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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 comple...
Hypersensitivity Disorders
CAUSES OF HYPERSENSITIVITY DISEASES
• Autoimmunity.
• Failure of the normal mechanisms of self-tolerance results
in reacti...
•
•
•
•
•
•
•
•
•
•

Reactions against microbes.
Immune responses against microbial antigens may cause disease if the reac...
• Reactions against environmental antigens.
• Most healthy individuals do not react against
common, generally harmless env...
DISEASES CAUSED BY ANTIBODIES
• Antibody-mediated diseases are produced either by antibodies
that bind to antigens on part...
Diseases Caused by Antibodies Against Fixed
Cell and Tissue Antigens
•
•

•
•

Antibodies against tissue antigens cause di...
• 2) Antibodies deposited in tissues recruit
neutrophils and macrophages, which bind to the
antibodies or to attached comp...
• 3) Antibodies that bind to normal cellular
receptors or other proteins may interfere
with the functions of these recepto...
Immune Complex–Mediated Diseases
• Immune complexes that cause disease composed of
antibodies bound to either self antigen...
•
•
•
•
•
•
•
•
•

The occurrence of diseases caused by immune complexes was
suspected.
At that time, diphtheria infection...
Diseases Caused by Antibodies Against Fixed
Cell and Tissue Antigens
• 1)Antibodies that bind to cell surface antigens may...
• 2)Antibodies deposited in tissues recruit neutrophils and
macrophages, which bind to the antibodies or to attached
compl...
• Antibodies that cause cell- or tissue-specific diseases are
usually auto antibodies produced as part of an autoimmune
re...
Experimental Models of Immune
Complex–Mediated Diseases

• Serum Sickness

• analyses of experimental models of serum sick...
•
•
•

•
•
•

In these tissues, the antibodies in the complexes may activate
complement, with a concomitant fall in serum ...
Gell and Coombs Classification
(Type I (IgE-mediated
(Type II (Fc and complement-mediated
(Type III (Immune complex-mediat...
Type I Hypersensitivity:
History of Discoveries
•
•
•
•

Anaphylaxis: Portier and Richet, 1902
Histamine: Dale and Laidlaw...
Type I Hypersensitivity Diseases
•
•
•
•
•

Allergic rhinoconjunctivitis (hay fever(
Asthma
Eczema (atopic dermatitis(
Acu...
Gell and Coombs Classification
•
•
•
•

Type I (IgE-mediated(
Type II (Fc and complement-mediated(
Type III (Immune comple...
Type II Hypersensitivity Reactions:
Mechanisms of Tissue Damage
• Complement-mediated cytolysis
• Antibody-dependent cell-...
Type II
Reactions
Type II Hypersensitivity Reactions:
Examples of Diseases
• Transfusion reactions
• Hemolytic disease of the newborn
(Rh in...
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 comple...
Type III Hypersensitivity
Mechanisms of Tissue Injury
• In situ activation of complement
• Anaphylatoxin-mediated activati...
Type III Hypersensitivity
Examples of Diseases
• Arthus reaction
• Hypersensitivity pneumonitis
• Immune complex-mediated
...
The Arthus Reaction
• Occurs with introduction of antigen into an
individual with high titer antibody
• Requires both comp...
Hypersensitivity Pneumonitis Syndromes
and Associated Antigens
•
•
•
•
•
•

Farmer’s lung (thermophilic actinomycetes)
Mal...
Serum Sickness
• Fever, rash, joint pain, lymphadenopathy,
occasionally glomerulonephritis
• Timecourse: days to weeks aft...
Serum
Sickness
Reactions
Serum
Sickness
Reactions
Common
Locations of
Vascular
Involvement
Autoimmune
Glomerulonephritis
Gell and Coombs Classification
•
•
•
•

Type I (IgE-mediated)
Type II (Fc and complement-mediated)
Type III (Immune comple...
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
Hypersenstivity
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Hypersenstivity

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Hypersenstivity

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  • Types of antibody-mediated diseases. Antibodies may bind specifically to tissue antigens (A), or they may be deposited
    as immune complexes that are formed in the circulation (B). In both cases, the deposited antibodies induce inflammation, leading to tissue injury.
  • A, Antibodies opsonize cells and may activate complement, generating complement products that also opsonize cells, leading to phagocytosis of the cells through phagocyte Fc receptors or C3 receptors.
  • B, Antibodies recruit leukocytes by binding to Fc receptors or by activating complement and thereby releasing byproducts that are chemotactic for leukocytes.
  • Antibodies specific for cell surface receptors for hormones or neurotransmitters may stimulate the activity of the receptors even in the absence of the hormone (left panel) or may inhibit binding of the neurotransmitter to its receptor (right panel). TSH, thyroid stimulating hormone
  • Transcript of "Hypersenstivity"

    1. 1. Definition of Hypersensitivity An immunologic reaction which produces tissue damage on re exposure to antigen.
    2. 2. Gell and Coombs Classification • • • • Type I (IgE-mediated) Type II (Fc and complement-mediated) Type III (Immune complex-mediated) Type IV (Delayed-type hypersensitivity)
    3. 3. Hypersensitivity Disorders
    4. 4. CAUSES OF HYPERSENSITIVITY DISEASES • Autoimmunity. • Failure of the normal mechanisms of self-tolerance results in reactions against one’s own cells and tissues. • Autoimmune diseases are estimated to affect 2% to 5% of the population in developed countries. • The incidence of these disorders is rising. Many of these diseases are common in individuals 20- to 40y . • They are more common in women than in men. • Autoimmune diseases are chronic and debilitating. • Many new treatments for these disorders have been developed based on scientific principles.
    5. 5. • • • • • • • • • • 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.
    6. 6. • Reactions against environmental antigens. • Most healthy individuals do not react against common, generally harmless environmental substances. • 20% of the population is abnormally responsive to one or more of these substances. • These individuals produce immunoglobulin E (IgE) antibodies that cause allergic diseases. • Some individuals become sensitized to environmental antigens and chemicals that contact the skin and develop T cell reactions that lead to cytokine-mediated inflammation, resulting in contact sensitivity.
    7. 7. DISEASES CAUSED BY ANTIBODIES • Antibody-mediated diseases are produced either by antibodies that bind to antigens on particular cells or in extracellular tissues or by antigen-antibody complexes that form in the circulation and are deposited in vessel walls. • The lesions can be induced in a normal animal by the adoptive transfer of immunoglobulin purified from the blood or affected tissues of individuals with the disease. • It is occasionally seen in children of mothers suffering from antibody-mediated diseases. • These infants may be born with transient manifestations because of transplacental passage of antibodies.
    8. 8. Diseases Caused by Antibodies Against Fixed Cell and Tissue Antigens • • • • Antibodies against tissue antigens cause disease by three main mechanisms: 1) Antibodies that bind to cell surface antigens - may directly opsonize cells - may activate the complement system resulting in the production of complement proteins that opsonize cells. These opsonized cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of IgG antibodies and receptors for complement proteins. This is the principal mechanism of cell destruction in 1- Autoimmune hemolytic anemia. 2- Autoimmune thrombocytopenic purpura. 3- Hemolysis in transfusion reactions.
    9. 9. • 2) Antibodies deposited in tissues recruit neutrophils and macrophages, which bind to the antibodies or to attached complement proteins by IgG Fc and complement receptors. • These leukocytes are activated by signaling from Fc receptors, and leukocyte products, including lysosomal enzymes and reactive oxygen species, are secreted and cause tissue injury. • The mechanism of injury in antibody mediated glomerulonephritis and many other diseases is inflammation and leukocyte activation.
    10. 10. • 3) Antibodies that bind to normal cellular receptors or other proteins may interfere with the functions of these receptors or proteins and cause disease without inflammation or tissue damage. • Antibody-mediated functional abnormalities are the cause of Graves’ disease and myasthenia gravis. gravis
    11. 11. Immune Complex–Mediated Diseases • Immune complexes that cause disease composed of antibodies bound to either self antigens or foreign antigens. • The pathologic features of diseases caused by immune complexes reflect the site of immune complex deposition. • Not determined by the cellular source of the antigen. • Therefore, immune complex–mediated diseases tend to affect multiple tissues and organs.
    12. 12. • • • • • • • • • The occurrence of diseases caused by immune complexes was suspected. At that time, diphtheria infections were being treated with serum from horses immunized with the diphtheria toxin. von Pirquet noted that joint inflammation (arthritis), rash, and fever developed in patients injected with the antitoxin-containing horse serum. It was not due to the infection or a toxic component of the serum itself. First, these symptoms appeared even after the injection of horse serum not containing the antitoxin, so it is not due to the anti-diphtheria antibody. Second, the symptoms appeared at least a week after the first 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 serum. The host made antibodies to horse serum proteins, these antibodies formed complexes with the injected proteins, and the disease was due to the antibodies or immune complexes. He called this serum sickness and it is the prototype for systemic immune complex–mediated disorders.
    13. 13. Diseases Caused by Antibodies Against Fixed Cell and Tissue Antigens • 1)Antibodies that bind to cell surface antigens may directly opsonize cells, or they may activate the complement system, resulting in the production of complement proteins that opsonize cells. • These opsonized cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of IgG antibodies and receptors for complement proteins. • This is the principal mechanism of cell destruction in autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura. • The same mechanism is responsible for hemolysis in transfusion reactions
    14. 14. • 2)Antibodies deposited in tissues recruit neutrophils and macrophages, which bind to the antibodies or to attached complement proteins by IgG Fc and complement receptors. • These leukocytes are activated by signaling from the receptors, particularly Fc receptors, and leukocyte products, including lysosomal enzymes and reactive oxygen species, are secreted and cause tissue injury. • The mechanism of injury in antibody mediated glomerulonephritis and many other diseases is inflammation and leukocyte activation. • 3)Antibodies that bind to normal cellular receptors or other proteins may interfere with the functions of these receptors or proteins and cause disease without inflammation or tissue damage. • Antibody-mediated functional abnormalities are the cause of Graves’ disease and myasthenia gravis.
    15. 15. • 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. Less commonly, the antibodies may be produced against a foreign (e.g., microbial) antigen that is immunologically cross-reactive with a component of self tissues. • In a rare sequel of streptococcal infection called rheumatic fever, antibodies produced against the bacteria cross-react with antigens in the heart, deposit in this organ, and cause inflammation and tissue damage. • Tissue deposits of antibodies may be detected by morphologic examination in some of these diseases, and the deposition of antibody is often associated with local complement activation, inflammation, and tissue injury
    16. 16. Experimental Models of Immune Complex–Mediated Diseases • Serum Sickness • analyses of experimental models of serum sickness. Immunization of an animal such as a rabbit with a large dose of a foreign protein antigen leads to the formation of antibodies against the antigen (Fig. 184). • These antibodies bind to and form complexes with circulating antigen, which are initially cleared by macrophages in the liver and spleen. • As more and more antigen-antibody complexes are formed, some of them are deposited in vascular beds.
    17. 17. • • • • • • In these tissues, the antibodies in the complexes may activate complement, with a concomitant fall in serum complement levels. Complement activation leads to recruitment and activation of inflammatory cells, predominantly neutrophils, at the sites of immune complex deposition, and the neutrophils cause tissue injury. Neutrophils also bind to the immune complexes by their Fcγ receptors, and Fc receptor signaling activates the leukocytes to produce substances that damage tissues, as in diseases caused by antibodies against fixed tissues. Because the complexes are deposited mainly in small arteries, renal glomeruli, and the synovia of joints, the clinical and pathologic manifestations are vasculitis, nephritis, and arthritis. The clinical symptoms are usually short-lived, and the lesions heal unless the antigen is injected again. This type of disease is an example of acute serum sickness. A more indolent and prolonged disease, called chronic serum sickness, is produced by multiple injections of antigen, which lead to the formation of smaller complexes that are deposited most often in the kidneys, arteries, and lungs.
    18. 18. Gell and Coombs Classification (Type I (IgE-mediated (Type II (Fc and complement-mediated (Type III (Immune complex-mediated (Type IV (Delayed-type hypersensitivity • • • •
    19. 19. 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
    20. 20. Type I Hypersensitivity Diseases • • • • • Allergic rhinoconjunctivitis (hay fever( Asthma Eczema (atopic dermatitis( Acute urticaria Anaphylaxis
    21. 21. Gell and Coombs Classification • • • • Type I (IgE-mediated( Type II (Fc and complement-mediated( Type III (Immune complex-mediated( Type IV (Delayed-type hypersensitivity(
    22. 22. Type II Hypersensitivity Reactions: Mechanisms of Tissue Damage • Complement-mediated cytolysis • Antibody-dependent cell-mediated cytotoxicity (ADCC(
    23. 23. Type II Reactions
    24. 24. Type II Hypersensitivity Reactions: Examples of Diseases • Transfusion reactions • Hemolytic disease of the newborn (Rh incompatibility) • Hyperacute graft rejection • Drug-induced hemolytic anemia
    25. 25. Transfusion Reactions
    26. 26. Hemolytic Disease of the Newborn
    27. 27. Hemolytic Disease of the Newborn
    28. 28. Mechanisms Of Drug Hypersensitivity
    29. 29. Gell and Coombs Classification • • • • Type I (IgE-mediated) Type II (Fc and complement-mediated) Type III (Immune complex-mediated) Type IV (Delayed-type hypersensitivity)
    30. 30. Type III Hypersensitivity Mechanisms of Tissue Injury • In situ activation of complement • Anaphylatoxin-mediated activation of mast cells and phagocytes • Complex-mediated phagocytosis and release of phagocyte granule enzymes and cytokines into the local microenvironment
    31. 31. Type III Hypersensitivity Examples of Diseases • Arthus reaction • Hypersensitivity pneumonitis • Immune complex-mediated glomerulonephritis • Serum sickness
    32. 32. The Arthus Reaction • Occurs with introduction of antigen into an individual with high titer antibody • Requires both complement & phagocytes • Peaks at 3-6 hours after exposure • Histology: massive influx of neutrophils, edema, sometimes necrosis
    33. 33. Hypersensitivity Pneumonitis Syndromes and Associated Antigens • • • • • • Farmer’s lung (thermophilic actinomycetes) Malt worker’s lung (Aspergillus spores) Pigeon fancier’s disease (avian proteins) Cheese washer’s lung (Penicillium spores) Furrier’s lung (fox fur) Laboratory technician’s lung (rat urine proteins)
    34. 34. Serum Sickness • Fever, rash, joint pain, lymphadenopathy, occasionally glomerulonephritis • Timecourse: days to weeks after introduction of foreign antigen • Causes: allogeneic serum, drugs, infections, autoimmune disorders
    35. 35. Serum Sickness Reactions
    36. 36. Serum Sickness Reactions
    37. 37. Common Locations of Vascular Involvement
    38. 38. Autoimmune Glomerulonephritis
    39. 39. Gell and Coombs Classification • • • • Type I (IgE-mediated) Type II (Fc and complement-mediated) Type III (Immune complex-mediated) Type IV (Delayed-type hypersensitivity)
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