Chapter 18
that cause the damage. In essence, then, allergy is immunity
gone wrong, for the response is inappropriate to the stimulus.
A word about terminology is useful here: There are three
major types of hypersensitivity, as categorized by the differ-
ent immunologic effector pathways involved in the infl
tory response. The term
is sometimes used popularly to
denote only one of these types, that mediated by IgE antibodies.
We will follow the common practice, however, of using the term
in its broader sense as synonymous with
To develop a particular allergy, a genetically predisposed
person must fi rst be exposed to the allergen. This initial expo-
sure causes “sensitization.” It is the subsequent exposures that
elicit the damaging immune responses we recognize as the dis-
ease. The diversity of allergic responses refl ects the different
immunological effector pathways elicited. The classifi cation of
allergic diseases is based on these mechanisms (
Table 18–10
In one type of allergy, the infl
ammatory response is
independent of antibodies. It is due to pronounced secretion
of cytokines by helper T cells activated by antigen in the area.
These cytokines themselves act as infl
ammatory mediators and
also activate macrophages to secrete their potent mediators.
Because it takes several days to develop, this type of allergy is
known as
delayed hypersensitivity
The skin rash that appears
after contact with poison ivy is an example.
In contrast to this are the various types of antibody-
mediated allergic responses. One important type is called
immune-complex hypersensitivity
It occurs when so many
antibodies (of either the IgG or IgM types) combine with
free antigens that large numbers of antigen-antibody com-
plexes precipitate out on the surface of endothelial cells or are
trapped in capillary walls, particularly those of the renal cor-
puscles. These immune complexes activate complement, which
then induces an infl ammatory response that damages the tis-
sues immediately surrounding the complexes.
The more common type of antibody-mediated allergic
responses, however, are those called
immediate hypersen-
because they are usually very rapid in onset. They
are also called
IgE-mediated hypersensitivity
because they
involve IgE antibodies.
Immediate Hypersensitivity
In immediate hypersensitivity,
initial exposure to the antigen leads to some antibody synthe-
sis and, more important, to the production of memory B cells
that mediate active immunity. Upon re-exposure, the antigen
elicits a more powerful antibody response. So far, none of this
is unusual, but the difference is that the particular antigens that
elicit immediate hypersensitivity reactions stimulate, in geneti-
cally susceptible persons, the production of type IgE antibod-
ies. Production of IgE requires the participation of a particular
subset of helper T cells that are activated by the allergens pre-
sented by B cells. These activated helper T cells then release
cytokines that preferentially stimulate differentiation of the B
cells into IgE-producing plasma cells.
Upon their release from plasma cells, IgE antibodies cir-
culate throughout the body and become attached, via bind-
ing sites on their Fc portions, to connective-tissue mast cells
Figure 18–21
). When the same antigen type subsequently
enters the body and combines with the IgE bound to the mast
cell, this triggers the mast cell to secrete many infl
mediators, including
various eicosanoids, and che-
mokines. All of these mediators then initiate a local infl amma-
tory response. (The entire sequence of events just described for
mast cells can also occur with basophils in the circulation.)
Thus, the symptoms of IgE-mediated allergy refl ect the
various effects of these infl ammatory mediators and the body
site in which the antigen-IgE-mast cell combination occurs.
For example, when a previously sensitized person inhales rag-
weed pollen, the antigen combines with IgE on mast cells
in the respiratory passages. The mediators released cause
increased secretion of mucus, increased blood fl
ow, swelling
of the epithelial lining, and contraction of the smooth muscle
surrounding the airways. Thus, there follow the symptoms of
congestion, runny nose, sneezing, and diffi
culty in breathing
that characterize hay fever. Immediate hypersensitivities to
penicillin and insect venoms sometimes occur, and these are
usually correlated with IgE production.
Allergic symptoms are usually localized to the site of
antigen entry. If very large amounts of the chemicals released
by the mast cells (or blood basophils) enter the circulation,
however, systemic symptoms may result and cause severe
hypotension and bronchiolar constriction. This sequence of
events, called
can cause death due to circulatory
and respiratory failure. It can be elicited in some sensitized
people by the antigen in a single bee sting.
The very rapid components of immediate hypersensitiv-
ity often proceed to a
late-phase reaction
lasting many hours
or days, during which large numbers of leukocytes, particu-
larly eosinophils, migrate into the infl amed area. The chemo-
attractants involved are cytokines released by mast cells and
helper T cells activated by the allergen. The eosinophils, once
in the area, secrete mediators that prolong the infl ammation
and sensitize the tissues, so that less allergen is needed the
next time to evoke a response.
Given the inappropriateness of most immediate hyper-
sensitivity responses, how did such a system evolve? The nor-
mal physiological function of the IgE-mast cell-eosinophil
pathways is to repel invasion by multicellular parasites that
cannot be phagocytized. The mediators released by the mast
cells stimulate the infl ammatory response against the para-
sites, and the eosinophils serve as the major killer cells against
them by secreting several toxins. How this system also came
to be inducible by harmless agents is not clear.
Table 18–10
Major Types of Hypersensitivity
Delayed hypersensitivity
—Mediated by helper T cells and
macrophages; independent of antibodies
Immune-complex hypersensitivity
—Mediated by antigen-
antibody complexes deposited in tissue
Immediate hypersensitivity
—Mediated by IgE antibodies,
mast cells, and eosinophils
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