Al ergy: An Overview

Transcription

1 Allergy: An Overview

2 Allergy 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

3 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.

4 Allergens Allergens are nonparasite antigens that can stimulate an hypersensitivity response. Allergens bind to IgE and trigger degranulation of chemical mediators. Characteristics of allergens Small 15-40,000 MW proteins. Specific protein components Often enzymes. Low dose of allergen Mucosal exposure. Most allergens promote a Th2 immune.

5 The Hygiene Hypothesis Epidemiologists began to notice differences between the immune systems of city kids and farm kids. Farm kids were less likely to have allergies. David Strachan, an epidemiologist at St. George s University of London, hypothesize that bacteria were the key to proper develop our immune system.

6 Hypersensitivity 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.

7 Classification of Immunologic Reactions (Gell and Coombs)

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9 Hypersensitivity Reactions

10 Allergy Allergy Ig E mediated (Type I hypersensitivity) Non Ig E mediated

11 IgE Mediated: Type I 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.

12 Atopy 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.

13 Genes Identified to date in Atopy

14 Common allergens associated with type I hypersenstivity 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

15 Mechanism 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.

16 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

17 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.

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22 Mast Cell 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.

23 Mast Cell Activation

24 Mast cell Minutes Classic Allergic Reaction Flushing Hypotension Increased mucus production Pruritus Smooth muscle contraction Vascular leakage Hours Late phase Reaction Eosinophil infiltration Neutrophil infiltration Fibrin deposition Mononuclear infiltration Tissue destruction

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26 Fc Receptor structure

27 Signal transduction pathway mediated by Antigen binding to IgE

28 Performed Mediators/ Primary Mediators 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.

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

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31 Important Clinical Aspects of Immediate Hypersensitivity Main organ Disease Main symptoms Lung Asthma Wheezing, dyspnea, tachypnea Nose and Eyes Skin Intestinal tract Rhinitis, conjunctivitis Hay fever Eczema (atopic dermatitis) Urticaria Allergic gastroenteropathy Runny nose, redness and itching of eyes Pruritic, vesicular lesions Pruritic, bullous lesions Vomiting diarrhea Systemic Anaphylaxis Shock, hypotension, wheezing Typical allergens Pollens, house dust, animal danders Pollens Uncertain Various foods Drugs Various food Insect venom;bee Drugs; penicillin Foods; Peanuts Route of entery Inhalation Contact with mucous membrane Uncertain Ingestion Various Ingestion Sting Various Ingestion

32 Type II Hypersensitivity If plasma cells start producing antibodies that are errantly directed against circulating cells such as RBCs or platelets, these circulating cells can be opsonized. This opsonization targets the cells for destruction by neutrophils and macrophages, eliminating them in the spleen.

33 Type II Hypersensitivity An inflammatory response begins when antibodies bound to cells or tissues activate complement. From here, products of complement activate macrophages and neutrophils. Once activated, these cells release pro-inflammatory mediators, lysosomal enzymes and reactive oxygen species, causing inflammation and leading to cell lysis. In addition, antibodies that are bound to antigens can directly bind the Fc receptors of neutrophils and monocytes, activating these cells.

34 Type II Hypersensitivity Antibodies may also cause functional derangements in a variety of different systems. Auto-antibodies may act as agonists or competitive antagonists of a variety of different receptor types. This can be disastrous, particularly if the receptor being stimulated is involved in endocrine or neuromuscular signaling. This kind of derangement may happen with or without inflammation.

35 Allergic Hypersensitivity: Non IgE Mediated 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.

36 Type III Hypersensitivity Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. The pathologic reaction is usually initiated when antigen combines with antibody in the circulation, creating immune complexes that typically deposit in vessel walls. Less frequently, the complexes may be formed at sites where antigen has been planted previously (called in situ immune complexes). The antigens that form immune complexes may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or endogenous, if the individual produces antibody against self antigens (autoimmunity). Immune complex mediated diseases tend be systemic, but often preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis), all of which are common sites of immune complex deposition.

37 Phases of type III HS reactions Formation of immune complexes. Autoantibodies form antigen-antibody complexes. Deposition of immune complexes. In the next phase the circulating antigenantibody complexes are deposited in various tissues. The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but the major influences seem to be the characteristics of the complexes and local vascular alterations. In general, complexes that are of medium size, formed in slight antigen excess, are the most pathogenic. Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and tend to deposit; hence, immune complex disease often affects glomeruli and joints. Inflammation and tissue injury. Once immune complexes are deposited in the tissues, they initiate an acute inflammatory reaction. During this phase (approximately 10 days after antigen administration), clinical features such as fever, urticaria, joint pains (arthralgias), lymph node enlargement, and proteinuria appear. Wherever complexes deposit the tissue damage is similar. The mechanisms of inflammation and injury were discussed above, in the discussion of antibody-mediated injury. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.

38 Immune complex disease. The sequential phases in the induction of systemic immune complex mediated diseases (type III hypersensitivity).

39 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, Antigenpresenting cell.

40 Laboratory Diagnosis IgE-Mediated Allergies Skin Tests Blood Tests

41 Skin Tests 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

42 Laboratory 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.

43 Nasal smear/ Spirometry Nasal smear Elevated eosinophil levels can be consistent with allergic rhinitis. Spirometry or pulmonary function tests offer an objective means of assessingasthma. Peakflow meters can also be used for this and can be used by patients at home to monitor their status

44 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.

45 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.

46 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

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