Allergy: An Overview - unimi.itusers.unimi.it/minucci/Molecular Immunology Module2017-18/1718... · Allergy: An Overview Type of hypersensitivity reactions of the immune system. Allergy

Allergy: An Overview

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

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.

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.

The Hygiene Hypothesis

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.

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

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

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.

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.

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.

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

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.

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 antigen-

antibody 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.

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

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