Chapter 09 1

Hypersensitive Reactions
An immune response mobilizes a battery of effector molecules that act to remove antigen.
Generally, these effector molecules induce a localized inflammatory response that
eliminates antigen without extensively damaging the host’s tissue. Under certain
circumstances, however, this inflammatory response can have deleterious effects,
resulting in significant tissue damage or even death. This inappropriate immune response
is termed hypersensitivity or allergy. Although the word hypersensitivity implies an
increased response, the response is not always heightened but may, instead, be an
inappropriate immune response to an antigen. Hypersensitive reactions may develop in
the course of either humoral or cell-mediated responses. Anaphylactic reactions within
the humoral branch initiated by antibody or antigen-antibody complexes are known as
immediate hypersensitivity, because the symptoms are manifest within minutes or hours
after a sensitized recipient encounters antigen. Delayed-type hypersensitivity (DTH) is
so named in recognition of the delay of symptoms until days after exposure.
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Gell and Coombs Classification

Several forms of hypersensitive reaction can be distinguished, reflecting differences in

the effector molecules generated in the course of the reaction. In immediate
hypersensitive reactions, different antibody isotypes induce different immune effector
molecules. IgE antibodies, for example, induce mast-cell degranulation with release of
histamine and other biologically active molecules. IgG and IgM antibodies, on the other
hand, induce hypersensitive reactions by activating complement. The effector molecules
in the complement reactions are the membrane-attack complex and such complement
split products as C3a, C4a, and C5a. In delayed-type hypersensitivity reactions, the
effector molecules are various cytokines secreted by activated TH or TC cells.

As it became clear that several different immune mechanisms give rise to hypersensitive
reactions, P. G. H. Gell and R. R. A. Coombs proposed a classification scheme in which
hypersensitive reactions are divided into four types. Three types of hypersensitivity occur
within the humoral branch and are mediated by antibody or antigen-antibody complexes:

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IgE-mediated (type I), antibody-mediated (type II), and immune complex–mediated (type
III). A fourth type of hypersensitivity depends on reactions within the cell-mediated
branch, and is termed delayed-type hypersensitivity, or DTH (type IV). Each type
involves distinct mechanisms, cells, and mediator molecules. This classification scheme
has served an important function in identifying the mechanistic differences among
various hypersensitive reactions, but it is important to point out that secondary effects
blur the boundaries between the four categories.

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IgE-Mediated (Type I) Hypersensitivity

A type I hypersensitive reaction is induced by certain types of antigens referred to as

allergens, and has all the hallmarks of a normal humoral response. That is, an allergen
induces a humoral antibody response for soluble antigens, resulting in the generation of
antibody-secreting plasma cells and memory cells. The plasma cells secrete IgE. This
class of antibody binds with high affinity to Fc receptors on the surface of tissue mast
cells and blood basophils. Mast cells and basophils coated by IgE are said to be
sensitized. A later exposure to the same allergen cross-links the membrane-bound IgE on
sensitized mast cells and basophils, causing degranulation of these cells. The
pharmacologically active mediators released from the granules act on the surrounding
tissues. The principal effects-vasodilation and smooth-muscle contraction- may be either
systemic or localized, depending on the extent of mediator release.

Antibody-Mediated Cytotoxic (Type II) Hypersensitivity

Type II hypersensitive reactions involve antibody-mediated destruction of cells. Antibody

can activate the complement system, creating pores in the membrane of a foreign cell, or
it can mediate cell destruction by antibody dependent cell-mediated cytotoxicity
(ADCC). In this process, cytotoxic cells with Fc receptors bind to the Fc region of
antibodies on target cells and promote killing of the cells. Antibody bound to a foreign
cell also can serve as an opsonin, enabling phagocytic cells with Fc or C3b receptors to
bind and phagocytose the antibody-coated cell.

Immune Complex–Mediated (Type III) Hypersensitivity

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The reaction of antibody with antigen generates immune complexes. Generally this
complexing of antigen with antibody facilitates the clearance of antigen by phagocytic
cells. In some cases, however, large amounts of immune complexes can lead to tissue-
damaging type III hypersensitive reactions. The magnitude of the reaction depends on the
quantity of immune complexes as well as their distribution within the body. When the
complexes are deposited in tissue very near the site of antigen entry, a localized reaction
develops. When the complexes are formed in the blood, a reaction can develop wherever
the complexes are deposited. In particular, complex deposition is frequently observed on
blood-vessel walls, in the synovial membrane of joints, on the glomerular basement
membrane of the kidney, and on the choroid plexus of the brain. The deposition of these
complexes initiates a reaction that results in the recruitment of neutrophils to the site. The
tissue there is injured as a consequence of granular release from the neutrophil. Type III
hypersensitive reactions develop when immune complexes activate the complement
system’s array of immune effector molecules. The C3a, C4a, and C5a complement split
products are anaphylatoxins that cause localized mast-cell degranulation and consequent
increase in local vascular permeability. C3a, C5a, and C5b are also chemotactic factors
for neutrophils, which can accumulate in large numbers at the site of immune-complex
deposition. Larger immune complexes are deposited on the basement membrane of blood
vessel walls or kidney glomeruli, whereas smaller complexes may pass through the
basement membrane and be deposited in the sub epithelium. The type of lesion that
results depends on the site of deposition of the complexes. Much of the tissue damage in
type III reactions stems from release of lytic enzymes by neutrophils as they attempt to
phagocytose immune complexes. The C3b complement component acts as an opsonin,
coating immune complexes.

A neutrophil binds to a C3b-coated immune complex by means of the type I complement

receptor, which is specific for C3b. Because the complex is deposited on the basement
membrane surface, phagocytosis is impeded, so that lytic enzymes are released during the
unsuccessful attempts of the neutrophil to ingest the adhering immune complex. Further
activation of the membrane-attack mechanism of the complement system can also
contribute to the destruction of tissue. In addition, the activation of complement can

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induce aggregation of platelets, and the resulting release of clotting factors can lead to
formation of microthrombi.

Type IV or Delayed-Type Hypersensitivity (DTH)

When some subpopulations of activated TH cells encounter certain types of antigens, they
secrete cytokines that induce a localized inflammatory reaction called delayed-type
hypersensitivity (DTH). The reaction is characterized by large influxes of nonspecific
inflammatory cells, in particular, macrophages.

This type of reaction was first described in 1890 by Robert Koch, who observed that
individuals infected with Mycobacterium tuberculosis developed a localized
inflammatory response when injected intradermally with a filtrate derived from a
mycobacterial culture. He called this localized skin reaction a “tuberculin reaction.”
Later, as it became apparent that a variety of other antigens could induce this response, its
name was changed to delayed-type or type IV hypersensitivity in reference to the delayed
onset of the reaction and to the tissue damage (hypersensitivity) that is often associated
with it. The term hypersensitivity is somewhat misleading, for it suggests that a DTH
response is always detrimental. Although in some cases a DTH response does cause
extensive tissue damage and is in itself pathologic, in many cases tissue damage is
limited, and the response plays an important role in defense against intracellular
pathogens and contact antigens. The hallmarks of a type IV reaction are the delay in time
required for the reaction to develop and the recruitment of macrophages as opposed to
neutrophils, as found in a type III reaction. Macrophages are the major component of the
infiltrate that surrounds the site of inflammation.

Phases of the DTH Response

The development of the DTH response begins with an initial sensitization phase of 1–2
weeks after primary contact with an antigen. During this period, TH cells are activated
and clonally expanded by antigen presented together with the requisite class II MHC
molecule on an appropriate antigen presenting cell. A variety of antigen-presenting cells
have been shown to be involved in the activation of a DTH response, including
Langerhans cells and macrophages. Langerhans cells are dendritic cells found in the

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epidermis. These cells are thought to pick up antigen that enters through the skin and
transport it to regional lymph nodes, where T cells are activated by the antigen. In some
species, including humans, the vascular endothelial cells express class II MHC molecules
and also function as antigen-presenting cells in the development of the DTH response.
Generally, the T cells activated during the sensitization phase are CD4+, primarily of the
TH1 subtype, but in a few cases CD8+ cells have also been shown to induce a DTH
response. The activated T cells previously were called TDTH cells to denote their
function in the DTH response, although in reality they are simply a subset of activated
TH1 cells (or, in some cases, TC cells). A subsequent exposure to the antigen induces the
effector phase of the DTH response. In the effector phase, TH1 cells secrete a variety of
cytokines that recruit and activate macrophages and other nonspecific inflammatory cells.
A DTH response normally does not become apparent until an average of 24 h after the
second contact with the antigen; the response generally peaks 48–72 h after second
contact. The delayed onset of this response reflects the time required for the cytokines to
induce localized influxes of macrophages and their activation.Once a DTH response
begins, a complex interplay of nonspecific cells and mediators is set in motion that can
result in tremendous amplification. By the time the DTH response is fully developed,
only about 5% of the participating cells are antigen-specific TH1 cells; the remainder are
macrophages and other nonspecific cells. Macrophages are the principal effector cells of
the DTH response. Cytokines elaborated by TH1 cells induce blood monocytes to adhere
to vascular endothelial cells and migrate from the blood into the surrounding tissues.
During this process the monocytes differentiate into activated macrophages. Activated
macrophages exhibit increased levels of phagocytosis and an increased ability to kill
microorganisms through various cytotoxic mediators. In addition, activated macrophages
express increased levels of class II MHC molecules and cell-adhesion molecules and
therefore function more effectively as antigen-presenting cells.

The influx and activation of macrophages in the DTH response is important in host
defense against parasites and bacteria that live within cells, where circulating antibodies
cannot reach them. The heightened phagocytic activity and the buildup of lytic enzymes
from macrophages in the area of infection lead to nonspecific destruction of cells, and
thus of the intracellular pathogen. Generally, the pathogen is cleared rapidly with little

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tissue damage. However, in some cases, especially if the antigen is not easily cleared, a
prolonged DTH response can itself become destructive to the host as the intense
inflammatory response develops into a visible granulomatous reaction. A granuloma
develops when continuous activation of macrophages induces the macrophages to adhere
closely to one another, assuming an epithelioid shape and sometimes fusing to form
multinucleated giant cells. These giant cells displace the normal tissue cells, forming
palpable nodules, and release high concentrations of lytic enzymes, which destroy
surrounding tissue. In these cases, the response can damage blood vessels and lead to
extensive tissue necrosis. The response to Mycobacterium tuberculosis illustrates the
double-edged nature of the DTH response. Immunity to this intracellular bacterium
involves a DTH response in which activated macrophages wall off the organism in the
lung and contain it within a granuloma-type lesion called a tubercle. Often, however, the
concentrated release of lytic enzymes from the activated macrophages within tubercles
damages lung tissue. Some examples of truly hypersensitive conditions, in which tissue
damage far outweighs any beneficial effects.

Hypersensitive Reactions Prepared by: Dr. Sadia Mumtaz