receptor

Fc

receptors

Neutrophil

enzymes,

reactive

oxygen

species Complement activation

C

C3b

Fig. 11.8 Effector mechanisms of antibody-mediated diseases. Antibodies cause disease by A, Inducing

inflammation at the site of deposition; B, Opsonizing cells (such as red cells) for phagocytosis; and C, Interfering with normal cellular functions, such as hormone receptor signaling. All three mechanisms are seen with

antibodies that bind directly to their target antigens, but immune complexes cause disease mainly by inducing

inflammation (A). TSH, Thyroid-stimulating hormone.

228 CHAPTER 11 Hypersensitivity

Examples and Treatment of Diseases Caused

by Cell- or Tissue-Specific Antibodies

Antibodies specific for cell and tissue antigens are the

cause of many human diseases, involving blood cells,

heart, kidney, lung, and skin (Fig. 11.9). Examples of antitissue antibodies are those that react with the glomerular

basement membrane and induce inflammation, a form of

glomerulonephritis. Antibodies against cells include those

that opsonize blood cells and target them for phagocytosis, as in autoimmune hemolytic anemia (red cell destruction) and autoimmune thrombocytopenia (destruction

of platelets). Antibodies that interfere with hormones

or their receptors were mentioned earlier. In most of

these cases, the antibodies are autoantibodies, but less

commonly, antibodies produced against a microbe may

cross-react with an antigen in the tissues. For instance, in

Autoimmune

(idiopathic)

thrombocytopenic

purpura

Autoimmune

hemolytic anemia

Pemphigus

vulgaris

Goodpasture

syndrome

Rheumatic fever

Myasthenia gravis

Graves disease

(hyperthyroidism)

Pernicious anemia

Bleeding

Hemolysis,

anemia

Skin blisters

(bullae)

Nephritis,

lung hemorrhage

Myocarditis,

arthritis

Muscle weakness,

paralysis

Hyperthyroidism

Anemia due

to abnormal

erythropoiesis,

nerve damage

Platelet membrane

proteins (gpIIb/IIIa

integrin)

Erythrocyte membrane

proteins (Rh blood group

antigens, I antigen)

Proteins in intercellular

junctions of epidermal

cells (epidermal cadherin)

Collagen in basement

membranes of kidney

glomeruli and

lung alveoli

Streptococcal cell wall

antigen; antibody crossreacts with myocardial

antigen

Acetylcholine receptor

Thyroid stimulating

hormone (TSH) receptor

Intrinsic factor of gastric

parietal cells

Opsonization and

phagocytosis

of platelets

Opsonization and

phagocytosis

of erythrocytes

Antibody-mediated

disruption of

intercellular adhesions

Complement and

Fc receptor–mediated

inflammation

Inflammation,

macrophage activation

Antibody inhibits

acetycholine binding,

down-modulates

receptors

Antibody-mediated

stimulation of

TSH receptors

Neutralization of

intrinsic factor,

decreased absorption

of vitamin B12

Antibody-mediated

disease

Target antigen Mechanisms

of disease

Clinicopathologic

manifestations

Fig. 11.9 Human antibody-mediated diseases (type II hypersensitivity). The figure lists examples of

human diseases caused by antibodies. In most of these diseases, the role of antibodies is inferred from the

detection of antibodies in the blood or the lesions, and in some cases by similarities with experimental models in which the involvement of antibodies can be formally established by transfer studies.

CHAPTER 11 Hypersensitivity 229

rare instances, streptococcal infection stimulates the production of antibacterial antibodies that cross-react with

antigens in the heart, producing the cardiac inflammation

that is characteristic of rheumatic fever.

Therapy for antibody-mediated diseases is intended

mainly to limit inflammation and its injurious consequences with drugs such as corticosteroids. In severe

cases, plasmapheresis is used to reduce levels of circulating antibodies. In hemolytic anemia and thrombocytopenia, splenectomy is of clinical benefit because the

spleen is the major organ where opsonized blood cells

are phagocytosed. Some of these diseases respond well

to treatment with intravenous IgG (IVIG) pooled from

healthy donors. How IVIG works is not known; it may

bind to the inhibitory Fc receptor on myeloid cells and B

cells and thus block activation of these cells (see Chapter

7, Fig. 7.15), or it may reduce the half-life of pathogenic

antibodies by competing for binding to the neonatal

Fc receptor in endothelial cells and macrophages (see

Chapter 8, Fig. 8.2). Treatment of patients with an antibody specific for CD20, a surface protein of mature

B cells, results in depletion of the B cells and may be

useful for treating some antibody-mediated disorders.

Other approaches in development for inhibiting the

production of autoantibodies include treating patients

with antibodies that block CD40 or its ligand and thus

inhibit helper T cell–dependent B cell activation and

antibodies to block cytokines that promote the survival of B cells and plasma cells. There is also interest in

inducing tolerance in cases in which the autoantigens

are known.

DISEASES CAUSED BY ANTIGENANTIBODY COMPLEXES

Antibodies may cause disease by forming immune

complexes that deposit in blood vessels (Fig. 11.7B).

Many acute and chronic hypersensitivity disorders are

caused by, or are associated with, immune complexes (Fig.

11.10); these are called type III hypersensitivity disorders.

Immune complexes usually deposit in blood vessels,

especially vessels through which plasma is filtered at high

pressure (e.g., in renal glomeruli and joint synovium).

Therefore, in contrast to diseases caused by tissue

antigen-specific antibodies, immune complex diseases

tend to be systemic and often manifest as widespread vasculitis involving sites that are particularly susceptible to

immune complex deposition, such as kidneys and joints.

Systemic lupus

erythematosus

Polyarteritis

nodosa

Poststreptococcal

glomerulonephritis

DNA, nucleoproteins,

others

In some cases,

microbial antigens

(e.g., hepatitis B virus

surface antigen); most

cases unknown

Streptococcal

cell wall antigen(s)

Nephritis, arthritis,

vasculitis

Nephritis

Immune complex

disease

Antibody

specificity

Clinicopathologic

manifestations

Vasculitis

Serum sickness

(clinical and

experimental)

Arthus reaction

(experimental)

Various protein

antigens

Various protein

antigens

Cutaneous

vasculitis

Systemic vasculitis,

nephritis, arthritis

Fig. 11.10 Immune complex diseases (type III hypersensitivity). Examples of human diseases caused

by the deposition of immune complexes, as well as two experimental models. In the diseases, immune

complexes are detected in the blood or in the tissues that are the sites of injury. In all the disorders, injury is

caused by complement-mediated and Fc receptor–mediated inflammation.

230 CHAPTER 11 Hypersensitivity

Etiology, Examples, and Therapy of Immune

Complex–Mediated Diseases

Antigen-antibody complexes, which are produced during

normal immune responses, cause disease only when

they are formed in excessive amounts, are not efficiently

removed by phagocytes, and become deposited in tissues.

Complexes containing positively charged antigens are

particularly pathogenic because they bind avidly to negatively charged components of the basement membranes

of blood vessels and kidney glomeruli. Once deposited in

the vessel walls, the Fc regions of the antibodies activate

complement and bind Fc receptors on neutrophils, activating the cells to release damaging proteases and reactive oxygen species. This inflammatory response within

the vessel wall, called vasculitis, may cause local hemorrhage or thrombosis leading to ischemic tissue injury. In

the kidney glomerulus, the vasculitis can impair the normal filtration function, leading to renal disease.

The first immune complex disease studied was

serum sickness, seen in subjects who received antitoxincontaining serum from immunized animals for the treatment of infections. Some of these treated individuals

subsequently developed a systemic inflammatory disease.

This illness could be recreated in experimental animals by

systemic administration of a protein antigen, which elicits

an antibody response and leads to the formation of circulating immune complexes. This can occur as a complication

of any therapy involving injection of foreign proteins, such

as antibodies against microbial toxins, snake venoms and

T cells that are usually made in goats or rabbits, and even

some humanized monoclonal antibodies that are used to

treat different diseases and may differ only slightly from

normal human Ig.

A localized immune complex reaction called the

Arthus reaction was first studied in experimental animals. It is induced by subcutaneous administration of

a protein antigen to a previously immunized animal; it

results in the formation of immune complexes at the site

of antigen injection and a local vasculitis. In a small percentage of vaccine recipients who have previously been

vaccinated or already have antibodies against the vaccine

antigen, a painful swelling that develops at the injection

site represents a clinically relevant Arthus reaction.

In human immune complex diseases, the antibodies

may be specific for self antigens or microbial antigens.

In several systemic autoimmune diseases, many of the

clinical manifestations are caused by vascular injury when

complexes of the antibodies and self antigens deposit in

vessels in different organs. For example, in systemic lupus

erythematosus, immune complexes of anti-DNA antibodies and DNA can deposit in the blood vessels of almost

any organ, causing vasculitis and impaired blood flow,

leading to a multitude of different organ pathologies and

symptoms. Several immune complex diseases are initiated

by infections. For example, in response to some streptococcal infections, individuals make antistreptococcal antibodies that form complexes with the bacterial antigens.

These complexes deposit in kidney glomeruli, causing an

inflammatory process called poststreptococcal glomerulonephritis that can lead to renal failure. Other immune

complex diseases caused by complexes of antimicrobial

antibodies and microbial antigens lead to vasculitis. This

may occur in patients with chronic infections with certain

viruses (e.g., the hepatitis virus) or parasites (e.g., malaria).

 

Type of

hypersensitivity

Pathologic immune mechanisms Mechanisms of tissue

injury and disease

Immediate

hypersensitivity

(Type I)

Antibodymediated

diseases

(Type II)

Immune

complex–

mediated

diseases

(Type III)

T cellmediated

diseases

(Type IV)

Th2 cells, IgE antibody, mast cells, eosinophils

IgM, IgG antibodies against cell surface or

extracellular matrix antigens

Immune complexes of circulating antigens

and IgM or IgG antibodies deposited in

vascular basement membrane

1. CD4+ T cells (cytokine-mediated inflammation)

2. CD8+ CTLs (T cell–mediated cytolysis)

Mast cell–derived

mediators (vasoactive

amines, lipid mediators,

cytokines)

Cytokine-mediated

inflammation (eosinophils,

neutrophils)

Complement- and

Fc receptor–mediated

recruitment and

activation of leukocytes

(neutrophils, macrophages)

Opsonization and

phagocytosis of cells

Abnormalities in cellular

function, e.g., hormone or

neurotransmitter

receptor signaling

Complement- and

Fc receptor–mediated

recruitment and

activation of leukocytes

1. Macrophage activation,

 cytokine-mediated

 inflammation

2. Direct target cell lysis,

 cytokine-mediated

 inflammation

Neutrophils

Antigen-antibody complex

Fc

receptor Complement

Inflammatory cell

Antibody

CD4+

T cell

CD8+

T cell

Macrophage

Mast cell

Mediators

IgE

Allergen

Blood

vessel

wall

Cytokines

Fig. 11.1 Types of hypersensitivity reactions. In the four major types of hypersensitivity reactions, different

immune effector mechanisms cause tissue injury and disease. CTLs, Cytotoxic T lymphocytes; Ig, immunoglobulin.

CHAPTER 11 Hypersensitivity 221

Any atopic individual may be allergic to one or more

of these antigens. It is not understood why only a

small subset of common environmental antigens elicit

Th2-mediated reactions and IgE production, or what

characteristics of these antigens are responsible for

their behavior as allergens.

In secondary lymphoid organs, IL-4 secreted by Tfh

cells stimulates B lymphocytes to switch to IgE-producing plasma cells. Therefore, atopic individuals

produce large amounts of IgE antibody in response to

antigens that do not elicit IgE responses in other people. IL-4 and IL-13 secreted by Th2 cells induce some

of the responses of tissues in allergic reactions, such as

intestinal motility and excess mucus secretions. Th2

cells also secrete IL-5, which promotes eosinophilic

inflammation that is characteristic of tissues affected

by allergic diseases. Because the majority of Th2 cells

migrate to peripheral tissues, whereas Tfh cells remain

in secondary lymphoid organs, they likely serve different roles in allergic responses. Switching to IgE occurs

mainly in the lymphoid organs and therefore helper

function is provided by Tfh cells. Th2 cells may contribute to any isotype switching that occurs in peripheral

sites of allergic reactions, and, more importantly, are

responsible for inflammation and eosinophil activation

at these sites.

The propensity toward differentiation of IL-4 and

IL-5 producing T cells, and resulting atopic diseases

such as asthma, has a strong genetic basis. A major

known risk for developing allergies is a family history of atopic disease, and gene association studies

indicate that many different genes play contributory roles. Some of these genes encode cytokines or

receptors known to be involved in T and B lymphocyte responses, including IL-4, IL-5, and IL-13, and

IL-4 receptor; how these gene variants contribute

to atopic diseases is not known. Mutations of filaggrin, a protein required for barrier function of skin,

increases risk for atopic dermatitis in early childhood, and subsequent allergic diseases including

asthma.

Various environmental factors besides exposure to allergens, including air pollution and exposure to microbes, have a profound influence on the

propensity to develop allergies, and this may be

one reason why the incidence of allergic diseases,

especially asthma, is increasing in industrialized

societies.

Mediators

Antigen activation

of Tfh cells and

stimulation of IgE

class switching

in B cells

Production of IgE

Binding of IgE

to FceRI on

mast cells

B cell

Tfh cell

IgE-secreting

plasma cell

IgE

Mast

cell

Repeat

exposure

 to allergen

Activation of

mast cell: release

of mediators

First exposure

 to allergen

FceRI

Allergen

Immediate

hypersensitivity

reaction (minutes after

repeat exposure to

allergen)

Late-phase

reaction (6–24

hours after

repeat exposure

to allergen)

Vasoactive amines,

lipid mediators Cytokines

Fig. 11.2 The sequence of events in immediate hypersensitivity. Immediate hypersensitivity reactions are initiated by

the introduction of an allergen, which stimulates Th2 and IL-4/

IL-13–producing Tfh cells and immunoglobulin E (IgE) production. IgE binds to Fc receptors (FceRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to

secrete the mediators that are responsible for the pathologic

reactions of immediate hypersensitivity.

222 CHAPTER 11 Hypersensitivity

Activation of Mast Cells and Secretion of

Mediators

IgE antibody produced in response to an allergen

binds to high-affinity Fc receptors, specific for the e

heavy chain, that are expressed on mast cells (see Fig.

11.2). Thus, in an atopic individual, mast cells are coated

with IgE antibody specific for the antigen(s) to which

the individual is allergic. This process of coating mast

cells with IgE is called sensitization, because it makes the

mast cells sensitive to activation by subsequent encounter with that antigen. In normal individuals, by contrast,

mast cells may carry IgE molecules of many different

specificities because many antigens may elicit small IgE

responses, and the amount of IgE specific for any one

antigen is not enough to cause immediate hypersensitivity reactions upon exposure to that antigen.

Mast cells are present in all connective tissues, especially

under epithelia, and they are usually located adjacent to

blood vessels. Which of the body’s mast cells are activated

by binding of an allergen often depends on the route of

entry of the allergen. For example, inhaled allergens activate mast cells in the submucosal tissues of the bronchus,

whereas ingested allergens activate mast cells in the wall of

the intestine. Allergens that enter the blood via absorption

from the intestine or by direct injection may be delivered

to all tissues, resulting in systemic mast cell activation.

The high-affinity receptor for IgE, called FceRI, consists of three polypeptide chains, one of which binds the

Fc portion of the e heavy chain very strongly, with a Kd

of approximately 10-11 M. (The concentration of IgE

in the plasma is approximately 10-9 M, which explains

why even in normal individuals, mast cells are always

coated with IgE bound to FceRI.) The other two chains

of the receptor are signaling proteins. The same FceRI

is also present on basophils, which are circulating cells

with many of the features of mast cells, but normally the

number of basophils in the blood is very low and they

are not present in tissues, so their role in immediate

hypersensitivity is not as well established as the role of

mast cells.

When mast cells sensitized by IgE are exposed to

the allergen, they are activated to secrete inflammatory mediators (Fig. 11.4). Mast cell activation results

from binding of the allergen to two or more IgE antibodies on the cell. When this happens, the FceRI molecules

that are carrying the IgE are cross-linked, triggering biochemical signals from the signal-transducing chains of

FceRI. The signals lead to the release of inflammatory

mediators.

The most important mediators produced by mast

cells are vasoactive amines and proteases stored in and

released from granules, newly generated and secreted

products of arachidonic acid metabolism, and cytokines (see Fig. 11.4). These mediators have different

actions. The major amine, histamine, causes increased

vascular permeability and vasodilation, leading to the

leak of fluid and plasma proteins into tissues, and stimulates the transient contraction of bronchial and intestinal

A B

Mast cells

Vascular

Edema congestion

Eosinophils

Clinical

manifestations

0 1 4 8 12 16 20

Hours after allergen exposure

Late-phase

reaction

Immediate Allergen exposure

C

Fig. 11.3 Immediate hypersensitivity. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen

exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later.

B, Morphology of the immediate reaction is characterized by vasodilation, congestion, and edema. C, The

late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.

(Micrographs courtesy Dr. Daniel Friend, Department of Pathology, Brigham and Women’s Hospital, Boston.)

CHAPTER 11 Hypersensitivity 223

smooth muscle. Proteases may cause damage to local tissues. Arachidonic acid metabolites include prostaglandins, which cause vascular dilation, and leukotrienes,

which stimulate prolonged bronchial smooth muscle

contraction. Cytokines induce local inflammation (the

late-phase reaction, described next). Thus, mast cell

mediators are responsible for acute vascular and smooth

muscle reactions and more prolonged inflammation, the

hallmarks of immediate hypersensitivity.

Cytokines produced by mast cells stimulate the

recruitment of leukocytes, which cause the latephase reaction. The principal leukocytes involved in

this reaction are eosinophils, neutrophils, and Th2

cells. Mast cell–derived tumor necrosis factor (TNF)

and IL-4 promote neutrophil- and eosinophil-rich

inflammation. Chemokines produced by mast cells

and by epithelial cells in the tissues also contribute to

leukocyte recruitment. Eosinophils and neutrophils

P

P

P

P

FceRI IgE

Cytokines

Enzymatic

modification of

arachidonic acid

Transcriptional

activation of

cytokine genes

Vascular

dilation,

smooth

muscle

contraction

Tissue

damage

Vascular

dilation

Smooth

muscle

contraction

Inflammation

(leukocyte

recruitment)

Vasoactive

amines

Proteases Prostaglandins

Leukotrienes

Cytokines

(e.g., TNF)

Signaling pathways

Granule with

preformed

mediators

Lipid

mediators

Allergen

Signaling

chains

of FceRI

ITAM

Secretion Secretion

Granule

exocytosis

Fig. 11.4 Production and actions of mast cell mediators. Cross-linking of IgE on a mast cell by an allergen stimulates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the signaling

chains of the IgE Fc receptor (FceRI), which then initiates multiple signaling pathways. These signaling pathways stimulate the release of mast cell granule contents (amines, proteases), the synthesis of arachidonic

acid metabolites (prostaglandins, leukotrienes), and the synthesis of various cytokines. TNF, Tumor necrosis

factor.

224 CHAPTER 11 Hypersensitivity

liberate proteases, which cause tissue damage, and

Th2 cells may exacerbate the reaction by producing

more cytokines. Eosinophils are prominent in many

allergic reactions and are an important cause of tissue injury in these reactions. These cells are activated

by the cytokine IL-5, which is produced by Th2 cells

and innate lymphoid cells.

Clinical Syndromes and Therapy

Immediate hypersensitivity reactions have diverse

clinical and pathologic features, all of which

are attributable to mediators produced by mast

cells in different amounts and in different tissues

(Fig. 11.5).

• Some mild manifestations, such as allergic rhinitis

and sinusitis, which are common in hay fever, are

reactions to inhaled allergens, such as a protein of

ragweed pollen. Mast cells in the nasal mucosa produce histamine, and Th2 cells produce IL-13, and

these two mediators cause increased production of

mucus. Late-phase reactions may lead to more prolonged inflammation.

• In food allergies, ingested allergens trigger mast cell

degranulation, and the released histamine and other

mediators causes increased peristalsis, resulting in

vomiting and diarrhea.

• Asthma is a clinical syndrome characterized by difficulty in breathing, cough, and wheezing, related to

intermittent obstruction of expiratory airflow. The

most common cause of asthma is respiratory allergy

in which inhaled allergens stimulate bronchial mast

cells to release mediators, including leukotrienes,

which cause repeated bouts of bronchial constriction and airway obstruction. In chronic asthma, large

numbers of eosinophils accumulate in the bronchial

mucosa, excessive secretion of mucus occurs in the

airways, and the bronchial smooth muscle becomes

hypertrophied and hyperreactive to various stimuli.

Some cases of asthma are not associated with IgE

production and may be triggered by cold or exercise;

how either of these causes bronchial hyperreactivity

is unknown.

• The most severe form of immediate hypersensitivity

is anaphylaxis, a systemic reaction characterized by

edema in many tissues, including the larynx, accompanied by a fall in blood pressure (anaphylactic

shock) and bronchoconstriction. Some of the most

frequent inducers of anaphylaxis include bee stings,

injected or ingested penicillin-family antibiotics, and

ingested nuts or shellfish. The reaction is caused by

widespread mast cell degranulation in response to

the systemic distribution of the antigen, and it is life

threatening because of the sudden fall in blood pressure and airway obstruction.

The therapy for immediate hypersensitivity diseases

is aimed at inhibiting mast cell degranulation, antagonizing the effects of mast cell mediators, and reducing inflammation (Fig. 11.6). Common drugs include

antihistamines for hay fever, inhaled beta-adrenergic

agonists and corticosteroids that relax bronchial smooth

muscles and reduce airway inflammation in asthma,

and epinephrine in anaphylaxis. Many patients benefit

from repeated administration of small doses of allergens, called desensitization or allergen-specific immunotherapy. This treatment may work by changing the T

cell response away from Th2 dominance or the antibody

response away from IgE, by inducing tolerance in allergen-specific T cells, or by stimulating regulatory T cells

(Tregs). Antibodies that block various cytokines or their

receptors, including IL-4 and IL-5, are now approved for

Clinical

syndrome

Clinical and

pathological

manifestations

Allergic rhinitis,

sinusitis

(hay fever)

Food allergies

Asthma

Anaphylaxis

(may be

caused by

drugs, bee

sting, food)

Increased mucus

secretion; inflammation

of upper airways, sinuses

Increased peristalsis due

to contraction of

intestinal muscles

Airway obstruction caused

by bronchial smooth

muscle hyperactivity;

inflammation and

tissue injury

Fall in blood pressure

(shock) caused by

vascular dilation;

airway obstruction due to

laryngeal edema

Fig. 11.5 Clinical manifestations of immediate hypersensitivity reactions. Immediate hypersensitivity may be manifested in many other ways, as in development of skin lesions

(e.g., urticaria, eczema).

CHAPTER 11 Hypersensitivity 225

the treatment of some forms of asthma and atopic dermatitis, and other cytokine antagonists are being tested

in patients.

Before concluding the discussion of immediate

hypersensitivity, it is important to address the question

of why evolution has preserved an IgE antibody– and

mast cell–mediated immune response whose major

effects are pathologic. There is no definitive answer to

this puzzle, but immediate hypersensitivity reactions

likely evolved to protect against pathogens or toxins. It is

known that IgE antibody and eosinophils are important

mechanisms of defense against helminthic infections,

and mast cells play a role in innate immunity against

some bacteria and in destroying venomous toxins produced by arachnids and snakes.

DISEASES CAUSED BY ANTIBODIES

SPECIFIC FOR CELL AND TISSUE

ANTIGENS

Antibodies, typically of the IgG class, may cause disease, called type II hypersensitivity disorders, by binding to their target antigens in different tissues (Fig.

11.7A). Antibody-mediated hypersensitivity reactions

have long been recognized as the basis of many chronic

immunologic diseases in humans. Antibodies against

Syndrome Therapy Mechanism of action

Anaphylaxis

Asthma

Various

allergic

diseases

Epinephrine

Corticosteroids

Leukotriene antagonists

Beta adrenergic receptor

antagonists

Desensitization

(repeated administration

of low doses of allergens)

Causes vascular smooth

muscle cell contraction,

increases cardiac output

(to counter shock), and

inhibits bronchial smooth

muscle cell contraction

Reduce inflammation

Relax bronchial smooth

muscle and reduce

inflammation

Relax bronchial

smooth muscles

Unknown; may inhibit IgE

production and increase

production of other Ig

isotypes; may induce

T cell tolerance

Anti-IgE antibody Neutralizes and

eliminates IgE

Antihistamines Block actions of

histamine on vessels and

smooth muscles

Cromolyn

Antibodies that block

cytokines and their

receptors: anti-IL-5 and

anti-IL-5R (asthma),

anti-IL-4R (atopic

dermatitis)

Inhibits mast cell

degranulation

Block actions of cytokines

Fig. 11.6 Treatment of immediate hypersensitivity reactions. The figure summarizes the principal mechanisms of action of the various drugs used to treat allergic disorders. Ig, Immunoglobulin.

226 CHAPTER 11 Hypersensitivity

cells or extracellular matrix components may deposit in

any tissue that expresses the relevant target antigen; thus,

diseases caused by such antibodies usually are specific

for a particular tissue. The antibodies that cause disease

are most often autoantibodies against self antigens. The

production of autoantibodies results from a failure of

self-tolerance. In Chapter 9 we discussed the mechanisms

by which self-tolerance may fail, but why this happens in

any human autoimmune disease is still not understood.

Mechanisms of Antibody-Mediated Tissue

Injury and Disease

Antibodies specific for cell and tissue antigens may

deposit in tissues and cause injury by inducing local

inflammation, they may induce phagocytosis and

destruction of cells, or they interfere with normal cellular functions (Fig. 11.8).

• Inflammation. Antibodies against tissue antigens

induce inflammation by attracting and activating

leukocytes. IgG antibodies of the IgG1 and IgG3

subclasses bind to neutrophil and macrophage Fc

receptors and activate these leukocytes, resulting in

inflammation (see Chapter 8). The same antibodies,

as well as IgM, activate the complement system by

the classical pathway, resulting in the production of

complement by-products that recruit leukocytes and

induce inflammation. When leukocytes are activated

at sites of antibody deposition, these cells release

reactive oxygen species and lysosomal enzymes that

damage the adjacent tissues.

• Opsonization and phagocytosis. If antibodies bind

to cells, such as erythrocytes, neutrophils, and platelets, the cells are opsonized and may be ingested and

destroyed by host phagocytes.

Mechanism of

antibody deposition

Effector mechanisms

of tissue injury

Immune complex–mediated tissue injury

Injury caused by anti-tissue antibody

Circulating immune

complexes

Complementand Fc receptormediated

recruitment and

activation of

inflammatory cells Site of deposition of

immune complexes

Blood

vessel

Neutrophils

Vasculitis

Tissue injury

Complement- and Fc

receptor-mediated

recruitment and

activation of

inflammatory cells

Antibody

deposition

Neutrophils Macrophages

Antigen in

extracellular

matrix

B

A

Fig. 11.7 Types of antibody-mediated diseases. Antibodies (other than IgE) may cause tissue injury and disease

by: A, Binding directly to their target antigens on cells (not shown) and in the extracellular matrix (type II hypersensitivity); or B, By forming immune complexes that deposit mainly in blood vessels (type III hypersensitivity).

CHAPTER 11 Hypersensitivity 227

• Abnormal cellular responses. Some antibodies

may cause disease without directly inducing tissue

injury. For example, in pernicious anemia, autoantibodies specific for a protein required for absorption of vitamin B12 cause a multisystem disease

due to B12 deficiency. In some cases of myasthenia

gravis, antibodies against the acetylcholine receptor

inhibit neuromuscular transmission, causing paralysis. Other antibodies may directly activate receptors,

mimicking their physiologic ligands. The only known

example is a form of hyperthyroidism called Graves

disease, in which antibodies against the receptor for

thyroid-stimulating hormone activate thyroid cells

even in the absence of the hormone.

Muscle

Nerve

ending

Antibody

to ACh

receptor

ACh

receptor

Acetylcholine

(ACh)

A Complement- and Fc receptor–mediated inflammation

Complement

by-products

(C5a, C3a)

Neutrophil

activation

Inflammation and

tissue injury

Abnormal physiologic responses without cell/tissue injury

Antibody against

TSH receptor

Thyroid

epithelial

cell

Thyroid hormones

Antibody stimulates

receptor without hormone

Antibody inhibits binding

of neurotransmitter

 to receptor

Opsonization and phagocytosis

Opsonized

cell

Fc receptor

Complement activation

C3b receptor

Phagocyte

Phagocytosed cell

Phagocytosis

B

TSH