The Beginnings Of An Immune Response
Macrophages play an important role in instigating innate immune
responses
As noted above, a major player in
the initiation of immune responses is the macrophage. These cells
are relatively abundant in most tissues (approaching 10–15% of the total cell number in some areas of the body) and act as
sentinels for infectious agent through an array of pathogen recognition
receptors (PRRs) borne on their plasma membranes as well as other cellular
compartments such as endosomes. Tissue macrophages are relatively quiescent cells,
biding their time sampling the environment around them through continuous
phagocytosis. However, upon entry of a microorganism that engages one or more
of their PRRs (such as a Toll‐like receptor or a NOD‐like receptor), a
startling transition occurs. Engagement of the PRR on the macrophage switches
on a battery of genes that equip it to carry out a number of new functions
(Figure 1.12).
First, the macrophage is put on a
state of high alert (i.e., becomes activated) and is now better at engulfing
and killing any microorganisms it encounters (this will be discussed in detail
in the next section). Second, the macrophage begins to secrete cytokines and
chemokines that have effects on nearby endothelial cells lining the blood
capillaries; this makes the capillaries in this area more permeable than
they would normally be. In turn, the increased vascular permeability permits
two other things to happen. Plasma proteins that are normally largely
restricted to blood can now invade the tissue at the point of infection and
many of these proteins have microbicidal properties. A second consequence of
increased vascular permeability is that neutrophils can now gain
access to the site of infection. Recall from our earlier discussion that
neutrophils, like macrophages, are also adept at phagocytosis but are normally
not permitted to enter tissues owing to their potentially destructive behavior.
Upon entry into an infected tissue, activated neutrophils proceed to attack and
engulf any microorganisms they encounter with gusto. We
will deal with the specific mechanisms that neutrophils employ to attack and
kill microbes later in this chapter.
The inflammatory response
Inflammation is the term given to
the series of events that sur- round an immune response and display a number of
characteristic features, including local swelling (edema), redness (due to
capillary dilation), pain, and heat. These features are the collective
consequence of the release of cytokines, chemokines, and vasoactive amines from
macrophages and mast cells upon the initial encounter with a pathogen.
Byproducts of complement activation (i.e., C3a and C5a), which will be
discussed later, also contribute to the inflammatory response through promoting
neutrophil chemotaxis, as well as activation of mast cells (Figure 1.13). All
of these inflammatory mediators help to recruit neutrophils as well as plasma
proteins to the site of infection by inducing vasodilation of the blood vessels
close to the site of infection and by acting as chemotactic factors for
neutrophils circulating in blood. The extra cells and fluid that gather at the
site of an infection (which contribute to the swelling seen), the increased
redness of skin tone in the area, and associated tenderness constitute the
classic inflammatory reaction.
Mast cells collaborate with macrophages to promote vascular
permeability
As we have already alluded to
above, the macrophage plays a key role in the initiation of an inflammatory
response through the secretion of cytokines and chemokines in response to engagement of its PRRs and through encounter
with opsonized microbes (Figure 1.12). However, another innate immune cell, the
mast cell, is instrumental in provoking increased permeability of
blood vessels due to release of the contents of the numerous cytoplasmic granules
that such cells possess (Figure 1.8). Mast cell granules contain, among other
factors, copious amounts of the vasoactive amino acid histamine (Figure 1.14).
Mast cell degranulation can be provoked by direct injury, in response to
complement components (C3a and C5a), encounter with PAMPs and through binding
of specific antigen to a class of antibody (IgE) that binds avidly to mast
cells via surface receptors (we will discuss antibody classes at length in
Chapter 3). Histamine provokes dilation of postcapillary venules, activates the
local endothelium, and increases blood vessel permeability. Irritation of nerve
endings is another consequence of histamine release and is responsible for the
pain often associated with inflammation, an evolutionary adaptation that most
likely encourages the host to protect the infected or injured area to minimize
further damage.
The relaxation induced in
arteriolar walls causes increased blood flow and dilatation of the small
vessels, whereas contraction of capillary endothelial cells allows exudation of
plasma proteins. Under the influence of the chemotaxins, neutrophils slow down
and the surface adhesion molecules they are stimulated to express cause them to
marginate to the walls of the capillaries, where they pass through gaps between
the endothelial cells (diapedesis) and move up the concentration
gradient of chemotactic factors until they come face to face with complement‐opsonized
microbes (the details of complement‐ mediated opsonization will be
discussed a little later in this chapter).
Adherence to the neutrophil complement (C3b) receptors then takes place, C3a
and C5a (byproducts of complement activation which will be discussed later) at
relatively high concentrations in the chemotactic gradient activate neutrophil
killing mechanisms and, hey presto, the slaughter of the last act can begin!
Neutrophils are rapidly recruited to sites of infection
We have mentioned that the cytokines,
chemokines, and vasoactive factors (such as histamine) that are released by
activated macrophages and mast cells are instrumental in triggering neutrophil
recruitment from the circulation into the site of infection, a process called extravasation
(Figure 1.15). Because neutrophils are so numerous and so adept at
phagocytosis, their recruitment to an inflammatory site is a critical step in
innate immunity. So, let us take a look at this process in a little more detail. Normally, neutrophils circulate
in the bloodstream and are prevented from adhering to blood vessel walls owing
to the rapid rate of movement of the blood within the vessels. To exit the
bloodstream, neutrophils must first lightly adhere to and roll along the vessel
wall until they gain a firm foothold that allows them to come to a stop,
whereupon they initiate the process of squeezing between the endothelium. The
cytokines secreted by activated macrophages, especially TNFα and IL-1β, have
particular roles in this regard, as the latter cytokines increase the
adhesiveness of the endothelial cells lining the blood capilleries closest to
the site of infection through triggering the exposure of P‐and
E‐selectins on these cells. The selectins present on the activated
endothelium permit neutrophils to initiate the stopping process and to start
rolling along the endothelial wall through binding interactions with carbohydrate ligands (e.g., sialyl‐LewisX) present on the neutrophil cell surface (Figure 1.15).
At this stage, the neutrophil
will also experience the chemotactic factors, such as IL‐8 and complement
products, that are emanating from the site of infection. These factors initiate
the process of neutrophil activation, which triggers conformational changes in
adhesion molecules called integrins (e.g., LFA‐1, CR3) on the
neutrophil surface that permits stronger interactions with their cognate intercellular
cell adhesion molecules (ICAMs) receptors on the activated endothelium
that arrests the neutrophil. Finally, neutrophils squeeze between the slightly
wider gaps in the activated endothelium than normal (due to the relaxation effects of histamine) and start to
follow the gradient of chemotactic factors (IL‐8, complement factors C3a and
C5a) to its source. As we have seen earlier (Figure 1.10), this process is very
efficient indeed and results in huge increases in neutrophil numbers at the
site of infection within a matter of hours.
A similar process is also used to
recruit monocytes from the bloodstream to reinforce their
macrophage counterparts within the tissues, but this wave of recruitment
usually takes place 6–8 hours after the peak of neutrophil extravasation and
under the influence of a different chemokine, monocyte chemotactic protein‐1 (MCP‐1). Indeed, one of the reasons for the recruitment of extra
monocytes (which differentiate into macrophages upon entering the tissues) is
to help remove all of the battle‐ weary neutrophils, many of which will be
stuffed to the gills with microbes, as well as other debris from the tissue and
to initiate the process of wound healing.
