Informations on exams • II year BMC:

• English or Italian (free choice)

• I year MBC: • Mandatory English

EXAM vote: 1.Journal Club presentation 2.“Open” written exam

1.1 argument free (e-mail) 2.1 argument chosen at the exam

ALLERGY: AN OVERVIEW

Contents

Allergy

Hypersensitivity

Allergy: IgE Mediated: Type I

Immunopathogenesis

Performed Mediators

Food Hypersensitivity

Laboratory Tests

Prevention

Treatment

Type of hypersensitivity reactions of the immune system. Allergy

may involve more than one type of reaction. An allergy is a reaction to something that does not affect most

other people. Substances that often cause reactions are: Pollen Dust mites Mold spores Pet dander Food Insect stings Medicines …….

• Mechanisms of tissue injury are the same as the effector

mechanisms of defense against infectious pathogens • The problem is that these reactions are poorly controlled

Allergy

Risk factor Host factors; heredity, gender, race, and age HLA and non-HLA genes

Environmental factor; infectious diseases during early childhood, environmental pollution, allergen levels and dietary changes.

Allergy

Hypersensitivity (hypersensitivity reaction) refers to

undesirable immune reactions produced by the normal immune system.

Hypersensitivity reactions require a pre-sensitized (immune)

state of the host. Hypersensitivity reactions: four types; based on the

mechanisms involved and time taken for the reaction, a particular clinical condition (disease) may involve more than one type of reaction.

Hypersensitivity

Classification of Immunologic Reactions (Gell and Coombs)

Hypersensitivity Reactions

Allergy

Ig E mediated (Type I hypersensitivity)

Non Ig E mediated

Allergy

Overreaction to an allergen that is contacted through skin,

inhaled through lung, swallowed or injected. Individuals must be previously sensitized

Triggered by harmless substances such as; pollen, dust, animal

danders, food, … can also occur as a result of drug or bee stings or stings from other insects (an allergen).

An allergen; an antigen that causes allergy. Either inhaled,

ingested, .. Can be complete protein antigens (Pollen and animal dander) or low molecular weight proteins.

IgE Mediated: Type I

Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.

Etiology is unknown but there is strong evidence for a

complex of genes with a variable degree of expression encoding protein factors.

Allergic rhinitis, allergic athma, atopic dermatitis are the

most common manifestation of atopy. Allergic gastroenteropathy is rara. These manifestation may coexist in the same patients at different times. Atopy can be asymptomatic.

Atopy

Genes Identified to date in Atopy

Proteins Foreign serum Vaccines Plant pollens Rye grass Ragweed Timothy grass Birch trees Drugs Penicillin Sulfonamides Local anethetics Salicylates

Foods Nuts Seafood Eggs Peas, beans Milk Insect products Bee venom Wasp venom Ant venom Cockroach calyx Dust mites Mold spores Animal hair and dander

Common allergens associated with type I hypersenstivity

While first-time exposure may only produce a mild reaction, repeated exposures may lead to more serious reactions. Once a person is sensitized (has had a previous sensitivity reaction), even a very limited exposure to a very small amount of allergen can trigger a severe reaction. Most occur within seconds or minutes after exposure to the

allergen, but some can occur after several hours, particularly if the allergen causes a reaction after it is partially digested. In very rare cases, reactions develop after 24 hours.

Mechanism

Immunopathogenesis

Both mast cells and basophils are involved in

immunopathogenesis of IgE mediated diseases. Mast cells and basophils have a high affinity IgE cell membrane receptors for IgE. Immediate hypersensitivity reactions are mediated by IgE,

but T and B cells play important roles in the development of these antibodies

Phases of immediate hypersensitivity reactions

Phases of immediate hypersensitivity reactions. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. The immediate reaction (B) is characterized by vasodilation, congestion, and edema, and the late-phase reaction

(C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.

Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate

hypersensitivity

Mast cell are abundant in the mucosa of the

respiratory, gastrointestinal tracts and in the skin, where atopic reaction localize. Mast cell release mediator cause the pathophysiology

of the immediate and late phases of atopic diseases.

Mast Cell

Mast Cell Activation

Mast cell

Classic Allergic Reaction Flushing

Hypotension Increased mucus production

Pruritus Smooth muscle contraction

Vascular leakage

Late –phase Reaction Eosinophil infiltration Neutrophil infiltration

Fibrin deposition Mononuclear infiltration

Tissue destruction

Minutes Hours

Fc Receptor structure

Signal transduction pathway mediated by Antigen binding to IgE

Histamine: is one well-known mediator. This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Serotonin: increased vascular permeability and contraction of smooth Muscles. Tryptase: is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: include heparin and chondroitin sulfate. Chemotactic factors ………………….

Performed Mediators/ Primary Mediators

Performed Mediators/ Secondary Mediators • Platelet activating factor • Leukotriens • Prostaglandinin • Bardykainin • Cytokines • IL1 ,TNF • IL2,IL3,IL4,IL5,L6

http://drainameducci.blogspot.com/2011/08/hypersensitivity.html

Important Clinical Aspects of Immediate Hypersensitivity

Main organ Disease Main symptoms

Typical allergens

Route of entery

Lung Asthma Wheezing, dyspnea,

tachypnea

Pollens, house dust, animal

danders

Inhalation

Nose and Eyes Rhinitis, conjunctivitis Hay fever

Runny nose, redness and

itching of eyes

Pollens Contact with mucous

membrane Skin Eczema (atopic

dermatitis) Urticaria

Pruritic, vesicular lesions

Pruritic, bullous lesions

Uncertain Various foods

Drugs

Uncertain Ingestion Various

Intestinal tract Allergic gastroenteropathy

Vomiting diarrhea

Various food Ingestion

Systemic Anaphylaxis Shock, hypotension,

wheezing

Insect venom;bee Drugs; penicillin Foods; Peanuts

Sting Various

Ingestion

Type II Hypersensitivity

Type II Hypersensitivity

Type II Hypersensitivity

Food Hypersensitivity

Source: http://www.allergycentre.com.my/index.html

Food Hypersensitivity

Source: http://www.allergycentre.com.my/index.html

Immunopathologic responses into the following 7 categories: Inactivation/activation antibody reactions Cytotoxic or cytolytic antibody reactions Immune-complex reactions Allergic reactions T-cell cytotoxic reactions Delayed hypersensitivity reactions Granulomatous reactions This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions . In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reaction. References & more: http://emedicine.medscape.com/article/136217-overview#a0104

References: Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St. Louis, Mo: Mosby-Year Book; 1996:449-77

Immunopathologic Response Classification System Proposed by Sell et al., 1996

Hypersensitivity pneumonitis involves inhalation of

an antigen. This leads to an exaggerated immune response (hypersensitivity). Type III hypersensitivity and type IV hypersensitivity occur in hypersensitivity pneumonitis.

Allergic contact dermatitis.

…

Allergic Hypersensitivity: Non IgE Mediated

Result

Antigen source Mechanism Disease

Disease

Foreign Immunologic Allergy

Prophylaxis

Foreign Immunologic Immunity

Disease

Self Immunologic Autoimmunity

Disease

Foreign Toxic Toxicity

Comparison of Allergy with other Responses

Type IV Hypersensitivity Mechanisms of T cell–mediated (type IV)

hypersensitivity reactions. A, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). B, In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells. APC, Antigen-

presenting cell.

Laboratory Diagnosis

Skin Tests

Blood Tests

IgE-Mediated Allergies

The cutaneous test (prick test, puncture test epicutaneous test) Routine diagnosis in diseases (atopic or anaphylactic). A single drop of concentrated aqueous allergen extract placed

on the skin which is then pricked lightly with a needle point at the center of the drop. After 20 minutes the reaction is graded and recorded

Skin Tests

IgE levels may be elevated in patients who are atopic, but the level does not necessarily correlate with clinical symptoms. The tryptase level can be elevated, which is indicative

of mast cell degranulation. False-negative results can occur. An elevated eosinophil count may be observed in

patients with atopic disease. RAST/CAP RAST/CAP FEIA (fluorenzymeimmunoassay):

measures antigen-specific IgE.

Laboratory Tests

Nasal smear Elevated eosinophil levels can be consistent with

allergic rhinitis. Spirometry or pulmonary function tests offer an objective means of assessingasthma. Peak-

flow meters can also be used for this and can be used by patients at home to monitor their status

Nasal smear/ Spirometry

Standardized diagnostic allergens are not available for drugs

Penicillin is the only drug for which a standardized

diagnostic allergen exists. While nonstandardized skin

tests can be performed for the minor determinants in

penicillin or for other drugs (ie, by pricking the skin where

drug solution has been placed), these tests are only useful if

findings are positive.

Prevention

Avoid triggers such as foods and medications,…… that have caused an allergic reaction, even a mild one. This includes detailed questioning about ingredients when eating away from home. Ingredient labels should also be carefully examined. A medical ID tag should be worn by people who know that they

have serious allergic reaction. If any history of a serious allergic reactions, carry emergency

medications (such as diphenihydramine and injectable epinephrine. Do not use your injectable epinephrine on anyone else. They

may have a condition (such as a heart problem) that could be affected by this drug.

Treatment • Anaphylaxis: epinephrine (vasoconstriction,

bronchospasm resolution), oxygen (intubation sometimes required), anti-histamine, glucocorticoids

• Urticaria: anti-histamine, adrenergic agonists • Allergic rhinitis: anti-histamine, adrenergic agonists,

glucocorticoids, Immunotherapy • Asthma:

• Quick relief: ß-adrenergic agonists to release bronchospams • Long-term control: glucocorticoids

Treatment

Allergic diseases: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: 978-0838563007 ISBN-10: 0838563007 Anaphylaxis and Urticaria: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: 978-0838563007 ISBN-10: 0838563007 Adkinson NF Jr. Middleton’s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa: Mosby; 2003. Rakel RE. Textbook of Family Medicine. 7th ed. Philadelphia, Pa: WB Saunders; 2007. Miriam K Anand, Michael A Kaliner, et al., Advances in Immunology. N Engl. J.Med,. vol. 344, No.1. January4, 2001. Available from. http://emedicine.medscape.com/article/136217-overview#a0104 Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St. Louis, Mo: Mosby-Year Book; 1996:449-77

References &Further Reading

SariSabban. Allergy Pathway. 1September 2011The http://en.wikipedia.org/wiki/File:The_Allergy_Pathway.jpg

Wolfgang Ihloff. Allergy skin.30.1.2008. testing. http://en.wikipedia.org/wiki/File:Allergy_skin_testing.JPG

Mast cell. Http://en.wikipedia.org/wiki/File:Mast_cells.jpg Wenliang Zhang. Universty of Geogorgia. Immunology. The immune system..

http://wenliang.myweb.uga.edu/mystudy/immunology/ScienceOfImmunology/Hypersensitivitydiseases.html

Dr. M. Yadav. Food Hypersensitivity. http://www.allergycentre.com.my/index.html

Image Citation