Definition of Hypersensitivity

An immunologic reaction which produces tissue damage on re exposure to antigen.

Gell and Coombs Classification

• Type I (IgE-mediated)

• Type II (Fc and complement-mediated)

• Type III (Immune complex-mediated)

• Type IV (Delayed-type hypersensitivity)

Hypersensitivity Disorders

CAUSES OF HYPERSENSITIVITY DISEASES

• Autoimmunity. Autoimmunity. • Failure of the normal mechanisms of self-tolerance results Failure of the normal mechanisms of self-tolerance results

in reactions against one’s own cells and tissues. in reactions against one’s own cells and tissues. • Autoimmune diseases are estimated to affect 2% to 5% of Autoimmune diseases are estimated to affect 2% to 5% of

the population in developed countries. the population in developed countries. • The incidence of these disorders is rising. Many of these The incidence of these disorders is rising. Many of these

diseases are common in individuals 20- to 40y . diseases are common in individuals 20- to 40y . • They are more common in women than in men.They are more common in women than in men.• Autoimmune diseases are chronic and debilitating. Autoimmune diseases are chronic and debilitating. • Many new treatments for these disorders have been Many new treatments for these disorders have been

developed based on scientific principles. developed based on scientific principles.

• Reactions against microbes. • Immune responses against microbial antigens may cause disease if the reactions are

excessive or the microbes are unusually persistent. • T cell responses against persistent microbes may give rise to severe inflammation,

sometimes with the formation of granulomas; this is the cause of tissue injury in tuberculosis and some other chronic infections.

• If antibodies are produced against microbial antigens, the antibodies may bind to the antigens to produce immune complexes, which deposit in tissues and trigger inflammation.

• Rarely, antibodies or T cells against a microbe may cross-react with a host tissue.• In some diseases involving the intestinal tract, called inflammatory bowel disease,

the immune response is directed against commensal bacteria that normally reside in the gut and cause no harm.

• Sometimes the disease-causing immune response may be entirely normal, but in the process of eradicating the infection, host tissues are injured.

• In viral hepatitis, the virus that infects liver cells is not cytopathic, but it is recognized as foreign by the immune system.

• Cytotoxic T lymphocytes (CTLs) try to eliminate infected cells, and this normal immune response damages liver cells.

• This type of normal reaction is not considered hypersensitivity.

• Reactions against environmental antigens. • Most healthy individuals do not react against Most healthy individuals do not react against

common, generally harmless environmental common, generally harmless environmental substances.substances.

• 20% of the population is abnormally responsive to 20% of the population is abnormally responsive to one or more of these substances. one or more of these substances.

• These individuals produce immunoglobulin E These individuals produce immunoglobulin E (IgE) antibodies that cause allergic diseases. (IgE) antibodies that cause allergic diseases.

• Some individuals become sensitized to Some individuals become sensitized to environmental antigens and chemicals that contact environmental antigens and chemicals that contact the skin and develop T cell reactions that lead to the skin and develop T cell reactions that lead to cytokine-mediated inflammation, resulting in cytokine-mediated inflammation, resulting in contact sensitivity.contact sensitivity.

DISEASES CAUSED BY ANTIBODIESDISEASES CAUSED BY ANTIBODIES

• Antibody-mediated diseases are produced either by antibodies Antibody-mediated diseases are produced either by antibodies that bind to antigens on particular cells or in extracellular that bind to antigens on particular cells or in extracellular tissues or by antigen-antibody complexes that form in the tissues or by antigen-antibody complexes that form in the circulation and are deposited in vessel walls. circulation and are deposited in vessel walls.

• The lesions can be induced in a normal animal by the The lesions can be induced in a normal animal by the adoptive transfer of immunoglobulin purified from the blood adoptive transfer of immunoglobulin purified from the blood or affected tissues of individuals with the disease. or affected tissues of individuals with the disease.

• It is occasionally seen in children of mothers suffering from It is occasionally seen in children of mothers suffering from antibody-mediated diseases.antibody-mediated diseases.

• These infants may be born with transient These infants may be born with transient manifestations because of transplacental passage of manifestations because of transplacental passage of antibodies.antibodies.

Diseases Caused by Antibodies Against Fixed Diseases Caused by Antibodies Against Fixed Cell and Tissue AntigensCell and Tissue Antigens

• Antibodies against tissue antigens cause disease by three main Antibodies against tissue antigens cause disease by three main mechanisms:mechanisms:

• 1) Antibodies that bind to cell surface antigens 1) Antibodies that bind to cell surface antigens - may directly opsonize cells- may directly opsonize cells- may activate the complement system - may activate the complement system resulting in the production of complement proteins that opsonize cells. resulting in the production of complement proteins that opsonize cells.

• These opsonized cells are phagocytosed and destroyed by phagocytes These opsonized cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of IgG antibodies and that express receptors for the Fc portions of IgG antibodies and receptors for complement proteins. receptors for complement proteins.

• This is the principal mechanism of cell destruction in This is the principal mechanism of cell destruction in 1- Autoimmune hemolytic anemia.1- Autoimmune hemolytic anemia.2- Autoimmune thrombocytopenic purpura. 2- Autoimmune thrombocytopenic purpura. 3- Hemolysis in transfusion reactions.3- Hemolysis in transfusion reactions.

• 2) Antibodies deposited in tissues recruit 2) Antibodies deposited in tissues recruit neutrophils and macrophages, which bind to the neutrophils and macrophages, which bind to the antibodies or to attached complement proteins by antibodies or to attached complement proteins by IgG Fc and complement receptors. IgG Fc and complement receptors.

• These leukocytes are activated by signaling from These leukocytes are activated by signaling from Fc receptors, and leukocyte products, including Fc receptors, and leukocyte products, including lysosomal enzymes and reactive oxygen species, lysosomal enzymes and reactive oxygen species, are secreted and cause tissue injury. are secreted and cause tissue injury.

• The mechanism of injury in antibody mediated The mechanism of injury in antibody mediated glomerulonephritis and many other diseases is glomerulonephritis and many other diseases is inflammation and leukocyte activation.inflammation and leukocyte activation.

• 3) Antibodies that bind to normal cellular 3) Antibodies that bind to normal cellular receptors or other proteins may interfere receptors or other proteins may interfere with the functions of these receptors or with the functions of these receptors or proteins and cause disease without proteins and cause disease without inflammation or tissue damage. inflammation or tissue damage.

• Antibody-mediated functional abnormalities Antibody-mediated functional abnormalities are the cause of Graves’ disease and are the cause of Graves’ disease and myasthenia gravismyasthenia gravis.

Immune Complex–Mediated DiseasesImmune Complex–Mediated Diseases

• Immune complexes that cause disease composed of Immune complexes that cause disease composed of antibodies bound to either self antigens or foreign antibodies bound to either self antigens or foreign antigens.antigens.

• The pathologic features of diseases caused by The pathologic features of diseases caused by immune complexes reflect the site of immune immune complexes reflect the site of immune complex deposition.complex deposition.

• Not determined by the cellular source of the Not determined by the cellular source of the antigen.antigen.

• Therefore, immune complex–mediated diseases Therefore, immune complex–mediated diseases tend to affect multiple tissues and organs.tend to affect multiple tissues and organs.

• The occurrence of diseases caused by immune complexes was The occurrence of diseases caused by immune complexes was suspected. suspected.

• At that time, diphtheria infections were being treated with serum from At that time, diphtheria infections were being treated with serum from horses immunized with the diphtheria toxin.horses immunized with the diphtheria toxin.

• von Pirquet noted that joint inflammation (arthritis), rash, and fever von Pirquet noted that joint inflammation (arthritis), rash, and fever developed in patients injected with the antitoxin-containing horse developed in patients injected with the antitoxin-containing horse serum. serum.

• It was not due to the infection or a toxic component of the serum itself. It was not due to the infection or a toxic component of the serum itself. • FirstFirst, these symptoms appeared even after the injection of horse serum , these symptoms appeared even after the injection of horse serum

not containing the antitoxin, so it is not due to the anti-diphtheria not containing the antitoxin, so it is not due to the anti-diphtheria antibody. antibody.

• SecondSecond, the symptoms appeared at least a week after the first injection , the symptoms appeared at least a week after the first injection of horse serum and more rapidly with each repeated injection. of horse serum and more rapidly with each repeated injection.

• So this disease was due to a host response to some component of the So this disease was due to a host response to some component of the serum. serum.

• The host made antibodies to horse serum proteins, these antibodies The host made antibodies to horse serum proteins, these antibodies formed complexes with the injected proteins, and the disease was due formed complexes with the injected proteins, and the disease was due to the antibodies or immune complexes. to the antibodies or immune complexes.

• He called this serum sickness and it is the prototype for systemic He called this serum sickness and it is the prototype for systemic immune complex–mediated disorders.immune complex–mediated disorders.

Diseases Caused by Antibodies Against Fixed Diseases Caused by Antibodies Against Fixed Cell and Tissue AntigensCell and Tissue Antigens

• 1)Antibodies that bind to cell surface antigens may directly 1)Antibodies that bind to cell surface antigens may directly opsonize cells, or they may activate the complement opsonize cells, or they may activate the complement system, resulting in the production of complement proteins system, resulting in the production of complement proteins that opsonize cells. that opsonize cells.

• These opsonized cells are phagocytosed and destroyed by These opsonized cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of phagocytes that express receptors for the Fc portions of IgG antibodies and receptors for complement proteins.IgG antibodies and receptors for complement proteins.

• This is the principal mechanism of cell destruction in This is the principal mechanism of cell destruction in autoimmune hemolytic anemia and autoimmune autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura. thrombocytopenic purpura.

• The same mechanism is responsible for hemolysis in The same mechanism is responsible for hemolysis in transfusion reactionstransfusion reactions

• 2)Antibodies deposited in tissues recruit neutrophils and 2)Antibodies deposited in tissues recruit neutrophils and macrophages, which bind to the antibodies or to attached macrophages, which bind to the antibodies or to attached complement proteins by IgG Fc and complement receptors. complement proteins by IgG Fc and complement receptors.

• These leukocytes are activated by signaling from the These leukocytes are activated by signaling from the receptors, particularly Fc receptors, and leukocyte products, receptors, particularly Fc receptors, and leukocyte products, including lysosomal enzymes and reactive oxygen species, are including lysosomal enzymes and reactive oxygen species, are secreted and cause tissue injury. secreted and cause tissue injury.

• The mechanism of injury in antibody mediated The mechanism of injury in antibody mediated glomerulonephritis and many other diseases is inflammation glomerulonephritis and many other diseases is inflammation and leukocyte activation.and leukocyte activation.

• 3)Antibodies that bind to normal cellular receptors or other 3)Antibodies that bind to normal cellular receptors or other proteins may interfere with the functions of these receptors or proteins may interfere with the functions of these receptors or proteins and cause disease without inflammation or tissue proteins and cause disease without inflammation or tissue damage. damage.

• Antibody-mediated functional abnormalities are the cause of Antibody-mediated functional abnormalities are the cause of Graves’ disease and myasthenia gravis.Graves’ disease and myasthenia gravis.

• Antibodies that cause cell- or tissue-specific diseases are usually auto antibodies produced as part of an autoimmune reaction against antigens in these cells or tissues.

• Examples of these autoantibodies are listed in Table 18-2. Examples of these autoantibodies are listed in Table 18-2. Less commonly, the antibodies may be produced against a Less commonly, the antibodies may be produced against a foreign (e.g., microbial) antigen that is immunologically foreign (e.g., microbial) antigen that is immunologically cross-reactive with a component of self tissues. cross-reactive with a component of self tissues.

• In a rare sequel of streptococcal infection called rheumatic In a rare sequel of streptococcal infection called rheumatic fever, antibodies produced against the bacteria cross-react fever, antibodies produced against the bacteria cross-react with antigens in the heart, deposit in this organ, and cause with antigens in the heart, deposit in this organ, and cause inflammation and tissue damage. inflammation and tissue damage.

• Tissue deposits of antibodies may be detected by Tissue deposits of antibodies may be detected by morphologic examinationmorphologic examination in some of these diseases, and in some of these diseases, and the deposition of antibody is often associated with local the deposition of antibody is often associated with local complement activation, inflammation, and tissue injurycomplement activation, inflammation, and tissue injury

Experimental Models of Immune Experimental Models of Immune Complex–Mediated DiseasesComplex–Mediated Diseases

• Serum SicknessSerum Sickness• analyses of experimental models of serum sickness. analyses of experimental models of serum sickness.

Immunization of an animal such as a rabbit with a Immunization of an animal such as a rabbit with a large dose of a foreign protein antigen leads to the large dose of a foreign protein antigen leads to the formation of antibodies against the antigen (Fig. 18-formation of antibodies against the antigen (Fig. 18-4). 4).

• These antibodies bind to and form complexes with These antibodies bind to and form complexes with circulating antigen, which are initially cleared by circulating antigen, which are initially cleared by macrophages in the liver and spleen. macrophages in the liver and spleen.

• As more and more antigen-antibody complexes are As more and more antigen-antibody complexes are formed, some of them are deposited in vascular formed, some of them are deposited in vascular beds. beds.

• In these tissues, the antibodies in the complexes may activate In these tissues, the antibodies in the complexes may activate complement, with a concomitant fall in serum complement levels. complement, with a concomitant fall in serum complement levels.

• Complement activation leads to recruitment and activation of Complement activation leads to recruitment and activation of inflammatory cells, predominantly neutrophils, at the sites of immune inflammatory cells, predominantly neutrophils, at the sites of immune complex deposition, and the neutrophils cause tissue injury. complex deposition, and the neutrophils cause tissue injury.

• Neutrophils also bind to the immune complexes by their Fcγ receptors, Neutrophils also bind to the immune complexes by their Fcγ receptors, and Fc receptor signaling activates the leukocytes to produce and Fc receptor signaling activates the leukocytes to produce substances that damage tissues, as in diseases caused by antibodies substances that damage tissues, as in diseases caused by antibodies against fixed tissues. against fixed tissues.

• Because the complexes are deposited mainly in small arteries, renal Because the complexes are deposited mainly in small arteries, renal glomeruli, and the synovia of joints, the clinical and pathologic glomeruli, and the synovia of joints, the clinical and pathologic manifestations are vasculitis, nephritis, and arthritis. manifestations are vasculitis, nephritis, and arthritis.

• The clinical symptoms are usually short-lived, and the lesions heal The clinical symptoms are usually short-lived, and the lesions heal unless the antigen is injected again. This type of disease is an example unless the antigen is injected again. This type of disease is an example of acute serum sickness. of acute serum sickness.

• A more indolent and prolonged disease, called chronic serum sickness, A more indolent and prolonged disease, called chronic serum sickness, is produced by multiple injections of antigen, which lead to the is produced by multiple injections of antigen, which lead to the formation of smaller complexes that are deposited most often in the formation of smaller complexes that are deposited most often in the kidneys, arteries, and lungs.kidneys, arteries, and lungs.

Gell and Coombs Classification

•Type I (IgE-mediated)Type I (IgE-mediated)•Type II (Fc and complement-mediated)•Type III (Immune complex-mediated)•Type IV (Delayed-type hypersensitivity)

Type I Hypersensitivity: History of Discoveries

• Anaphylaxis: Portier and Richet, 1902• Histamine: Dale and Laidlaw, 1911• Transfer of sensitivity: Prausnitz & Küstner• Mast cells as main tissue source of

histamine: Riley and West, 1952• IgE immunoglobulin: Ishizaka and

Ishizaka, 1966

Type I Hypersensitivity Diseases

• Allergic rhinoconjunctivitis (hay fever)

• Asthma

• Eczema (atopic dermatitis)

• Acute urticaria

• Anaphylaxis

Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

Type II Hypersensitivity Reactions:Mechanisms of Tissue Damage

• Complement-mediated cytolysis

• Antibody-dependent cell-mediated cytotoxicity (ADCC)

Type II

Reactions

Type II Hypersensitivity Reactions:Examples of Diseases

• Transfusion reactionsTransfusion reactions

• Hemolytic disease of the newborn Hemolytic disease of the newborn (Rh incompatibility)(Rh incompatibility)

• Hyperacute graft rejectionHyperacute graft rejection

• Drug-induced hemolytic anemiaDrug-induced hemolytic anemia

Transfusion

Reactions

Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn

Mechanisms

Of Drug

Hypersensitivity

Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)

Type III HypersensitivityMechanisms of Tissue Injury

• In situIn situ activation of complement activation of complement

• Anaphylatoxin-mediated activation of mast Anaphylatoxin-mediated activation of mast cells and phagocytescells and phagocytes

• Complex-mediated phagocytosis and release Complex-mediated phagocytosis and release of phagocyte granule enzymes and cytokines of phagocyte granule enzymes and cytokines into the local microenvironmentinto the local microenvironment

Type III HypersensitivityExamples of Diseases

• Arthus reactionArthus reaction

• Hypersensitivity pneumonitisHypersensitivity pneumonitis

• Immune complex-mediated Immune complex-mediated glomerulonephritisglomerulonephritis

• Serum sicknessSerum sickness

The Arthus Reaction

• Occurs with introduction of antigen into an Occurs with introduction of antigen into an individual with high titer antibodyindividual with high titer antibody

• Requires both complement & phagocytesRequires both complement & phagocytes• Peaks at 3-6 hours after exposurePeaks at 3-6 hours after exposure• Histology: massive influx of neutrophils, edema, Histology: massive influx of neutrophils, edema,

sometimes necrosissometimes necrosis

Hypersensitivity Pneumonitis Syndromes and Associated Antigens

• Farmer’s lung (thermophilic actinomycetes)Farmer’s lung (thermophilic actinomycetes)• Malt worker’s lung (Aspergillus spores)Malt worker’s lung (Aspergillus spores)• Pigeon fancier’s disease (avian proteins)Pigeon fancier’s disease (avian proteins)• Cheese washer’s lung (Penicillium spores)Cheese washer’s lung (Penicillium spores)• Furrier’s lung (fox fur)Furrier’s lung (fox fur)• Laboratory technician’s lung (rat urine proteins)Laboratory technician’s lung (rat urine proteins)

Serum Sickness

• Fever, rash, joint pain, lymphadenopathy, Fever, rash, joint pain, lymphadenopathy, occasionally glomerulonephritisoccasionally glomerulonephritis

• Timecourse: days to weeks after Timecourse: days to weeks after introduction of foreign antigenintroduction of foreign antigen

• Causes: allogeneic serum, drugs, infections, Causes: allogeneic serum, drugs, infections, autoimmune disordersautoimmune disorders

Serum Sickness Reactions

Serum Sickness Reactions

Common Locations of

Vascular Involvement

Autoimmune Glomerulo-

nephritis

Gell and Coombs Classification

• Type I (IgE-mediated)• Type II (Fc and complement-mediated)• Type III (Immune complex-mediated)• Type IV (Delayed-type hypersensitivity)Type IV (Delayed-type hypersensitivity)