Hyper Sensitivities 09

7/30/2019 Hyper Sensitivities 09

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Hypersensitivity Reactions(Types I, II, III, IV)

April 15, 2009


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Inflammatory response - local, eliminatesantigenwithout extensively damaging the hosts tissue.

Hypersensitivity - immune & inflammatoryresponses that are harmful to the host (von

Pirquet, 1906)


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- Type I

Produce effectormolecules

Capable ofingesting foreignParticles

Association with

parasite infection


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Modified from

Abbas, Lichtman &Pillai, Table 19-1


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Type I hypersensitivity response


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IgE

VL

CL

VH

C1

Normal serumlevel = 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, airpollution, 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, J F. 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 inhumans

Systemic (anaphylactic shock) Asthma

Classification by immunopathological phenotypecan 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 - potentiallyfatal - due to food ingestion (eggs,shellfish, peanuts, drug reactions)

and insect stings - characterized byairway obstruction and a suddenfall 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 andhyperreactivity

Dominated by the presence of eosinophils,CD4+ T lymphocytes (Th2), and a largeproportion of CD4+ NKT cells expressing aninvariant 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 mucusoverproductionand eosinophilia

Anti-chemokinereceptors:CCR3, CCR4,CCR8 on Th2cells.

Anti-RANTES or-eotaxin abs topreventrecruitment of

eosinophils

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 orhouse dust mites in the upper respiratory tract - mucosaledema, mucus secretion, coughing, sneezing, difficult in

breathing - also associated with allergic conjunctivitis. Someevidence that asthma can develop in patients who haveallergic rhinitis. Treatment - antihistamines

Gastrointestinal tract

Result from release of mediators from intestinal mucosal andsubmucosal mast cells following sensitization through theg.I. route of exposure - enhanced peristalsis, increased fluidsecretion from intestinal cells, vomiting, and diarrhea. Thisis not the same as an anaphylactic response. Reactionsusually begin in childhood - often remit in late childhood or inadulthod.

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 hayfeverLancet I, 1572-1573 (1911)

i i i ll ifi h


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Desensitization/Allergen-Specific Immunotherapy

Subcutaneous or sublingual administration


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Peanut Fl our May Ease Peanut

Al l er gyfrom WebMD a health information Web site for patients

February 24, 2009. Eating a tiny bit of peanut flour

every day may increase peanut tolerance in childrenwho are allergic to peanuts, a new study shows.

Each child went home with instructions to eat 5 mgof 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 antigenspresent on cell surfaces or the extracellularmatrix (type IIA) or abs withagonistic/antagonistic properties (type IIB).

Mechanisms of damage: Opsonization and complement- and Fc receptor-

mediated phagocytosis

Complement- and Fc receptor-mediatedinflammation

Antibody-mediated cellular dysfunction


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Kumar et al. Robbins and Cotran Pathologic Basis of Disease

Examples: autoimmune hemolytic anemia, autoimmunethrombocytopenic purpura


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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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Examples: Graves disease (hyperthyroidism), myastheniagravis


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Non-autoimmune type IIreactions

Transfusion reactions (ABOincompatibility

Hemolytic disease of the newborn

(erythroblastosis fetalis)


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Type III hypersensitivity (immune complex


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Type III hypersensitivity (immune complexdisease)

Mechanisms of

Ab deposit ion

Effector mechanisms

of tissue injury

Abbas and Lichtman, Cellular and Molecular Immunology (5th edition). Elsevier 2003.

Serum sickness - a transient immune complex-


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pmediated syndrome

Arthus reaction


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Arthus reaction

Peaks @ 4-8 hoursVisible edemaSeverehemorrhageCan be followed by

ulceration


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Formation of circulating immune

complexes contributes to thepathogenesis 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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Balkwill & Rolph, Germ Zappers, Cold Spring Harbor Laboratory Press, 2001


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Balkwill & Rolph, Germ Zappers, Cold Spring Harbor Laboratory Press, 2001

Type IV hypersensitivity (DTH)


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Type IV hypersensitivity (DTH)

Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005

(Th1)

IFN-, LT, IL-2, IL-3, GM-CSF, MIF

IL-8, MCP-1


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A t i di di t d


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Autoimmune diseases mediated

by direct cellular damage

Top - Goldsby et al, Figure 20-1- Hashimotos thyroiditis

Bottom - Goldsby et al, Figure 20-3 - Type I diabetes


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Clinical and patch test appearances of contact


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hypersensitivity

Roitt 24.2

Tuberculin-type hypersensitivity reaction


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Roitt 24.8

DTH in the skin


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DTH in the skin



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Uses of tuberculin-type reactions

Demonstration of past infection with amicroorganism.

Assessment of cell-mediated immunity.


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APC/IL-12

CD4+Th1 (IL-2)/IFN-

Monocytes

The importance of TNF- in the formation ofl


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granulomas

Roitt 24.17

Diseases associated with granuloma


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Diseases associated with granuloma

formation:

Leprosy Tuberculosis

Schistosomiasis Sarcoidosis

Crohns disease


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Saunders and Britton. Immunol. Cell Biol. 85: 103-111, 2007.

Chemokine expressionin tissues from


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ssues o

M. tuberculosis-infectedindividuals

Saunders & Britton. Immunol. Cell Bioll. 85:103-111, 2007

Tuberculosis


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Roitt 24.23

Sarcoidosis (lymph node)


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Roitt 24.25


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Skin Reactions

Roitt 23.9

Immediate Arthus DTH

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Hyper Sensitivities 09