This document discusses hypersensitivity and immune-mediated disorders. It defines hypersensitivity as an immunologic reaction that causes tissue damage upon reexposure to an antigen. There are four types of hypersensitivity reactions classified by Gell and Coombs: type I involves IgE antibodies, type II involves IgG antibodies and complement, type III involves immune complex formation, and type IV involves delayed-type hypersensitivity and T cells. Causes of hypersensitivity diseases include reactions against self-antigens due to failures in self-tolerance (autoimmunity), reactions against microbes, and reactions against environmental antigens. Diseases can be caused by antibodies against cells/tissues or immune complexes deposited in tissues.

1. Definition of Hypersensitivity
An immunologic reaction which produces
tissue damage on re exposure to antigen.

2. Gell and Coombs Classification
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Type I (IgE-mediated)
Type II (Fc and complement-mediated)
Type III (Immune complex-mediated)
Type IV (Delayed-type hypersensitivity)

3. Hypersensitivity Disorders

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.

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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. • 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. 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. Diseases Caused by Antibodies Against Fixed
Cell and Tissue Antigens
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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. • 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. • 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

12. 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.

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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.

18. 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

19. • 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.

20. • 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

22. 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.

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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.

24. 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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25. Type I Hypersensitivity:
History of Discoveries
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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

26. Type I Hypersensitivity Diseases
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Allergic rhinoconjunctivitis (hay fever(
Asthma
Eczema (atopic dermatitis(
Acute urticaria
Anaphylaxis

27. Gell and Coombs Classification
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Type I (IgE-mediated(
Type II (Fc and complement-mediated(
Type III (Immune complex-mediated(
Type IV (Delayed-type hypersensitivity(

28. Type II Hypersensitivity Reactions:
Mechanisms of Tissue Damage
• Complement-mediated cytolysis
• Antibody-dependent cell-mediated
cytotoxicity (ADCC(

31. Type II
Reactions

32. Type II Hypersensitivity Reactions:
Examples of Diseases
• Transfusion reactions
• Hemolytic disease of the newborn
(Rh incompatibility)
• Hyperacute graft rejection
• Drug-induced hemolytic anemia

33. Transfusion
Reactions

34. Hemolytic Disease of the Newborn

35. Hemolytic Disease of the Newborn

36. Mechanisms
Of Drug
Hypersensitivity

38. Gell and Coombs Classification
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Type I (IgE-mediated)
Type II (Fc and complement-mediated)
Type III (Immune complex-mediated)
Type IV (Delayed-type hypersensitivity)

39. 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

40. Type III Hypersensitivity
Examples of Diseases
• Arthus reaction
• Hypersensitivity pneumonitis
• Immune complex-mediated
glomerulonephritis
• Serum sickness

41. 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

43. Hypersensitivity Pneumonitis Syndromes
and Associated Antigens
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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)

44. 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

45. Serum
Sickness
Reactions

46. Serum
Sickness
Reactions

47. Common
Locations of
Vascular
Involvement

48. Autoimmune
Glomerulonephritis

49. Gell and Coombs Classification
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Type I (IgE-mediated)
Type II (Fc and complement-mediated)
Type III (Immune complex-mediated)
Type IV (Delayed-type hypersensitivity)