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Immune Responses Are Tailored Towards Particular Types Of Infection


Immune Responses Are Tailored Towards Particular Types Of Infection
Not all pathogens are equal
We will shortly get into the specifics of the immune system, but before doing so it is useful to consider the diversity of infectious agents that our immune systems may encounter (Figure 1.1), and to contemplate whether a “one size fits all” immune response is likely to suffice in all of these situations. One of the frustrations expressed by many students of immunology is that the immune system appears to be almost byzantine in its complexity. Although this is indeed partly true, the reasons for this are two‐fold. First, because there are different types of infection, immune responses need to be tailored towards the particular class of infection (whether viral, extra-cellular bacterial, intracellular bacterial, worm, fungal, etc.) in order to mount the most effective immune response towards a particular infectious agent. Second, although there is indeed complexity in the immune system, there is also a great deal of order and repeated use of the same basic approach when recognizing pathogens and initiating an immune response. Therefore, although many of molecules used in the pursuit of pathogen recognition belong to different classes, many of these plug into the same effector mechanisms as soon as the pathogen is successfully identified. So, dear reader, please bear with us while we try to make sense of the apparent chaos. But mean-while, let us get back to pathogens to consider why our immune systems need to be fairly elaborate and multi‐layered.

Infectious agents are a broad church and have evolved different strategies to invade and colonize our bodies, as well as to evade immune detection. Some, such as yeasts and extracellular bacteria, are happy to live in the extracellular space, stealing nutrients that would otherwise nourish our own tissues. Others, such as intracellular bacteria and viruses, invade the cytoplasm and even our genomes and may lurk for months or years within our bodies. Then there are the large worms (helminths) and unicellular eukaryotic protozoa that live parasitic lifestyles with their own particular adaptations.


Because of the diversity of infectious agents, all of which have their own strategies to evade and neutralize the best efforts of our immune systems, we have responded by evolving multiple ways of dealing with intruders, depending on the nature of the infectious agent and how this type of infection is best dealt with. Indeed, it is the constant threat of infection (rather than environmental change) that is the major driver of natural selection over the short term, as viruses and bacteria can mutate with frightening speed to acquire adaptations that can leave their hosts highly vulnerable to infection. For this reason, genes that are involved in the functioning and regulation of the immune system are among the most diverse among human and animal populations (i.e., undergoing the fastest rates of mutation) and are frequently duplicated into large gene families (which are typically variations on a very useful theme) that permits us to hedge our bets and stay ahead in the ongoing battle against those organisms that would have us for lunch.
Because of the diverse nature of the infectious agents that we are confronted with, immune responses come in a number of different flavors and are tailored towards the nature of the pathogen that provoked the response in the first place. As the book progresses, we will elaborate on this concept in much more detail, but do keep this in mind when trying to understand the underlying simplicity among the apparent complexity of the immune responses that we will encounter.

There are different types of immune response
So, what do we mean by different types of immune response? We are not going to be exhaustive at this stage, but let us consider the difference between how our immune system might deal with a virus versus an extracellular bacterium. For both pathogen classes, a system that enables us to recognize these agents and to remove them, either by destroying them (through membrane lysis) or by eating them up (through phagocytosis) followed by degradation within endosomes, would likely be very effective. And indeed, our immune systems have evolved a number of ways of doing both of these things; as we have mentioned earlier, there are multiple classes of proteins that recognize and lyse bacteria and viruses in the extracellular space (complement, acute phase proteins, antimicrobial peptides) and the same proteins are frequently involved in decorating infectious agents for recognition and phagocytosis by phagocytic cells (e.g., macrophages and neutrophils) that are specialized in doing just that. Molecules that are involved in the decoration of infectious agents to prepare them for removal are called opsonins (from the Greek, to prepare for eating) in immunological parlance. So far, so good.
However, once the virus enters a cell, the proteins and phagocytic cells mentioned above will no longer be of any use in dealing with this type of infection as proteins cannot freely diffuse across the plasma membrane to either lyse or tag the infectious agent for phagocytosis. So, it is here that the immune response to an extracellular bacterial infection versus an intracellular viral infection must diverge, as now we need a way of looking inside cells to see whether they are infected or not. Consequently, we have evolved a number of intracellular PRRs that can detect pathogens that have entered cells, and this results in the production of signals (e.g., cytokines and chemokines) that alert the immune system to the presence of an infectious agent. Just as importantly, we have also evolved a fiendishly clever way of displaying the breakdown products of pathogens to cells of the adaptive immune system (major histocompatibility complex [MHC] molecules are centrally involved in this process) irrespective of whether the infectious agent lives inside or outside the cell. We will deal with MHC molecules extensively in Chapters 4 and 5. The latter process enables a cell that has been infected by a virus to display fragments of viral proteins on its plasma membrane, within grooves present in MHC molecules that have evolved for this purpose, thereby alerting cells of the immune system to the nature of its predicament. Ingenious!
So, how does our immune system deal with a virus or other pathogen that has invaded a host cell? Although some specialized phagocytic cells (i.e., macrophages) can kill intracellular bacteria that have invaded them, most cells cannot do this very effectively and so another solution is required. For most other cell types, this is achieved through killing the infected cell (typically by apoptosis) and removing it through phagocytosis, which is easy to write, but involves a series of steps that permit the recognition of infected host cells, the delivery of the “kiss of death” and the engulfment of the infected corpse in a manner that minimizes the escape of the pathogen lurking within. Our immune systems have solved the intracellular infection problem by evolving cells (called cytotoxic T‐cells and natural killer cells) that have the ability to detect infected cells and to kill them; we will deal with natural killer (NK) cells in detail later in this chapter.
Obviously, such powers of life or death carry with them the heavy responsibility of ensuring that uninfected cells are not accidently killed, as it is a basic tenet of multicellularity that one does not go around randomly killing good cellular citizens. Thus, a number of checks and balances have been incorporated into this killing system to ensure that only errant cells are dis- patched in this way. We will deal with the detailed mechanisms of cytotoxic T‐cell‐mediated killing in Chapter 8.
However, some pathogens require a different approach, which involves sending in large numbers of highly phagocytic cells (such as neutrophils) into a tissue that can also deploy destructive proteases, carbohydrases (such as lysozyme), and other nasty molecules into the extracellular space in order to quickly overwhelm and destroy a rapidly dividing pathogen, or a worm parasite. This type of response comes with a certain degree of collateral damage (due to the use of enzymes that do not discriminate between friend and foe) and is typically only mounted when this is warranted.
From the preceding discussion, we hope that it will be evident that different types and severities of immune responses are necessary to fight different types of infection and it is for this reason that the immune system has a variety of cells and weapons at its disposal. Thus, there are different types of immune response, broadly dictated by whether a pathogen lives intracellularly or extracellularly.

The PRRs of the innate immune system generate a molecular fingerprint of pathogens
As we have already alluded to, the PRRs not only help to identify the presence of infectious agents through detection of their associated PAMPs, but they also convey information as to the nature of the infectious agent (whether of fungal, bacterial or viral origin) and the location of the infectious agent (whether extracellular, intracellular, endosomal, cytoplasmic, or nuclear). This is because, as we shall see later, the various classes of PRRs (e.g., Toll‐like receptors, C‐type lectin receptors, NOD‐like receptors, cytoplasmic DNA sensors) are specific for different types of pathogen components (i.e., PAMPs), and reside in different cellular compartments. Thus, we have an ingenious system where the combination of PRRs that is engaged by an infectious agent conveys important information about the precise nature and location of infection and generates a molecular fingerprint of the pathogen. In turn, this information is then used to shape the most effective immune response towards the particular pathogen class that provoked it.

Cytokines help to shape the type of immune response that is mounted in response to a particular pathogen
We have already mentioned that cytokines are involved in communication between cells of the immune system and help to alert the correct cell types that are appropriate for dealing with different classes (i.e., whether viral, bacterial, yeast, etc.) of infectious agents. Cytokines are also capable of triggering the maturation and differentiation of immune cell subsets into more specialized effector cell classes that possess unique capabilities to enable them to fight particular types of infection. In this way, detection of an infection (i.e., PAMPs) by a particular class of PRR is translated into the most appropriate immune response through the production of particular patterns of cytokines and chemokines. These cytokine patterns then call into play the correct cell types and trigger maturation of these cells into even more specific effector cell subtypes. Later, in Chapter 8, we will see how this process is used to produce specialized subsets of T‐cells that are central to the process of adaptive immunity. Let us now look at how the different layers of our immune defenses are organized.