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leukotrienes. Both of these agents result in vasodilation, in
essence causing the endothelium lined blood barrier to become
more or less ―leaky.‖ Dilated local blood vessels, capillaries,
and small venules/arterioles subsequently allow fluid (edema)
to accumulate in the damaged area. If the breach in the
mechanical barrier is deep enough, damaged blood vessels also
directly flood the local area with leukocytes, red blood cells
(RBCs), and platelets. Plasma (blood minus the cells) contains
critical components to mediate the development of
inflammation. On the positive side, the immediate consequence
of tissue damage allows direct delivery of nutrients and oxygen
to the affected area. Fluid entering the site also contains liverderived factors, which are always present in circulating blood.
Many of these molecules are effective at coagulation and
repair, working to direct the clotting cascade and the
production of fibrin. Plasma serine proteases, normally present
as inactive molecules, are activated; some of these function to
produce kinins to mediate firbrinolytic events, vascular
permeability, and sensation of pain. Other proteins and enzymes,
released by platelets, help to further drive and direct the initial
response. Indeed, these factors initiate molecular changes that,
from an immunological standpoint, are extremely beneficial.
Clotting and formation of a fibrin matrix impede the movement
of microorganisms in the local area; generation of breakdown
products in the cascading events also attracts and activates
incoming leukocytes.
The Role of Antibodies In Inflammation
A major benefit of the influx of fluid is the direct delivery
of relatively high levels of antibodies to the area. The circulating
plasma is filled with antibodies that, as a group, have the ability
to recognize just about any shape or form of antigen. Depending
on prior exposure or positive vaccination status, there may also
be an abundance of specific antibodies reactive to antigenic
features present in destructive pathogens.
Antibody entry to the area offers multiple functions, the
most critical of which resides within the end of the antibody
molecule that can recognize unique shapes and forms, with a
specific and unique binding site for foreign substances. This
allows for binding directly to the pathogen or to pathogenderived proteins. In effect, antibodies recognize toxins and
deleterious factors; recognition results in the inhibition and
neutralization of their toxic properties. Direct binding inhibits
organism movement and can block attachment and adhesion to
target host cells. Antibody recognition of multiple regions on the
microorganism can result in a latticework structure, a precipitate,
which promotes organism clearance.
The opposite end of the antibody molecule has a constant
structure that confers biological function. Innate phagocytes
contain surface receptors for the constant end of the antibody
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molecule. These receptors assist pathogen engulfment, specifically
targeting foreign agent destruction using intracellular enzymes.
The term for coating the organism with antibodies is opsonization.
Targeted engulfment is referred to as phagocytosis.
Biological Functions of Complement
Opsonization of organisms has another role. Simply
coating the agent with antibodies targets it for attack by
serum enzymes that comprise the complement cascade (Fig.
2.2). Complement is a term that refers to heat labile factors
in the serum that cause immune cytolysis. As a group,
complement comprises at least 50 distinct proteins that affect
multiple biological functions. The complement components
may be circulating in the blood, may be expressed on cell
surfaces, and may even be found as intracellular-residing
proteins. These components are normally inert in serum;
however, a cascade of events occurs when these molecules
interact with signaling agents. Activation of complement
enzymes results in sub- sequent cleavage of proteins to
yield specific polypeptide fragments with short-lived
enzymatic functions related to inflammation. In essence,
proteolytic degradation of the complement components
drives many aspects of immunity.
Various pathways exist to initiate complement activation.
One pathway, referred to as the classical pathway, utilizes
antibodies as the initiating signal. The sheer action of
antibodies bound to pathogenic determinants on organisms
forms the basis of a physical structure. Complement
components interact with the pathogen-bound antibodies.
The first complement component (called C1) interacts with
the constant portion of specific classes of antibody bound to
the surface of the bacteria. This initiates a cascading series
of reactions, whereby a complex structure is built upon the
bacterial cell surface. Synthesis of this structure culminates in
a pore channel, called a membrane attack complex (MAC),
which causes osmotic lysis of the pathogen or infected cell.
Two other pathways of complement activation, the
alternate pathway and the lectin pathway, function to allow
direct lysis of microorganisms in the absence of antibodies.
In these enzymatic cascades, complement components bind
directly to pathogens via the recognition of bacterial sugars
and lipids. Similar to the events described here, the
deposition of complement on the invading pathogen leads to
a cascade of enzymatic reactions, culminating in pore
channel assembly on the organism surface. Further- more,
breakdown products of the cascading pathway results in the
production of smaller molecules, opsonins, which remain
deposited on the pathogens. The opsonins act as molecular
beacons, allowing interaction with receptors on
macrophages, monocytes, and neutrophils to enhance
phagocytosis and elevate mechanisms of targeted organism
destruction. Finally, a relatively new concept for intracellular
functions of complement has been identified, where the
complement has the ability to affect normal cell physiology.
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An intracellular vesicle, referred to as the complosome,
has a strong impact on cell processes and metabolism, perhaps
exerting influence on how the host cell adjusts to the presence
of intracellular pathogens. Overall, complement and its
related components exert multiple biological functions that
are critical components of inflammation, including activation
and regulation of both innate and adaptive immune
functions (Fig. 2.3). Complement will be discussed again
when examining defense mechanisms against infectious
agents.
Activation and Directed Migration
of Leukocytes
One of the most prevalent by-products of the complement
enzymatic cascade is the production of molecules with the
ability to call in and activate leukocytes. This chemical
attraction is termed chemotaxis. Proteolytic degradation of
complement components releases leukocyte chemotactic
factors referred to as anaphylatoxins. For example,
breakdown products of complement component C3 are
chemotactic for eosinophils. Proteolytic
Pathogen Recognition and Cytokine
Signaling
Phagocytes bear several unique receptors that recognize
microbial components, bind bacterial carbohydrates, and
induce phagocytosis. Recognition can occur directly
through mannose receptors, scavenger receptors, or Tolllike receptors (TLRs), receptors that detect common
pathogenic motifs (pathogen-associated molecular patterns;
PAMPs). Recognition through any of these receptors
represents a ―danger‖ signal that initiates a proinflammatory
response (Fig. 2.4); triggering of these cell surface sensors
activates gene regulation. In addition, internal protein
complexes, such as the inflammasome, further the response
to the recognition event via internal processing of inactive
forms of proinflammatory molecules to produce mature and
active mediators. The result is the release of small chemical
mediators called cytokines. Cytokines represent cell-derived
secreted mediators that allow cells to communicate with
each other. They regulate development and behavior of
immune effector cells and facilitate cross-talk at low
concentrations (10-10
–10-15 M). They are short-lived and
bind to cell surface receptors. They may act alone or in
concert with one another synergistically. They are
considered pleiotropic because they exert multiple actions
on multiple different cell types, with overlapping and
redundant functions. Another common name for these
molecules is lymphokines, which are basically cytokines
produced by cells of the lymphoid lineage. Finally, many
cytokines also function as growth factors for specific cell
subsets (Table 2.2).
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It was mentioned earlier in this chapter that trauma also
may serve as a trigger for inflammation. In addition to the
PAMP molecules described here, a unique subset of
danger-associated molecular patterns (DAMPs), can trigger
similar responses. In this case, innate immune recognition
of host intracellular molecules released by injured tissue can
jump-start the immune response. Multiple DAMP
components have been identified, including those released
during cell death from the nucleus, the cytosol, and the
mitrochondria.
Feedback and Adaptation from a Distance
There is considerable activity between cells at the local
site of the inflammatory response. Indeed, we will see in later
chapters that the direct interaction of cells that initiate the
proinflammatory response with incoming lymphocytes
triggers adaptive cell activity. Cell-to-cell contact gives the
advantage of directly delivering cytokines and mediators,
allowing functional lymphocyte development in the
immediate area to target productive immune function.
However, there is also a great need for systemic
communication that can mediate responses across great
distances to direct cells and organs located distant from the
site of tissue damage.
A special subclass of chemical mediators responsible for
attracting cells to the area of inflammation is called
chemokines. Chemokines assist in leukocyte migration into
tissue (diapedesis). As a class, they are small polypeptides
synthesized by a wide variety of cell types, all of which
Pathological Consequences of the
Inflammatory Response
The initiation of the pro inflammatory responses is extremely
potent to limit the spread of microorganisms; however, full clearance
of the infectious agent typically requires adaptive immune
components. Fig. 2.5 schematically reviews the stimuli, cell
responses, and pathological consequences that are involved in
moving from acute to chronic inflammation. The productivity and
success of the acute inflammatory response lie in the ability of
external or internal agents to activate innate responses that lead to
the production of pro inflammatory mediators. Assistance from
environ- mental cues (released clotting factors, kininogens, and
complement) is critical to the preparation of vascular beds to allow
cellular influx.
Activation of local response is followed by activity of the
lymphatics to functionally drain fluids, cells, and debris to nearby
lymph nodes, where phagocytic antigen presenting cells ―show‖
digested pieces of the foreign protein to cells of the adaptive
immune response.