CHAPTER 3Immunity, Infection, & Inflammation 75increase the production of arachidonic acid derivatives,
including thromboxane A 2. The role of this compound in the
balance between clotting and anticlotting activity at the site of
vascular injury is discussed in Chapter 32.
Platelet production is regulated by the colony-stimulating
factors that control the production of megakaryocytes, plus
thrombopoietin, a circulating protein factor. This factor,
which facilitates megakaryocyte maturation, is produced con-
stitutively by the liver and kidneys, and there are thrombopoi-
etin receptors on platelets. Consequently, when the number of
platelets is low, less is bound and more is available to stimulate
production of platelets. Conversely, when the number of
platelets is high, more is bound and less is available, produc-
ing a form of feedback control of platelet production. The
amino terminal portion of the thrombopoietin molecule has
the platelet-stimulating activity, whereas the carboxyl termi-
nal portion contains many carbohydrate residues and is con-
cerned with the bioavailability of the molecule.
When the platelet count is low, clot retraction is deficient and
there is poor constriction of ruptured vessels. The resulting
clinical syndrome (thrombocytopenic purpura) is character-
ized by easy bruisability and multiple subcutaneous hemor-
rhages. Purpura may also occur when the platelet count is
normal, and in some of these cases, the circulating platelets are
abnormal (thrombasthenic purpura). Individuals with throm-
bocytosis are predisposed to thrombotic events.
INFLAMMATION &
WOUND HEALING
LOCAL INJURY
Inflammation is a complex localized response to foreign sub-
stances such as bacteria or in some instances to internally pro-
duced substances. It includes a sequence of reactions initially
involving cytokines, neutrophils, adhesion molecules, com-
plement, and IgG. PAF, an agent with potent inflammatory ef-
fects, also plays a role. Later, monocytes and lymphocytes are
involved. Arterioles in the inflamed area dilate, and capillary
permeability is increased (see Chapters 33 and 34). When the
inflammation occurs in or just under the skin (Figure 3–13), itCLINICAL BOX 3–2
Autoimmunity
Sometimes the processes that eliminate antibodies against
self antigens fail and a variety of different autoimmune dis-
eases are produced. These can be B cell- or T cell-mediated
and can be organ-specific or systemic. They include type 1
diabetes mellitus (antibodies against pancreatic islet B cells),
myasthenia gravis (antibodies against nicotinic cholinergic
receptors), and multiple sclerosis (antibodies against myelin
basic protein and several other components of myelin). In
some instances, the antibodies are against receptors and are
capable of activating those receptors; for example, antibod-
ies against TSH receptors increase thyroid activity and cause
Graves’ disease (see Chapter 20). Other conditions are due to
the production of antibodies against invading organisms
that cross-react with normal body constituents (molecular
mimicry). An example is rheumatic fever following a strep-
tococcal infection; a portion of cardiac myosin resembles a
portion of the streptococcal M protein, and antibodies in-
duced by the latter attack the former and damage the heart.
Some conditions may be due to bystander effects, in which
inflammation sensitizes T cells in the neighborhood, causing
them to become activated when otherwise they would not
respond. However, much is still uncertain about the patho-
genesis of autoimmune disease.CLINICAL BOX 3–3
Tissue Transplantation
The T lymphocyte system is responsible for the rejection of
transplanted tissue. When tissues such as skin and kidneys
are transplanted from a donor to a recipient of the same spe-
cies, the transplants “take” and function for a while but then
become necrotic and are “rejected” because the recipient de-
velops an immune response to the transplanted tissue. This is
generally true even if the donor and recipient are close rela-
tives, and the only transplants that are never rejected are
those from an identical twin. A number of treatments have
been developed to overcome the rejection of transplanted
organs in humans. The goal of treatment is to stop rejection
without leaving the patient vulnerable to massive infections.
One approach is to kill T lymphocytes by killing all rapidly di-
viding cells with drugs such as azathioprine, a purine antime-
tabolite, but this makes patients susceptible to infections and
cancer. Another is to administer glucocorticoids, which in-
hibit cytotoxic T cell proliferation by inhibiting production of
IL-2, but these cause osteoporosis, mental changes, and the
other facets of Cushing syndrome (see Chapter 22). More re-
cently, immunosuppressive drugs such as cyclosporine or
tacrolimus (FK-506) have found favor. Activation of the T
cell receptor normally increases intracellular Ca2+, which acts
via calmodulin to activate calcineurin (Figure 3-11). Cal-
cineurin dephosphorylates the transcription factor NF-AT,
which moves to the nucleus and increases the activity of
genes coding for IL-2 and related stimulatory cytokines. Cy-
closporine and tacrolimus prevent the dephosphorylation of
NF-AT. However, these drugs inhibit all T cell-mediated im-
mune responses, and cyclosporine causes kidney damage
and cancer. A new and promising approach to transplant re-
jection is the production of T cell unresponsiveness by using
drugs that block the costimulation that is required for normal
activation (see text). Clinically effective drugs that act in this
fashion could be of great value to transplant surgeons.