Hypersensitivity Flashcards
1
Q
Type I Hypersensitivity
A
- 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
2
Q
Common source of allergens
A
- 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
3
Q
Type I- Initial Sensitization
A
- 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
4
Q
Subsequent Exposures
A
- 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
5
Q
Effects of Mast Cell Mediators
A
- 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
6
Q
Mast cell granules
A
- 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
7
Q
Mediators lead to influx of inflammatory cells
A
- 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
8
Q
Eosinophil and parasites
A
- 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
9
Q
Response to Subcutaneous Allergen
A
- 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)
10
Q
Response to Inhaled Antigen
A
- 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
11
Q
Allergic Asthma
A
Acute:
-mucosal mast cell captures antigen
-inflammatory mediators contact smooth muscle, increase mucus secretion from airway epithelium, and increase blood vessel permeability
Chronic:
-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
12
Q
Cellular Infiltrate and Inflammation in Chronic Asthma Leads to Tissue Remodeling
A
-left occlusion of the airway of patient with chronic asthma by mucus plug (MP); right-inflammatory cell infilitrate and epithelium injury (L=lumen)
13
Q
Reactions to Adsorbed Allergen-Food Allergies
A
- 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
14
Q
Responses to Systemic Allergen- Systemic Anaphylaxis
A
- 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)
15
Q
Genetic predisposition
A
-genes that contribute include MHC and non-MHC (TcR, IL-4, IL-4 receptor, IgE receptor
16
Q
Hypersensitivity in Developed Countries
A
- 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
17
Q
Treatment for Type I
A
- 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
18
Q
Type II, III, and IV Hypersensitivity
A
- 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
19
Q
Type II Hypersensitivity
A
- 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
20
Q
Type III Hypersensitivity
A
- 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
21
Q
Arthus Reaction
A
- 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
22
Q
Serum Sickness
A
- 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
23
Q
Type IV Hypersensitivity
A
- 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
24
Q
Delayed-type hypersensitivity
A
- 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
25
Q
Contact hypersensitivity
A
- 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
26
Q
Celiac Disease
A
- Gluten-sensitive enteropathy
- gliadin antigen
- villous atrophy in small bowel, malabsorption
27
Q
Th1 T cells and IV hypersensitivity
A
- 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
28
Q
Treatments of Type II, III, IV
A
- 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
