered the response in the first place. This rapidly swells the ranks of lymphocytes (through a process called clonal expansion, which enables the rapid division of cells carrying a particular antigen receptor) capable of dealing with the infectious agent bearing the specific antigen and results in a memory response if the same antigen is encountered at some time in the future. We will look in detail at the receptors used by T‐ and B‐cells to see antigen in Chapter 4.
Innate and adaptive immune responses are interdependent
The innate and adaptive immune systems work in tandem to identify and kill infectious agents (Figure 1.5). As we shall see in later chapters, while the innate and adaptive immune systems have their own individual strengths, there are multiple points at which the innate immune system feeds into the adaptive immune system and visa versa. In this way, both systems synergize to deal with infectious agents. Thus, when an infection occurs, the innate immune system serves as a rapid reaction force that deploys a range of relatively nonspecific (but none-theless highly effective) weapons to eradicate the infectious agent, or at the very least to keep the infection contained. This gives time for the initially sluggish adaptive immune system to select and clonally expand cells with receptors that are capable of making a much more specific response that is uniquely tailored to the infectious agent. The adaptive immune response to an infectious agent reinforces and adds new weapons to the attack mounted by the innate immune system.
Although it was once fashionable to view the innate immune system as somewhat crude and clumsy when compared to the relative sophistication of the adaptive immune system, an explosion of new discoveries over the past 10–15 years has revealed that the innate immune system is just as highly adapted and sophisticated as the adaptive immune system. Moreover, it has also become abundantly clear that the adaptive immune system is highly dependent on cells of the innate immune system for the purposes of knowing when to respond, how to respond, and for how long.
The main reason for this, as we discussed earlier, is that the innate immune system uses hard‐wired receptors (PRRs) that are highly reliable in terms of discriminating self from nonself. In contrast, because the adaptive immune system uses receptors that are generated de novo through random genetic recombination in response to each infectious agent that is encountered, these receptors can easily end up recognizing self, a situation that is highly undesirable. Therefore, cells of the adaptive immune system require instruction (or permission) by cells of the innate system as to whether an immune response should be mounted towards a particular antigen. Furthermore, the precise nature of the PRRs that are engaged on cells of the innate immune system in the initial stages of an infection dictate the type of adaptive immune response that is required (through the production of specific cytokines and chemokines). We will return to these important issues later in this chapter, but for now let us consider the external barriers to infection in a little more detail.