Hypersensitivity Reactions (Types I, II, III, IV)
Transcript of Hypersensitivity Reactions (Types I, II, III, IV)
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Hypersensitivity Reactions (Types I, II, III, IV)
April 15, 2009
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Inflammatory response - local, eliminates antigenwithout extensively damaging the host’s tissue.
Hypersensitivity - immune & inflammatory responses that are harmful to the host (von Pirquet, 1906)
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- Type I
Produce effectormolecules
Capable ofingesting foreignParticles
Association withparasite infection
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Modified fromAbbas, Lichtman & Pillai, Table 19-1
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Type I hypersensitivity response
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IgE
VL
CL
VH
Cε1
Normal serum level = 0.0003 mg/ml
Binds to mastcell
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Binds Fc region of IgE
Intracellularsignal trans.
Link
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Initiation of degranulation
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Larche et al. Nat. Rev. Immunol 6:761-771, 2006
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Abbas, Lichtman & Pillai,19-8
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Factors in the development of allergic diseases
• Geographical distribution• Environmental factors - climate, air
pollution, socioeconomic status• Genetic risk factors• “Hygiene hypothesis”
– Older siblings, day care– Exposure to certain foods, farm animals– Exposure to antibiotics during infancy
• Cytokine milieu
Adapted from Bach, JF. N Engl J Med 347:911, 2002. Upham & Holt. Curr Opin Allergy Clin Immunol 5:167, 2005Also: Papadopoulos and Kalobatsou. Curr Op Allergy Clin Immunol 7:91-95, 2007
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IgE-mediated diseases in humans
• Systemic (anaphylactic shock)• Asthma
– Classification by immunopathological phenotype can be used to determine management strategies
• Hay fever (allergic rhinitis)• Allergic conjunctivitis• Skin reactions• Food allergies
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Diseases in Humans (I)
• Systemic anaphylaxis - potentially fatal - due to food ingestion (eggs, shellfish, peanuts, drug reactions) and insect stings - characterized by airway obstruction and a sudden fall in blood pressure.
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Diseases in Humans (II)Bronchial asthma
• Chronic inflammation– Intermittent & reversible airway obstruction– Chronic bronchial inflammation with
eosinophil infiltration– Bronchial smooth muscle hypertrophy and
hyperreactivity• Dominated by the presence of eosinophils,
CD4+ T lymphocytes (Th2), and a largeproportion of CD4+ NKT cells expressing an invariant T cell receptor that recognizesglycolipid antigens.
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National Heart Lung Blood Institute
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Kumar et al, Robbins and Cotran Pathologic Basis of Disease
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Anti-IL-13 -reduce mucus overproductionand eosinophilia
Anti-chemokinereceptors: CCR3, CCR4, CCR8 on Th2cells.
Anti-RANTES or-eotaxin abs toprevent recruitment ofeosinophils
Mediators and treatment of asthma
19-10
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Targeting Syk
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Diseases in Humans (III)• Upper respiratory tract
– Allergic rhinitis (hay fever) - reactions to plant pollen or house dust mites in the upper respiratory tract - mucosal edema, mucus secretion, coughing, sneezing, difficult in breathing - also associated with allergic conjunctivitis. Some evidence that asthma can develop in patients who have allergic rhinitis. Treatment - antihistamines
• Gastrointestinal tract– Result from release of mediators from intestinal mucosal and
submucosal mast cells following sensitization through the g.I. route of exposure - enhanced peristalsis, increased fluid secretion from intestinal cells, vomiting, and diarrhea. This is not the same as an anaphylactic response. Reactions usually begin in childhood - often remit in late childhood or in adulthod.
• Skin– Urticaria (wheal and flare) - mediated by histamine. – Eczema - late-phase reaction to allergen in the skin -
inflammation - can be treated with steroids.
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Urticaria
Copyright Slice of Life & Suzanne S. Stensaas - obtained from PEIR, Dept. of Pathology, UAB
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Atopic Eczema
Copyright Slice of Life & Suzanne S. Stensaas - obtained from PEIR, Dept. of Pathology, UAB
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Radioallergosorbent Test (RAST)
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1st study of allergen-specific immunotherapy:
Noon, L. Prophylactic inoculation against hay feverLancet I, 1572-1573 (1911)
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Desensitization/Allergen-Specific Immunotherapy
Subcutaneous or sublingual administration
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Peanut Flour May Ease Peanut Allergyfrom WebMD — a health information Web site for patients
February 24, 2009. Eating a tiny bit of peanut flourevery day may increase peanut tolerance in childrenwho are allergic to peanuts, a new study shows.
Each child went home with instructions to eat 5 mg of peanut flour mixed with yogurt each day, graduallyadding more peanut flour over the next six weeks.
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Protective role of IgE
Abbas & Lichtman 14-4
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Type II hypersensitivity
• Mediated by abs directed towards antigens present on cell surfaces or the extracellular matrix (type IIA) or abs with agonistic/antagonistic properties (type IIB).
• Mechanisms of damage:– Opsonization and complement- and Fc receptor-
mediated phagocytosis– Complement- and Fc receptor-mediated
inflammation– Antibody-mediated cellular dysfunction
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease
Examples: autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease
Examples: pemphigus vulgaris, Goodpasture syndrome
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005.
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Kumar et al. Robbins and CotranPathologic Basis of Disease. Elsevier2005
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005.
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease
Examples: Graves disease (hyperthyroidism), myastheniagravis
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Non-autoimmune type II reactions
• Transfusion reactions (ABO incompatibility
• Hemolytic disease of the newborn (erythroblastosis fetalis)
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Type III hypersensitivity (immune complex disease)
Mechanisms ofAb deposition
Effector mechanismsof tissue injury
Abbas and Lichtman, Cellular and Molecular Immunology (5th edition). Elsevier 2003.
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Serum sickness - a transient immune complex-mediated syndrome
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Arthus reaction
Peaks @ 4-8 hoursVisible edemaSevere hemorrhageCan be followed by
ulceration
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Formation of circulating immune complexes contributes to the pathogenesis of:
• Autoimmune diseases– SLE (lupus nephritis), rheumatoid arthritis
• Drug reactions– Allergies to penicillin and sulfonamides
• Infectious diseases– Poststreptococcal glomerulonephritis,
meningitis, hepatitis, mononucleosis, malaria, trypanosomiasis
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005.
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Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005.
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Balkwill & Rolph, Germ Zappers, Cold Spring Harbor Laboratory Press, 2001
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Balkwill & Rolph, Germ Zappers, Cold Spring Harbor Laboratory Press, 2001
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Type IV hypersensitivity (DTH)
Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005
(Th1)
IFN-γ, LT, IL-2, IL-3, GM-CSF, MIFIL-8, MCP-1
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Autoimmune diseases mediatedby direct cellular damage
Top - Goldsby et al, Figure 20-1- Hashimoto’s thyroiditisBottom - Goldsby et al, Figure 20-3 - Type I diabetes
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Clinical and patch test appearances of contact hypersensitivity
Roitt 24.2
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Tuberculin-type hypersensitivity reaction
Roitt 24.8
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DTH in the skin
Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005.
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Uses of tuberculin-type reactions
Demonstration of past infection with a microorganism.
Assessment of cell-mediated immunity.
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APC/IL-12
CD4+Th1 (IL-2)/IFN-γ
Monocytes
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The importance of TNF-α in the formation ofgranulomas
Roitt 24.17
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Diseases associated with granuloma formation:
• Leprosy• Tuberculosis• Schistosomiasis• Sarcoidosis• Crohn’s disease
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Saunders and Britton. Immunol. Cell Biol. 85: 103-111, 2007.
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Chemokine expressionin tissues fromM. tuberculosis-infectedindividuals
Saunders & Britton. Immunol. Cell Bioll. 85:103-111, 2007
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Tuberculosis
Roitt 24.23
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Sarcoidosis (lymph node)
Roitt 24.25
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Skin Reactions
Roitt 23.9
Immediate Arthus DTH