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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).