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Flashcards in Hypersensitivity Deck (28)

Type I Hypersensitivity

-immediate hypersensitivity
-mediated by IgE
-commonly called allergies or atopic disorders
-atopic individuals are 10-40% of the population are genetically susceptible and generally have higher levels of IgE and eosinophils
-clinical manifestations (anaphylactic reactions) depend on the route of entry of the antigen (allergen) and the location of the responding cells


Common source of allergens

-inhaled- plant pollens, dander, mold spores, feces of dust mites
-injected- insect venoms, vaccines
-ingested materials- food, orally administered drugs
-contacted materials- plant leaves, synthetic chemicals, metals
-many are relatively low molecular weight, highly soluble and stable proteins that are carried on particles
-contain peptides that can be presented by MHC II
-effective at activating Th2- type cytokines especially IL-4, and stimulating an IgE response


Type I- Initial Sensitization

-first exposure to allergen
-antigen activation of TH2 cells and stimulation of IgE class switching in B cells
-production of IgE
-binding of IgE to FCERI on mast cells

other mechanisms of mast cell degranulation:
-IgG cross-linking (IgE KO still develop antigen-induced degranulation)
-C5a binds to complement receptors


Subsequent Exposures

-allergen leads to mast cell degranulation
-repeated exposure to allergen
-activation of mast cell: release of mediators
-vasoactive amines, lipid mediators- immediate hypersensitivty reaction (minutes after repeated exposure to allergen)- wheal (swelling from leakage-histamine effect) and flare (engorged with RBCs)
-cytokines- late-phase reaction (2-4 hours after repeated exposure to allergen)- more widespread swelling inflammation


Effects of Mast Cell Mediators

-SRS-A (Slow releasing substance of anaphylaxis)- mixture of leukotrienes produced during response
-Serotonin-affects vascular permeability
-TNF stimulates expression of adhesion molecules on endothelial cells


Mast cell granules

-enzymes like trypase, which contribute to tissue remodeling
-toxic mediators like histamine, which increase vascular permeability and causes smooth muscle contractions
-cytokines especially TNF alpha, which promotes inflammation and stimulates other cytokine production
-chemokines like CCL3, which promotes influx of monocytes, macrophages and neutrophils
-lipid activators like leukotrienes, which cause smooth muscle contraction, increase vascular permeability and are involved in smooth muscle contraction


Mediators lead to influx of inflammatory cells

-basophils- blood granulocytes with structural and functional properties similar to mast cells
-eosinophils- bone-marrow derived granulocytes found in the inflammatory infiltrates of late phase reactions
-reciprocally regulated- TGFB, IL-3 lead to increased basophils and decreased eosinophils, which are stimulated by IL-5 and GM-CSF
-usually low levels unless activated and must be activated to express IgE FcR


Eosinophil and parasites

-granulocyte response promotes expulsion of parasites by increased peristalsis and mucus
-major basic protein- killing of parasites and host cells
-enzymes like eosinophil peroxidase- tissue remodeling


Response to Subcutaneous Allergen

-like insect saliva
-subcutaneous antigen, low dose
-mast-cell activation
-increased vascular permeability leads to localized swelling
-localized swelling- urticaria (hives); deeper, more diffuse swelling is angiodema. Also eczema
-mechanism in skin-testing for allergies (RAST assay for allergen-specific IgE)


Response to Inhaled Antigen

-allergic rhinitis
-first exposure to pollen
-extraction of antigen
-activation of antigen-specific T cells
-protuction of IgE and binding to mast cells
-peptides derived from pollen grains are presented by APCs to activate antigen-specific T cells, which secrete IL-4 resulting in isotype switch to IgE
-if eyes affected- allergic conjunctivitis
-inhaled antigen enter mucosa and activates mucosal mast cells locally
-mast-cell activation causes blood-vessel permeability and activation of epithelium
-eosinophils are recruited from blood and enter nasal passages with mucus


Allergic Asthma

-mucosal mast cell captures antigen
-inflammatory mediators contact smooth muscle, increase mucus secretion from airway epithelium, and increase blood vessel permeability
-chronic response mediated by cytokines and eosinophil products
-TH2 cells that produce IL-13
-chronic asthma can occur in the absence of allergen-persons with chronic asthma are hyper-responsive to other irritants in the air such as cigarette smoke


Cellular Infiltrate and Inflammation in Chronic Asthma Leads to Tissue Remodeling

-left occlusion of the airway of patient with chronic asthma by mucus plug (MP); right-inflammatory cell infilitrate and epithelium injury (L=lumen)


Reactions to Adsorbed Allergen-Food Allergies

-ingestion of antigen activates mucosal mast cells
-activated mast cells release histamine which acts on epithelium, blood vessels, and smooth muscle
-antigen diffuses into blood vessels and is widely disseminated causing urticaria. Smooth muscle contraction induces vomiting and diarrhea. Fluid outfloq into gut lumen
-common: milk,eggs, shellfish, fruit, nuts, legumes, grains, fish


Responses to Systemic Allergen- Systemic Anaphylaxis

-most severe form of a Type I reaction-antigens include drugs, serum, venom peanuts
-antigen in bloodstream enters tissues and activates connective tissue mast cells throughout the body
-mast cell degranulation and release of inflammatory mediators
-heart and vascular system: increased capillary premeability and entry of fluid into tissues, swelling of tissues including tongue, loss of blood pressure, reduced oxygen to tissues, irregular heartbeat, Anaphylactic shock
-respiratory- contraction of smooth muscle and constriction of throat and airways, difficulty in swallowing, difficulty in breathing, wheezing
-GI tract- contraction of smooth muscle, stomach cramps, vomiting, fluid outflow into gut, diarrhea
-treated with epinephrine (promotes the formation of tight junctions, relaxes bronchial smooth muscle, stimulates the heart)


Genetic predisposition

-genes that contribute include MHC and non-MHC (TcR, IL-4, IL-4 receptor, IgE receptor


Hypersensitivity in Developed Countries

-likely due to more vigilant hygiene and low parasite burden-IgE originally directed against parasites
-Hygiene hypothesis- poorer hygiene results in exposure to Th-1 inducing infections which protect against allergy
-but little allergy seen in worm infections that drive th-2?
-counter regulation hypothesis- infections lead to production of IL-10 and TGF-B which downregulate both Th1 and Th2 responses, so less hypersensitivity


Treatment for Type I

-avoid the allergen
-treat symptoms with antihistamines, corticosteroids, cromolyn sodium, montelukast (singulair), epinephrine, theophylline, albuterol
-desensitization- controlled exposure to increased dose of antigen over time leads to IgA and IgG antibodies which block binding of allergens to IgE on mast cells
-omalizumab- humanized anti-IgE
-block effector mechanisms of allergic response- eg anti-cytokines


Type II, III, and IV Hypersensitivity

-may occur in response to foreign antigen
-also when an individual's immune system reacts against autologous (self) or modulated self-antigens -> autoimmunity
-impacted by genetic susceptibility and environmental factors


Type II Hypersensitivity

-mediated by IgG
-antibodies bind to a cell-associated antigen or cell surface receptor and fix complement
-drug induced-drug binds to the surfaces of RBCs creating new epitopes. Lysis of RBCs- hemolytic anemia
-lysis of platelets- thrombocytopenia
-significant in ABO transfusion reactions
-Grave's disease, Hashimoto's thyroiditis, and insulin resistant diabetes


Type III Hypersensitivity

-large quantities of soluble antigens and their antibodies develop and form large latticed immune complexes
-isotype, valency, charge, and ability to fix complement determine IC pathogenicity
-latticed immune complexes are pathologically capable of depositing systemically in any of a variety of tissue sites, creating downstream cellular damage with many different clinical presentations
-IV- vasculitis, nephritis, arthritis; subcutaneous- arthus reaction; inhaled- Farmer's lung
-serum sickness, IgA nephrology, Lupus nephritis
-post strep glomerulonephritis


Arthus Reaction

-locally injected antigen in immune individual with IgG antibody
-local immune-complex formation activates complement. C5a binds to C5a receptor on mast cell
-binding of immune complex to FcyRIII on mast cell induces
-local inflammation, increased fluid and protein release, phagocytosis, and blood vessel occlusion
-PMNs attracted to site produce lysosomal enzymes, causing tissue damage
-Clinical- tetanus booster <5 years


Serum Sickness

-occurs after the development of antibody to antigen, about 7-10 days
-may occur after large amounts of foreign protein such as antisera for snake bite, mouse antibodies as therapeutics, streptokinase


Type IV Hypersensitivity

-reactions are mediated by antigen specific effector TH1 cells, which initiate inflammatory reactions via the production of cytokines in response to antigen
-occurs over 1-3 days
-require 100-1000 times more antigen than an antibody-mediated hypersensitivity
-reactions: delayed time hypersensitivity, contact hypersensitivity, celiac disease


Delayed-type hypersensitivity

-insect venom, mycobacterial proteins (tuberculin, lepromin)
-localized swelling: erythema, induration, cellular infiltarte, dermatitis
-antigen is introduced into subcutaneous tissue and processed by local APCs
-a TH1 effector cell recognizes antigen and releases cytokines which act as vascular endothelium
-recrutiment of T cells, phagocytes, fluid, and protein to site of antigen injection causes visible lesion


Contact hypersensitivity

-Haptens: Pentadecacatechol (poison ivy), DNFB
-small metal ions: nickel, chromate
-local epidermal reaction: erythema, cellular infilitrate, vesicles, intraepidermal abscesses
-CD4+ T cells activate other immune cells white CD8+ T cells kill chemical-reacted cells that display foreign antigen


Celiac Disease

-Gluten-sensitive enteropathy
-gliadin antigen
-villous atrophy in small bowel, malabsorption


Th1 T cells and IV hypersensitivity

-antigen is processed by tissue macrophages and stimulates TH1 cels
-chemokines- macrophage recruitment to site of antigen
-IFN-gamma- activates macrophages, increasing release of inflammatory mediators
-TNF-alpha and Lymphotoxin (TNF-beta): local tisue destruction, increased expression of adhesion molecules on local blood vessels
-IL-3/GM-CSF- monocyte production by bone marrow stem cells


Treatments of Type II, III, IV

-avoid the antigen
-reduce the impact of the immune response to the antigen with anti-inflammatories, steroids
-reduce the immune response in general (steroids, cytoxan) or specifically (targeting pathogenic T and B cells)
-induce regulation of the response- Treg (peptide vaccination)
-block the effector mechanisms of allergic response- cytokines, co-stimulatory molecules