Hypersensitivity

Question 1

Type I Hypersensitivity

Answer 1

• 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

Question 2

Common source of allergens

Answer 2

• 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

Question 3

Type I- Initial Sensitization

Answer 3

• 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

Question 4

Subsequent Exposures

Answer 4

• 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

Question 5

Effects of Mast Cell Mediators

Answer 5

• 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

Question 6

Mast cell granules

Answer 6

• 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

Question 7

Mediators lead to influx of inflammatory cells

Answer 7

• 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

Question 8

Eosinophil and parasites

Answer 8

• 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

Question 9

Response to Subcutaneous Allergen

Answer 9

• 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)

Question 10

Response to Inhaled Antigen

Answer 10

• 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

Question 11

Allergic Asthma

Answer 11

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

Question 12

Cellular Infiltrate and Inflammation in Chronic Asthma Leads to Tissue Remodeling

Answer 12

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

Question 13

Reactions to Adsorbed Allergen-Food Allergies

Answer 13

• 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

Question 14

Responses to Systemic Allergen- Systemic Anaphylaxis

Answer 14

• 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)

Question 15

Genetic predisposition

Answer 15

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

Question 16

Hypersensitivity in Developed Countries

Answer 16

• 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

Question 17

Treatment for Type I

Answer 17

• 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

Question 18

Type II, III, and IV Hypersensitivity

Answer 18

• 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

Question 19

Type II Hypersensitivity

Answer 19

• 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

Question 20

Type III Hypersensitivity

Answer 20

• 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

Question 21

Arthus Reaction

Answer 21

• 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

Question 22

Serum Sickness

Answer 22

• 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

Question 23

Type IV Hypersensitivity

Answer 23

• 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

Question 24

Delayed-type hypersensitivity

Answer 24

• 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

Question 25

Contact hypersensitivity

Answer 25

• 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

Question 26

Celiac Disease

Answer 26

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

Question 27

Th1 T cells and IV hypersensitivity

Answer 27

• 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

Question 28

Treatments of Type II, III, IV

Answer 28

• 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