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PATHOPHYSIOLOGIC FEATURES OF ALLERGIC CONDITIONS. Lecture from pathological physiology October 21, 2004. Immunopathologic reactions. Kuby et al., 2000. Definition of basic conceptions. Hypersensitivity
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PATHOPHYSIOLOGIC FEATURES OF ALLERGIC CONDITIONS Lecture from obsessive physiology October 21, 2004

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Immunopathologic responses Kuby et al., 2000

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Definition of fundamental originations Hypersensitivity A response to something in nature which most uncovered people endure. The components can be immunological (e. g. hypersensitivity) or other (i. e. non-unfavorably susceptible excessive touchiness) Although the word extreme touchiness infers an expanded reaction , the reaction is not generally elevated but rather may, rather, be an improper invulnerable reaction to an antigen.

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Atopy – a genetic inclination to the improvement of quick excessive touchiness responses against regular ecological antigens with propensity to create IgE antibodies to greatly little measures of actually occuring allergens. The anomalous IgE reaction of atopic people is in any event part hereditary – it regularly keeps running in families. Atopic people have unusually large amounts of circling IgE furthermore more than typical quantities of coursing eosinophils . These people are more vulnerable to hypersensitivities, for example, roughage fever , skin inflammation and asthma .

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Allergy – is a response of excessive touchiness interceded by immunologic instruments Allergic responses may create throughout either humoral or cell-intervened reaction Allergen alludes particularly to nonparasitic antigen equipped for fortifying sort I overly sensitive reactions in unfavorably susceptible people.

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Allergy because of IgE antibodies - I. kind of excessive touchiness - in subjects with atopy - AB, rhinitis, urticaria, sustenance hypersensitivities, creepy crawly sensitivities, hypersensitivity… . Sensitivity because of non-IgE components - III. sort of excessive touchiness - hypersensitivity interceded by invulnerable edifices - serum disorder Allergy because of cells - IV. sort of excessive touchiness, - unfavorably susceptible contact dermatitis - non-IgE related atopic dermatitis

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Allergic maladies - today Allergic illnesses go under one gathering of multifactorial (civilisation) ailments „Allergy" – from Greek („allos ergeia") = adjusted response's capacity (von Pirquet,1906) „anaphylaxis" – from Egypt 2140 b.c. Asthma - this term was utilized as a part of Homer's Illiada - Hippocrates, Galen Rhinitis – this term is known from 1533

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Development of hypersensitivity amid life Allergic ailments result from the relationship of a genotype (inalienable, genetic) and gained variables identified with the earth and way of life. They rely on upon the power of allergenic contact and immunologic reactivity (IgE discharge): Genetic powerlessness Allergen sensitisation Trigger elements

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GENETIC PREDISPOSITION A solitary „allergy chromosome" is not thought to exist, rather, the hereditary qualities of hypersensitivity are polygenic and impact different parts of the ailments, for example, IgE emission, cytokine communication and receptors. Prasad M, Chest 1997 Bomprezi et al. 2003

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Potential danger elements for unfavorably susceptible ailment A family history of hypersensitive infection is a solid danger component with a proclaimed organ or sickness specifity This innate tendence to create AB, AR or AD was named „atopy" by Coca in 1923 Polygenic legacy designs have been affirmed by improvements in sub-atomic hereditary qualities, specifically human genome mapping Špičák et al. 2004

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Genetic inclination for unfavorably susceptible malady

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Environmental components Environmental elements adjust the probability that hypersensitive illnesses will create in inclined invididuals. These variables incorporate… Some natural components can likewise worsen ailment , these are additionally called hastening elements (triggers) - allergens, exercise, cool air, drugs, aggravation gasses, climate changes and amazing enthusiastic expression.

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Th1/Th2 equalization in utero a po narození BIRTH Remodeling forms Amplification of insusceptible reaction Th-2 reaction Airway aggravation Th2-reaction Shift of invulnerable reaction Th-1 reaction No hypersensitive side effects CHILDHOOD Just et al. 2002

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Bousquet et al. 2002

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General system fundamental a sort I touchy response Exposure to allergen initiates B cells to frame IgE-emitting plasma cells. The emitted IgE particles tie to IgE-particular Fc receptors on pole cells and blood basophils. Second presentation to the allergen prompts crosslinking of the bound IgE, setting off the arrival of pharmacologically dynamic middle people, amines from these phones. They cause smooth muscle withdrawal, vasodilatation … .

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The early and late incendiary reaction in unfavorably susceptible ailment (asthma)

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The focal part of Th cells in pathophysiology of hypersensitive maladies Bousquet et al. 2002

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Th2 worldview in atopic infections Once into the life form, the allergen triggers a Th2 initiation. This actuation prompts IgE creation by B cells and to the early period of unfavorably susceptible reaction by means of the arrival of vaso-and broncho-dynamic go betweens by mastocytes and other effector cells. In parallel, IL-5 actuates eosinophils, prompting the late stage response and if allergen presentation is delayed, to the unending malady, by means of the creation of MBP and ECP. El Biaze et al. 2003

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Th1 Catch 22 in atopic illnesses The Th2 actuation is significant for the origin of atopy . Another sort of irritation, in which Th1 cells are available , is important to impel the improvement of the infection and in patients, the activating of indications . El Biaze et al. 2003

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Natural history from atopy to asthma (theory) The insusceptible framework is skewed during childbirth to a Th2 initiation, in as muchas hereditary components inclining to atopy are available. Atopy creates in light of allergens if there should be an occurrence of early microbial evasion, as indicated by cleanliness theory. Later, allergen presentation dependably animates the Th2 initiation, yet bronchial hyperreactivity and asthma are related to Th1 actuation. When asthma is available, manifestations are activated amid microbial presentation through an extra Th1 enactment. El Biaze et al. 2003

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Mast cell The pole cell assumes a focal part in starting both the early-stage asthmatic reaction, which results in bronchospasm, and the late-stage reaction, which results in irritation and hyperresponsiveness and some incessant irreversible changes.

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Mast cells enactment and degranulation

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Mast cell-go betweens Preformed (from granules) go betweens: - histamine, heparin, chymase, tryptase, proteases, eosinophil, chemotactic element and neutrophil chemotactic consider Newly created (lipid inferred) arbiters: - leukotrienes, prostaglandins, PAF, bradykinin and different cytokines: * TNF-alfa (actuation of fagocytes) * TGF-beta (fibrotisation) * IL-5 (incitement of the generation of eosinophils) * IL-6 (e.g. incitement of the generation Ig, incl. IgE)

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Biologic impacts of histamine H1 receptors: Bronchoconstriction, vasodilatation Increased vascular penetrability Increased bronchial bodily fluid discharge chemotactic element for eosinophils and neutrophils H2 receptors: Increased creation of HCl H3 receptors: particularly in CNS Špičák et al. 2004

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The optional middle people of pole cells Prostaglandins: - PGD2 : vasodilation, expanded vascular porousness, withdrawal of aspiratory smooth muscles, actuation of eosinophils, chemotaxis Leukotrienes: - LTC4, LTD4, LTE4 (SRS-An): Increased vascular penetrability, constriction of pneumonic smooth muscles - LTB4: chemotaxis of granulocytes PAF (platelet-initiating element): – key chemotactic component

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Basophils are granulocytes that circle in the blood of most vertebrates, in people, they represent 0,5-1,0% of the coursing white platelets. Their granulated cytoplasm stains with essential colors, thus the name basophil. They discharge pharmacologically dynamic substances from their cytoplasmatic granules. These substances assume a noteworthy part in certain unfavorably susceptible reactions.

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Eosinophils IL-5 is a fundamental variable for their differenciation LTB4, IL16, eotaxin (from T-cells and pole cells) are chemotactic elements for eosinophils They deliver a few - proinflammatory go betweens (essential peptides, TNF, PG, LT, cytokines) - receptive O2 metabolites - compounds (for instance elastase, colagenase… )

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The part of epithelial cells in unfavorably susceptible irritation Krejsek et al. 2004

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Innervation of human aviation route smooth muscle

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Clinical indication: Anaphylaxis An extreme, regularly life-undermining, systemic unfavorably susceptible response may variably include the skin, the GIT, the respiratory tract and the cardiovascular framework Allergic x Non-hypersensitive IgE non-IgE Etiopathogenesis: - drugs, - nourishment, - venom - latex, Krejsek et al. 2004

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Allergic rhinitis The most widely recognized atopic issue, influencing 10-20% of populaces is unfavorably susceptible rhinitis, usually known as feed fever - This outcomes from the response of airborne allergens with sharpened pole cells in the conjunctivae and nasal mucosa to affect the arrival of pharmacologically dynamic go betweens from pole cells ; these go betweens then cause confined vasodilation and expanded slim penetrability The manifestations incorporate watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as wll as sniffling and hacking - In 5