Immune Basis of Allergic Diseases PDF

IMMUNE BASIS OF ALLERGIC DISEASES Prof. dr Ilija Jeftic INTEGRATED ACADEMIC STUDIES OF PHARMACY Hypersensitivity reactions pathological immune reactions - excessive or inappropriate immune response the basic characteristic of hypersensitivity reactions is that they do n...

IMMUNE BASIS OF ALLERGIC DISEASES Prof. dr Ilija Jeftic INTEGRATED ACADEMIC STUDIES OF PHARMACY Hypersensitivity reactions pathological immune reactions - excessive or inappropriate immune response the basic characteristic of hypersensitivity reactions is that they do not correspond to the causative agent that caused them by the type of cells and molecules involved in pathogenesis, or by intensity (hypersensitivity reactions) can occur in two cases: - the immune response to foreign antigens can be impaired (qualitatively inadequate) or uncontrolled (quantitatively altered), resulting in tissue damage - the immune response can be directed towards one's own antigens - autoimmunity Hypersensitivity reactions According to the time required for the reaction to occur from contact with the antigen: early and late According to the pathogenesis of immune damage: Type I hypersensitivity (early hypersensitivity, anaphylactic type) Type II hypersensitivity (cytotoxic type) Type III hypersensitivity (immunocomplex type) Type IV hypersensitivity (late type, T cell-mediated hypersensitivity) Hypersensitivity reactions The first type of hypersensitivity is characterized by the creation of allergen-specific antibodies of the IgE class and the binding of these antibodies to the membrane of mast cells and basophilic leukocytes. The second type of hypersensitivity is characterized by the binding of IgG and IgM class antibodies to antigens on the membrane of one's own cells The third type of hypersensitivity develops when the formed immune complexes are deposited and cause the activation of the complement system and the accumulation of neutrophil leukocytes. The fourth type of hypersensitivity is the only form of hypersensitivity that is not mediated by antibodies, but by antigen-specific T cells Type of hypersensitive reactions Type I of hypersensitivity Allergic reactions of type I hypersensitivity are also called anaphylactic reactions (anaphylaxis), in contrast to protective reactions or prophylaxis (prophylaxis) genetic and environmental factors contribute to early hypersensitivity reactions Genetic factors polygenetic heritage familial tendency to the occurrence of type I hypersensitivity reactions is called atopy, and people prone to the occurrence of type I hypersensitivity are called atopies atopic patients react atypically to common allergens by activating Th2 lymphocytes, which results in excessive production of IgE antibodies Etiology – genetic factors Chromosome Gene The potential role of gene products in disease Cytokine group genes IL-4 and IL-13 stimulate the synthesis of IgE, and IL-5 (IL-3, IL-4, IL-5, IL-13, stimulates the proliferation and activation of eosinophils; 5q GM-CSF), CD14 gene, CD14 is a component of the LPS receptor that, interacting β2-adrenergic with TLR4, can influence the balance between Th1 vs. Th2 receptor gene response to antigen; The β2-adrenergic receptor regulates the contraction of bronchial smooth muscles 6p MHC class II gene Some alleles regulates T cell response to allergens. 11q β chain FcεRI It participates in the activation of mast cells 16 IL-4 receptor α chain Receptor subunit for both IL-4 and IL-13 gene 20p ADAM33 A metalloproteinase involved in airway remodeling 2q DPP10 Peptidases that can regulate the action of chemokines and cytokines Etiology – environment factors ALLERGENS are antigens that cause allergic reactions in genetically predisposed individuals Characteristics of allergens: proteins and glycoproteins enzymatic activity very soluble stable low molecular weight low concentrations in the environment Allergens The most common allergens are: pollen mites dance pet hair drugs insect products nutritional allergens (peanuts, nuts, milk, eggs, soy, fish, seafood, sesame...) I type hypersensitive reactions - pathogenesis - during the first contact with an allergen, a specific clone of B lymphocytes is activated, which begins the synthesis of IgE class antibodies the production of IgE antibodies depends on the activation of T lymphocytes specific for allergen epitopes one part of the synthesized IgE antibodies immediately binds to high-affinity receptors on the mast cell membrane (FcεRI), while the other part in circulation binds to identical receptors on basophilic leukocytes I type hypersensitive reactions - pathogenesis - upon re-exsposure (another contact), the allergen binds to antibodies on the membrane of mast cells and basophilic leukocytes and occurs: - degranulation of previously formed mediators from granules - activation of enzymes that synthesize lipid mediators (cyclooxygenase and lipoxygenase) and - transcription, translation and secretion of cytokines The role of IgE antibodies in early hypersensitivity FcεRI receptor on the membrane of mast cells and basophils activation of mast cells with degranulation of previously formed and synthesis of new mediators begins after binding of allergens to IgE antibodies on the mast cell membrane The role of IgE antibodies in early hypersensitivity during the first contact with the allergen, IgE binds (CH3 domain) to high-affinity receptors on the mast cell membrane (FcεRI) the amount of IgE in the serum is very small, it is found in traces (0.0003 mg/ml) The role of IgE antibodies in early hypersensitivity upon re-contact, there is bridging of IgE antibodies attached to the mast cell membrane and the process of degranulation anaphylactoid reaction: basically has a direct stimulation of mast cell degranulation (iodine contrast agents, local anesthetics, dextran, lectins-phytohemagglutinin, concavalin A...) Drug-induced anaphylaxis in the emergency room doi: 10.1002/ams2.282 Type I hypersensitive reactions - pathogenesis - early phase: - it is a consequence of the activation of mast cells and the production of mediators - vasodilatation, increased permeability of blood vessels and spasm of smooth muscles occur late phase: - begins 2-24 hours after contact with the allergen - it is characterized by the accumulation of inflammatory cells (especially eosinophilic leukocytes) and the occurrence of tissue damage  Mediators – type I hypersensitivity The most important mediators are: Arachidonic acid metabolites Histamine Prostaglandins - causes dilation of small blood vessels - that cause vasodilation - increases vascular permeability Leukotrienes - stimulates transient contraction of - that stimulate prolonged contraction of smooth muscles smooth muscles Proteases Cytokines - they damage the surrounding tissue - induce the occurrence of a local inflammatory reaction - stimulate the mobilization of leukocytes (eosinophils, neutrophils and Th2 cells) Mediators Clinically manifestation of type I hypersensitivity one or more clinical forms of this type of hypersensitivity may occur in the same person who has a genetic predisposition to the occurrence of type I hypersensitivity reactions which clinical form of type I hypersensitivity will occur depends on: - the nature of the allergen - ways of allergen entry - the number, localization and characteristics of mast cells and other cells in the target organ - the sensitivity of the target organ to the effect of the mediator Allergic rhinitis allergic rhinitis is clinical manifestation of type I hypersensitivity occurs seasonally (pollen) or throughout the year (house dust, dust mites) allergic rhinitis is a consequence of the activation of mast cells in the nasal mucosa by allergens manifested by increased secretion, sneezing and obstruction of the nasal cavity after exposure to the allergen (key mediators - histamine) Allergic conjunctivitis allergic conjunctivitis is also called seasonal conjunctivitis occurs seasonally (pollen) or throughout the year (house dust, dust mites) allergic conjunctivitis is a consequence of the activation of mast cells in the conjunctiva by allergens it is manifested by increased secretion, redness, irritation and itching, so frequent touching is a risk for eye infection Bronchial asthma Bronchial asthma is a disease characterized by: intermittent and reversible airway obstruction chronic bronchial inflammation by eosinophilic leukocytes as well as a population of CD4+ NKT cells that recognize glycolipid antigens hyperactivity of bronchial smooth muscles to bronchoconstriction stimulation Bronchial asthma- pathogenesis EARLY PHASE: consequence of the release of mediators histamine causes vasodilation prostaglandins lead to bronchoconstriction leukotrienes leads to increased production of mucus LATE PHASE: it is the result of local infiltration by eosinophils, neutrophils and Th2 cells Anaphylaxis systemic form of type I hypersensitivity that occurs due to the presence of allergens in the circulation: - after injection, - insect sting - absorption through epithelial surfaces - may be due to: - anaphylactic reactions - anaphylactoid reactions Urticaria and angioedema Urticaria: is a physical sign, not a disease the term urticaria refers to transient episodes of circumscribed, edematous, and erythematous lesions with raised edges that are accompanied by pruritus it occurs as a result of a sudden, local accumulation of fluid in the skin Angioedema: is a similar process that involves the deeper structures of the dermis, subcutaneous tissue or mucous membranes. Urticaria and angioedema usually coexist Urticaria and angioedema Atopic dermatitis Type I hypersensitivity reaction localized in the skin, which can be acute or chronic acute reactions (acute eczema) are more common they occur after local contact with an allergen on the skin surface after allergen binding to IgE antibodies on the mast cell membrane, histamine is released → vasodilation and increased vascular permeability the effects can be blocked by antihistamines Kazunari Sugita and Cezmi A. Akdis. Allergology International 2020; (69) 204-214 Atopic dermatitis The basis of this skin disease is a biphasic inflammation with an initial Th2 phase, while Th1 lymphocytes dominate in chronic lesions... Atopic dermatitis the diagnosis of atopic dermatitis (eczema) is made based on the clinical picture and on the basis of personal and family history - strong genetic predisposition for the development of atopic eczema is essencial environmental factors also play a significant role: - house mite as a provocative factor, - food intolerance, - Staphylococcus aureus infections exacerbate skin inflammation by releasing toxins that act as super-antigens Type II hypersensitivity lymphocytes are activated by antigens that are expressed on the cell membrane → activated B lymphocytes synthesize antibodies (IgG and/or IgM) that bind to membrane receptors → the effector phase of the response begins (activation of the complement system, phagocytosis, ADCC reaction) Type II hypersensitivity Type II hypersensitivity Type III hypersensitivity diseases caused by immune complexes arise as a result of excessive production of immune complexes, which cannot be removed from the circulation, so they are deposited in the tissues since the complexes are primarily deposited in small arteries, glomeruli and joint synovium, the pathological and clinical manifestations of these diseases are vasculitis, nephritis and arthritis these diseases are usually systemic Type III hypersensitivity antigen-antibody complexes exert their pathogenic effect after deposition in tissues after deposition in tissues, immune complexes trigger numerous effector mechanisms activation of effector mechanisms can cause tissue damage Type III hypersensitivity Type III hypersensitivity SLE Arthus reaction Arthus reaction Type IV hypersensitivity is mediated by T lymphocytes and not antibodies it can occur as a consequence of an autoimmune process or an excessive, persistent response to environmental antigens autoimmune reactions are usually directed against cellular antigens that have limited tissue distribution (usually not systemic) Type IV hypersensitivity reactions: - contact hypersensitivity - tuberculin form (body's response to microorganisms) - granulomatous form (granulomatous inflammation) Type IV hypersensitivity Type IV hypersensitivity in various T cell-mediated diseases tissue damage is caused by inflammation under the influence of cytokines mainly produced by CD4+ T lymphocytes or by killing of host cells by CD8+ cytotoxic T lymphocytes. Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005 Kumar et al. Robbins and Cotran Pathologic Basis of Disease. Elsevier 2005 Contact dermatitis in this form of type IV hypersensitivity, very small molecules, which are not immunogenic in themselves (haptens), pass through the epidermis and form complexes with body proteins after the activation of specific T lymphocytes (sensitization), memory cells are formed during the next contact with the same allergen, memory T lymphocytes are activated with the onset of infiltration and damage THANKS