Medicinal Chemistry

IMMUNOMODULATORS AND THEIR RECEPTORS 391

The tissue-level (histological) defense systems are composed primarily of the skin and
the mucous membranes (mucosa) that line the airways, mouth, and other portions of the
gastrointestinal system. Healthy, intact skin is probably the most important barrier
against chemical or biological insults.
When the barriers of the tissue-level defences are breached, the cytological and bio-
chemical components of the innate immune system take over. Within these latter two
components, the complement protein cascadeplays a dominant role. Complement is a
system of approximately 20 separate molecules (nine “classical” complement proteins
and ten or more cofactors) that continuously circulate within the bloodstream in an
inactive form. Frequently, they are stabilized in their inactive form through association
with cell membranes. However, when a “nonself” molecule becomes present within the
body, the complement system is activated. The nine proteins of complement are split
into fragments during the activation process. The complement protein C3b attaches
itself to the invading cell through a process called opsonization, thereby tagging the
invader so that it can be recognized and destroyed by neutrophils and macrophages.
Through this process, C3b acts as an opsonin.Complement proteins C3a and C5a then
attract the neutrophils and macrophages to the tagged (opsonized) invader. Complement
proteins C5b, C6, C7, C8, and C9 associate with one another to form a membrane
attack complex(MAC) that punches holes into the membrane of the invading cell. In
carrying out this function, complement is assisted by other molecules called cytokines
orchemokines(e.g., interleukin-8, IL-8) that facilitate the process whereby neutrophils
and monocytes leave the bloodstream to enter the tissue in which the invader is located.
The molecular by-products produced by complement activation and by the activities
of the innate immune system serve as molecular cues that, in turn, activate the adaptive
immune system.

6.1.3 The Adaptive Immune System

If the innate system fails, the adaptive immune system is mobilized to continue the
fight. This system constitutes the second line of defense against disease and has two
structural components:

1. The humoral immune system


2. The cell-mediated immune system

The adaptive immune system is much more sophisticated than the innate immune
system. Three characteristics reflect this degree of sophistication:

1. Unlike the innate system, which is relatively nonspecific, the adaptive system
   responds to unwanted cells or molecules in a specificmanner.


2. The adaptive system can discriminate between nonself (i.e., “foreign”) and self,
   thereby preventing an undesirable attack upon its own molecules or cells.


3. The adaptive immune system has the capacity to learn and to establish memory,
   thereby enabling it to respond more efficiently to a previously encountered unwanted
   antigen—an important property central to the therapeutic effectiveness of vaccines.

The two components of the adaptive immune system (humoral and cell-mediated) are
not competitive with each other; rather, they work together in harmony. This harmonious
attack is facilitated by the cooperative efforts of both B-type and T-type lymphocytes