Disorders of the Immune System

Disorders of the Immune System 1. 2. 3. 4. Hypersensitivity reactions Autoim m une diseases I m m unologic deficiency syndrom es Am yloidosis MECHANISMS OF HYPERSENSITIVITY REACTIONS 1. immediate hypersensitivity (type I hypersensitivity) releases of vasoactive and spasmogenic substances that act on vessels and smooth muscle and proinflammatory cytokines that recruit inflammatory cells. 2. antibody-mediated disorders (type II hypersensitivity) •antibodies directly cause injury of cells by phagocytosis or lysis and injury to tissues by inducing inflammation. • Or Antibodies interfere with cellular functions and cause disease without tissue injury. 3. immune complex-mediated disorders (type III ypersensitivity) •Ab bind Ag , induce inflammation directly or by activating complement. • The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals. 4. • Cell-mediated immune disorders (type IV hypersensitivity) sensitized T lymphocytes are the cause of the cellular and tissue injury. •Sequence of events in immediate hypersensitivity (type 1) : •introduction of an allergen • stimulates TH2 responses and IgE production. • IgE binds to Fc receptors (FcεRI) on mast cells •subsequent exposure to allergen • mast cells activation to secrete the mediators that are responsible for pathologic manifestations of immediate hypersensitivity . •Th2 secrete cytokines: •IL4 : Ab switching •IL5: recruitment of eosinophil •IL 13: secrete mucosa by Epi cells Mast cells origin Bone marrow distribution Tissue near blood vessels and nerves and in subepithelial sites morphology Cytoplasmic membrane-bound granules (contain a variety of biologically active mediators) activation activated by the cross-linking of high-affinity IgE Fc receptors stimulation mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a (anaphylatoxins), both act by binding to their receptors on the mast-cell membrane. •Secration of cytokine (IL-8) from MQ (macrophage-derived cytokines ) •Some drugs :codeine and morphine, adenosine, mellitin (present in bee venom), and physical stimuli ( heat, cold, sunlight). Basophils •similar to mast cells in many respects, •basophils circulate in the blood, not in tissues Mast cell mediators. • Upon activation, mast cells release various classes of mediators •ECF, eosinophil chemotactic factor • NCF, neutrophil chemotactic factor • PAF, platelet-activating factor • Primary Mediators ( mast-cell granules) 1) Biogenic amines. Histamine causes intense smooth muscle contraction, increased vascular permeability, and increased secretion by nasal, bronchial, and gastric glands . 2) Enzymes neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement (C3a) by acting on their precursor proteins. 3) Proteoglycans heparin, anticoagulant, and chondroitin sulfate. The proteoglycans serve to package and store the other mediators in the granules. Secondary Mediators (two classes of compounds (1) lipid mediators and (2) cytokines). Leukotrienes •Leukotrienes C4, and D4: the most potent vasoactive and spasmogenic agents (thousand times more active than histamine) . •Leukotriene B4 highly chemotactic for neutrophils, eosinophils, and Monocytes Prostaglandin D2 •the most abundant mediator derived by the cyclooxygenase pathway in mast cells: causing intense bronchospasm , increased mucus secretion. Platelet-activating factor (PAF) •PAF produced by some mast-cell populations, • causes platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, and vasodilation, pro-inflammatory actions, chemotactic for neutrophils and eosinophils. • it is not a product of arachidonic acid metabolism. Cytokines • Mast cells are sources of many cytokines (TNF, IL-I, IL-3, IL-4, IL5, IL-6, and GM-CSF) •Important in late-phase reaction of immediate hypersensitivity because of their ability to recruit and activate inflammatory cells. Summary of the Action of Mast Cell Mediators in Immediate (Type I) Hypersensitivity Action Vasodilation, increased vascular permeability Smooth muscle spasm Cellular infiltration Mediators Histamine PAF Leukotrienes C4, D4, E4 Neutral proteases that activate complement and kinins Prostaglandin D2 Leukotrienes C4, D4, E4 Histamine Prostaglandins PAF Cytokines (e.g., chemokines, TNF) Leukotriene B4 Eosinophil and neutrophil chemotactic factors (not defined biochemically) PAF, platelet-activating factor; TNF, tumor necrosis factor. Immediate (Type I) Hypersensitivity • • Kinetics of the immediate and late-phase reactions. 1) The immediate vascular and smooth muscle reaction to allergen: minutes after challenge (30-60 min) • 2) the late-phase reaction: 2 - 24 hours later up to days. • Morphology: • B) The immediate reaction: vasodilation, congestion, and edema • C) late phase reaction: infiltration of eosinophils, neutrophils, and T cells. Clinical symptoms Hypersensivity Type 1 Systemic anaphylaxis •vascular shock, • widespread edema, • difficulty in breathing. after administration of foreign proteins (antisera), hormones, enzymes, polysaccharides, and drugs (such as the antibiotic penicillin). •itching, hives, and skin erythema, followed shortly by a striking contraction of respiratory bronchioles and respiratory distress. •Laryngeal edema results in hoarseness. •GI: Vomiting, abdominal cramps, diarrhea •shock , die within the hour. Local Immediate Hypersensitivity Reactions (atopic allergy) •About 10% of the population suffers from allergies involving localized reactions to common environmental allergens ( pollen, Animal dander, house dust, foods, and the like). •Specific diseases include urticaria, angioedema, allergic rhinitis (hay fever), and some forms of asthma. Immediate (Type I) Hypersensitivity • rapidly developing immunologic reaction • minutes after the combination of Ag-Ab in individuals previously sensitized to the antigen (allergy) 1) Systemic disorder (fatal shock ) 2) local reaction depending on the entry of the allergen: • localized cutaneous swellings (skin allergy, hives) • nasal and conjunctival discharge (allergic rhinitis and conjunctivitis) • hay fever • bronchial asthma • allergic gastroenteritis (food allergy) Figure 12-1 Figure 12-11