CHAPTER 8

The Immune Hypersensitivities

Chapter Focus: To investigate concepts associated with disorders classi-

fied as immune hypersensitivity. Underlying mechanisms will discuss
the basis of response that culminates in clinical symptoms, focused on
the primary cellular and molecular components for the basis of pathol-
ogy development. The discussion will include allergic (Type I), cyto-
toxic (Type II), immune complex (Type III), and delayed-type (Type
IV) hypersensitive responses, concentrating on how a vigorous immune
response contributes toward tissue damage.

THE HYPERSENSITIVE DISORDERS

Immunological diseases can be grouped into two large categories of
deficiency and dysfunction. As previously discussed, immune defi-
ciency disorders are the result of the absence (congenital or acquired)
of one or more immune system elements. In contrast, disorders due to
immune dysfunction happen when a particular subset of immune
responses occur which are detrimental to the host. This response may
be against a foreign antigen or self-antigen and is usually defined as
inappropriate regulation of an effector response. This happens in the
absence of protection against pathogenic organisms. Notwithstanding,
the host is adversely affected. A healthy immune system occurs as a
result of balance between innate and adaptive immunity, cellular and
humoral immunity, inflammatory and regulatory networks and small
biochemical mediators (cytokines). Gell and Coombs understood the
nature of this imbalance as related to pathology, and in the late 1960s
and early 1970s classified these dysfunctional immune responses into
categories called hypersensitivity diseases.

The term hypersensitivity therefore refers to a definable immune

response that leads to deleterious host reactions rather than protection
against disease. Hypersensitivities are a major cause of clinical disease.
Although the mechanisms can be defined for each subclass, in reality,
there is considerable overlap in the underlying causes that contribute
to the hypersensitive responses and how they adversely affect tissues in

Introductory Immunology. DOI: http://dx.doi.org/10.1016/B978-0-12-420030-2.00008-1

Copyright © 2014 Elsevier Inc. All rights reserved.
98 Introductory Immunology

the body. The hypersensitivity reactions fall into four classes based on
their mechanisms and the ability to passively transfer response through
antibodies or through T lymphocytes. These responses include inap-
propriate antigenic response, excessive magnitude of response, pro-
longed duration of response, and innocent bystander effector reactions
leading to tissue damage. The major mechanisms are detailed below.

TYPE I HYPERSENSITIVITY: IgE-MEDIATED IMMEDIATE

HYPERSENSITIVITY
The Type I hypersensitivity is due to aberrant production and activity
of IgE against normally nonpathogenic antigens (commonly called
allergens) (Figure 8.1). This allergic hypersensitivity is also called imme-
diate hypersensitivity because of the speed of reaction development.
Mast cells and basophils ordinarily have high-affinity IgE receptors
that are constitutively filled with that immunoglobulin isotype.
Antigenic exposure results in a cross-linking of cell-bound IgE with the

Type I anaphylactic hypersensitivity (acute)

Allergen Allergen

IgE
IgE receptor

APC IgE
production
B cell

Mast cell
Presentation TCR basophil
to T helper
cells
IL-4 Degranulation
IL-5 histamines, leukotrienes
TH2 prostaglandins, PAF
IL-13

Vasodilation
Wheal and flare
• Edema
• Redness
• Itching

Figure 8.1 Type I hypersensitivity (also called immediate hypersensitivity) is due to aberrant production and
activity of IgE against normally nonpathogenic antigens (commonly called allergy). The IgE binds to mast cells
via high-affinity IgE receptors. Subsequent antigen exposure results in cross-linking of mast cell-bound IgE.
Activated mast cells release preformed mediators and synthesize new mediators, which are responsible for allergic
symptoms.
 Immune Hypersensitivity 99

allergen, followed by nearly immediate activation of those cells. This

results in a quick release of preformed mediators (e.g., histamine, leu-
kotrienes, etc.) and an immediate resynthesis of new mediators (i.e.,
chemotaxins, cytokines). The activity of these mediators is responsible
for the signs and symptoms of allergic diseases. Note that the IgE-
associated responses differ from the mechanisms of anaphylatoxins
(complement factors C3a, C4a, and C5a) which trigger mast cell
degranulation in the absence of IgE.
For any Type I reaction to occur, there must be a preexisting IgE
population specific for the allergen. By definition, a mature B-cell
response to the antigen has already developed, in part with CD41
T-helper 2 cytokines, such as IL-4 and IL-13 which promotes genera-
tion of plasma cell immunoglobulin production of the IgE isotype.

The prototype disorders for this hypersensitivity include allergic rhi-

nitis and seasonal allergies, as well as allergic asthma. The typical
allergens include pollens, fungal spores, and common dust mite and
other household antigens. Immunotherapy for severe reacting indivi-
duals is usually through diversion and development of immune
response other than those related to IgE synthesis. Pharmaceuticals
have been developed to inhibit mast cell degranulation, thus alleviating
many common symptoms. In severe cases where allergens are systemic,
anaphylactic shock may occur due to immediate vasoactive mediator
activity. This is characterized by a sudden and sharp drop in blood
pressure, urticaria, and breathing difficulties caused by exposure to a
foreign substance (such as bee venom, immediate drug reactivity, or
food allergies). Systemic allergic anaphylaxis is life threatening; emer-
gency treatment includes epinephrine injections, used as a heart stimu-
lant, vasoconstrictor, and bronchial relaxant.

TYPE II HYPERSENSITIVITY: ANTIBODY-MEDIATED CYTOTOXIC

HYPERSENSITIVITY
The Type II hypersensitivity is due to antibody reactivity against cell
membrane-associated antigen that results in cytolysis (Figure 8.2). The
mechanism may involve complement (cytotoxic antibody) or effector
lymphocytes that bind to target cell-associated antibody and effect
cytolysis via a complement-independent pathway (antibody-dependent
cellular cytotoxicity, ADCC). The end result of the antibody response
is cytolysis.
100 Introductory Immunology

Type II antibody-mediated hypersensitivity

Complement-mediated tissue destruction Antibody-dependent cell cytotoxicity (ADCC)

Complement fixation
Release of
C'
anaphylatoxins
C' C' C3a, C5a
Target cell

+ Ab
• Platelet
aggregation
to complexes
• Formation of Activation
microthrombi PMN

• Deposited immuno-
complexes and
malformation
in vessel walls Fc receptor
Fc receptor
Vasoactive mediator intermediates NK cell
• Kinin-forming enzymes
• Reactive oxygen and nitrogen

Figure 8.2 Type II hypersensitivity is due to antibody directed against cell membrane-associated antigen that
results in cytolysis. The mechanism may involve complement (cytotoxic antibody) that binds to target
cell-associated antibody, subsequently effecting cytolysis (depicted) or via a complement-independent pathway of
ADCC involving NK cells and targeted cell destruction (not shown).

In complement-mediated Type II hypersensitivity, IgG isotype anti-

body recognition of cell surface epitopes leads to assembly of the com-
plement C5 C9 membrane attack complex and subsequent lysis of the
cell. This reaction is the underlying mechanism in multiple disease
states, including that seen in autoimmune hemolytic anemia and Rh
incompatibility leading to erythroblastosis fetalis. In rare cases, phar-
maceutical agents, such as penicillin or chlorpromazine, can bind cells,
forming a novel antigenic surface complex that provokes antibody pro-
duction and Type II cytotoxic reactions.
A second mechanism for Type II reactions is characterized by
ADCC induced by natural killer (NK) cells recognizing IgG attached
to target cells bearing antigen. The constant portion of the antibody
(Fc region) is bound by Fc receptors on the NK cell, leading to perfor-
in release and NK cell-mediated lysis. Neutrophils, eosinophils, and
macrophages may also participate in ADCC. ADCC may be involved
in the pathophysiology of certain virus-induced immunological dis-
eases, such as those seen during active response to retroviral infection.
Cytotoxic antibodies mediate many immunologically based hemo-
lytic anemias while ADCC may be involved in the pathophysiology of
certain virus-induced immunological diseases. Prototype disorders
include many autoimmune-related diseases which bear evidence of
 Immune Hypersensitivity 101

tissue destruction. Goodpasture syndrome represents autoantibody

against basement membrane collagen type IV; deposition and accom-
panying complement activation leads to damage in both kidney and
lung tissues. Mediators of acute inflammation generated at the tissue
form end-product membrane attack complexes which cause cell lysis
and death. The reaction takes hours to a day, with chronic strain on
the body if the flared reaction continues unabated. Other disorders
include idiopathic thrombocytopenic purpura (platelet destruction) and
pemphigoid reactions resulting in skin blisters. And both myasthenia
gravis (muscle weakness) and Graves’ disease (hyperthyroidism) exhibit
autoantibody-mediated cytotoxic events, although these disease pro-
cesses are considerably more complex in nature and overlaps with
other hypersensitivity mechanisms.

TYPE III HYPERSENSITIVITY: IMMUNE COMPLEX-MEDIATED

HYPERSENSITIVITY
The Type III hypersensitivity results from soluble antigen antibody
immune complex deposition and subsequent events that activate com-
plement to summon polymorphonuclear leukocytes (Figure 8.3). The
antigens may be self or foreign (i.e., microbial). Such complexes are
deposited on membrane surfaces of various organs (e.g., kidney, lung,
synovium). The by-products of complement activation (C3a, C5a) are
chemotaxins for acute inflammatory cells, resulting in infiltration by
polymorphonuclear cells. Lysosomal enzymes are released which result
in tissue injury. Platelet aggregation occurs, resulting in microthrombus
formation in the vasculature. This type of hypersensitivity was classi-
cally characterized as the Arthus reaction, identified by high degree of
neutrophils and mast cell infiltrates, vasoactive amine release, erythema
and edema in response to intradermal injection of antigen.
These immune reactions result in the Type III inflammatory injury
readily seen in diseases such as rheumatoid arthritis, systemic lupus
erythematosus, and post-infectious arthritis. It is also evident during
post-streptococcal glomerulonephritis, where damage severely affects
kidney function.

An interesting example of the Type III reactions is that referred to

as serum sickness, which historically arose when antisera made in ani-
mals were repeatedly given to humans to neutralize toxins. Immune
102 Introductory Immunology

Type III immunocomplex-mediated hypersensitivity

Surface
antigen
C1q
C1q+C1r+C1s
Formation Antibody/
of MAC complement-
IgG mediated
C1, 4, 2, 3,5b, lysis
6, 7, 8, 9

NK cell

Fc receptor
Ca2+
NK/K cell-
IgG mediated lysis

Release of cytotoxic
granules
Target Surface antigen
IgG antibody
cell
coated target
cell

Figure 8.3 Type III hypersensitivity results from soluble antigen antibody immune complexes that activate com-
plement. The antigens may be self or foreign. Complexes are deposited on membrane surfaces of organs. The by-
products of complement activation are chemotaxins for acute inflammatory cells.

complexes would form in vivo after 1 3 days, when host B cells recog-
nized circulating foreign (heterologous) antibodies, and specific antibo-
dies were produced that targeted those foreign epitopes. Subsequent
particulates deposited in vascular beds, leading to pathologies.
Symptoms included anaphylactoid purpura, rashes, fever, myalgia, and
arthralgia. This type of reaction is still possible when intravenous
immunoglobulin is administered therapeutically, although matching
homologous human proteins limits reactivity. Of note, individuals can
exhibit similar pathologies to drugs; complexes of antibodies directed
toward chemotherapeutic agents (e.g., Penicillin) may lead to immune
complexes that deposit in vascular beds and result in vasculitis,
destruction of endothelium, and edema.

TYPE IV HYPERSENSITIVITY: DELAYED-TYPE (CELL-MEDIATED)

HYPERSENSITIVITY
The Type IV hypersensitivity (also called delayed-type hypersensitivity,
DTH) involves T cell antigen interactions that cause activation and
 Immune Hypersensitivity 103

Type IV cell-mediated hypersensitivity

Intradermal injection
of soluble tuberculin
CD4+ molecules
TH1

Sensitized T cell

IL-2, IFN-γ,
IL-1,TNF-α Activation
chemokines

Macrophage
recruitment
and activation

Tuberculin reaction
in skin
Reaction
2

to tuberculin
skin antigen
1
0

Figure 8.4 Type IV hypersensitivity (also called DTH) involves macrophage T cell antigen interactions that
cause activation, cytokine secretion, and potential granuloma formation. Shown here is the response to soluble
tuberculin antigens. Although CD41 T cells are depicted, they may give help to cyotoxic CD81 T cells to further
the response. The tissue injury is primarily due to the vigorous immune response rather than the inciting antigen.

cytokine secretion (Figure 8.4). This type of hypersensitivity requires

sensitized lymphocytes that respond 24 48 h after exposure to soluble
antigen. DTH reactions may involve T-helper cells (CD41) or cyto-
toxic T cells (CD81 CTLs), rather than antibodies. Diseases such as
tuberculosis, leprosy, and sarcoidosis as well as contact dermatitis are
all clinical examples where tissue injury is primarily due to the vigor-
ous immune response to released antigens rather than damage due to
the inciting pathogen itself. In these examples, sustained release of anti-
gen and continued activation of sensitized T cells results in amplified
tissue damage. Persistent infections may provoke excessive macro-
phage activation and granulomatous responses, leading to extended
fibrosis and necrosis of tissue.

A classic DTH reaction is exemplified in the tuberculin skin test

(Mantoux reaction). An individual sensitized to tuberculosis through
104 Introductory Immunology

exposure or infection develops CD41 lymphocytes specific for myco-

bacterial antigens. Intradermal injection of purified protein derivative
from mycobacteria (PPD) results in activation of sensitized CD41 T
cells. This is followed by secretion of cytokines which cause macro-
phage recruitment and activation. The final outcome is a localized
reactivity manifested by erythema and induration. Of interest, indivi-
duals who are HIV positive with low CD41 cell counts will not mount
significant DTH responses during the tuberculin skin test, providing
further evidence for the importance of this hypersensitive reaction in
protective immunity.

The Type IV reactions also can be identified in pathologies resulting

from viral infection. Here, the CD81 cells react to antigens presented
via class I MHC molecules or to antigens that are cell surface associ-
ated. Cytotoxic cells recognize the presented antigen and lyse the
infected target. Bystander killing may occur due to over-aggressive
responses, such as those seen during smallpox, measles, and herpes
infections, as well as in contact dermatitis.

ALTERNATE HYPERSENSITIVITY CLASSIFICATIONS

Many investigators have revisited these four classifications, especially
as the molecular knowledge of immunology has increased, and our
understanding of the clinical manifestation of disease has grown.
A fifth classification encompasses pathology leading to the granuloma-
tous response, in which encapsulation and isolation of specific patho-
gens leads to tissue pathology. These events are driven by innate
immunity or “foreign body” responses that lead to aggressive CD41
Th1 or Th2 type responses. The outcome of cytokines produced is
dependent in large part upon presentation of the particular persisting
antigen.

SUMMARY
• Robust dysfunctional immune responses may often lead to tissue
damage detrimental to the host.
• Allergic hypersensitivity (Type I) is an immediate hypersensitivity
due to aberrant activity of IgE against normally nonpathogenic
allergens, mediated through mast cell and basophil high-affinity IgE
receptors.
 Immune Hypersensitivity 105

• Cytotoxic hypersensitivity (Type II) results in tissue injury due to

antigens recognized by IgG and IgM antibodies. Complement depo-
sition triggers formation of the membrane attack complex, causing
lytic damage.
• Immune complex hypersensitivity (Type III) represents an immune
complex disorder in which reactivity in vivo leads to deposition of
immune particulates. Complement by-products initiate chemotaxic
influx of acute inflammatory cells, which release enzymes that result
in tissue injury.
• Delayed-type hypersensitivity (DTH, Type IV) involves T-helper
cells (CD41) or cytotoxic T cells (CD81 CTLs), rather than antibo-
dies. This is a cell-mediated event directed at released antigens in a
sensitized individual.