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.
