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.
