C h a p t e r 1 6
Disorders of the Immune Response
345
allergens include the proteins in plant pollens, house
dust mites, animal dander, foods, and chemicals like
the antibiotic penicillin. Exposure to the allergen can be
through inhalation, ingestion, injection, or skin contact.
Depending on the portal of entry, type I reactions may
be limited to merely annoying (e.g., seasonal rhinitis),
severely debilitating (asthma), or systemic and poten-
tially life-threatening (anaphylaxis).
Two types of cells are central to a type I hypersensi-
tivity reaction: type 2 helper T (T
H
2) cells and granule-
containing cells, such as mast cells and/or basophils.
1–4
There are two subsets of helper T cells (T
H
1 and T
H
2)
that develop from the same precursor CD4
+
T lym-
phocyte (see Chapter 15). T
H
1 cells differentiate in
response to microbes and stimulate the differentiation
of B cells into IgM- and IgG-producing plasma cells.
T
H
2 cell differentiation occurs in response to aller-
gens and helminths (intestinal parasites).
1
Cytokines
secreted by T
H
2 cells stimulate differentiation of B cells
into IgE-producing plasma cells, act as growth factors
for mast cells, and recruit and activate eosinophils.
The tissue-based mast cells and blood-based basophils
are both derived from hematopoietic precursor cells in
the bone marrow.
1
Mast cells are widely distributed in
connective tissue, especially in areas beneath the skin
and mucous membranes of the respiratory, gastrointes-
tinal, and genitourinary tracts and adjacent to blood
and lymph vessels.
5
This location places them near sur-
faces that are exposed to environmental antigens and
parasites. Basophils, which share many features with
mast cells, are granulocytes that circulate in the blood-
stream and represent less than 1% of peripheral leuko-
cytes (white blood cells). Both mast cells and basophils
contain preformed mediators of inflammation that are
stored in granules and released at the time of activation,
and both have high-affinity receptors for IgE antibodies
on their surface.
Type I hypersensitivity reactions begin with mast cell
or basophil sensitization. During the sensitization or
priming stage, allergen-specific IgE antibodies attach to
receptors on the surface of mast cells and basophils.
With subsequent exposure, the sensitizing allergen
binds to the cell-associated IgE and triggers a series
of events that ultimately lead to degranulation of the
sensitized mast cells or basophils, causing the release
of their preformed mediators (Fig. 16-1). Mast cells
are also the source of lipid-derived membrane prod-
ucts (e.g., prostaglandins and leukotrienes) and cyto-
kines that participate in the continued response to the
allergen.
Many type I hypersensitivity reactions, such as
bronchial asthma, have two well-defined phases: (1)
a primary or immediate-phase response characterized
by vasodilation, vascular leakage, and smooth muscle
contraction, and (2) a secondary or late-phase response
characterized by more intense infiltration of tissues with
eosinophils and other acute and chronic inflammatory
cells, as well as tissue destruction in the form of epithe-
lial cell damage.
The primary or immediate-phase response usually
occurs within 5 to 30 minutes of exposure to antigen
and subsides within 60 minutes. It is mediated by mast
cell degranulation and the release of preformed media-
tors. These mediators include histamine, prostaglandins,
leukotrienes, platelet activating-factor, interleukins, and
enzymes such as chymase and trypsin that lead to the
generation of kinins.
1
Histamine is a potent vasodilator
that increases the permeability of capillaries and venules
and causes smooth muscle contraction and broncho-
constriction. The kinins, which are a group of potent
inflammatory peptides, require activation through
enzymatic modification. Once activated, these peptide
mediators (e.g., bradykinin) produce vasodilation and
smooth muscle contraction.
The secondary or late-phase response occurs about
2 to 8 hours later and lasts for several days. It results from
the action of lipid mediators and cytokines involved
in the inflammatory response. The lipid mediators are
derived from mast cell membrane phospholipids, which
are broken down to form arachidonic acid. Arachidonic
acid, in turn, is the parent compound from which
the leukotrienes and prostaglandins are synthesized
TABLE 16-1
Classification of Hypersensitivity Responses
Type of Hypersensitivity
Immune Mechanism
Mechanism of Injury
Type I, immediate hypersensitivity
Type II, antibody-mediated
IgE antibody
IgM, IgG antibodies against cell surface
or extracellular matrix
Release of mast cell mediators
Phagocytosis and opsonization of cells;
complement- and receptor-mediated
recruitment and activation of inflammatory
cells (neutrophils, macrophages);
abnormalities in cellular functioning (e.g.,
hormone receptor signaling)
Type III, immune complex–mediated Formation of immune complexes
involving circulating antigens and
IgM or IgG antibodies
Complement-mediated recruitment and
activation of inflammatory cells
Type IV,T-cell–mediated
CD4
+
T cells (delayed-type
hypersensitivity) or CD8
+
cytotoxic
T-cell–mediated cytolysis
Macrophage activation of cytokine-mediated
inflammation; direct target cell killing,
cytokine-mediated inflammation
IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M.
