Lecture 8 - Hypersensitivity

-An exaggerated response to a typically harmless antigen that results in tissue injury, disease, or even death
- 4 groups - classified based on the immunologic mechanism

• Class I (aka anaphylactic hypersensitivity)
• Class II (aka antibody-mediated cytotoxic hypersensitivity)
• Class III (aka immune complex-mediated hypersensitivity)
• Class IV (aka cell-mediated hypersensitivity)

anaphylactic hypersensitivity

antibody-mediated cytotoxic hypersensitivity

immune complex-mediated hypersensitivity

cell-mediated hypersensitivity

• I, II and III are antibody-mediated, and called immediate hypersensitivity reactions (happen within few minutes to a few hours after contact with Ag)
• IV is T cell-mediated and called delayed hypersensitivity reaction (takes 24-48h)

allergies

hay fever, hives, allergic asthma, systemic anaphylaxis

IgE

the inherited tendency to develop classic allergic responses to naturally occurring inhaled or ingested allergens

- IgE
- basophils, mast cells, eosinophils,
- they have receptor for IgE

mast cells

Th1 and Th2 balance is shifted so that Th2 response will predominate

Il-4 and Il-13 - cytokines responsible for B cell differentiation and IgE production

30-60 minutes

1. sensitization
2. activation

--> APC presents allergen to Th2 cells
--> IgE produced by B cells
--> IgE binds FcR1 on mast cells

--> upon IgE binding
--> mast cells will be activated and release their granular contents including:
1. histamine (the most important factor)
2. other substances include heparin
3. Eosinophil chemotactic factor of anaphylaxis (ECF-A)
4. Neutrophil chemotactic factor of anaphylaxis (NCF-A)
5. Proteases (e.g., tryptase, chymase)

• Clinical presentation of allergy depending on the affected organ: skin (wheal-and-flare), lung (asthma), etc.

• 6-8 h after allergen exposure, basophils and mast cells release secondary mediators including platelet-activating factor (PAF); prostaglandin (PG) D2; leukotrienes (LT) B4, C4, D4, and E4; and cytokines. These are more potent than primary (immediate) mediators
• In the late phase, numerous cells, including eosinophils, neutrophils, Th2 cells, mast cells, basophils, and macrophages, infiltrate the allergen-filled tissue. They release additional mediators that prolong hyperactivity and cause further tissue damage

• Pollen
• Mold spores
• Animal dander
• Dust mites
• Insect venom
• Certain foods (peanuts, shellfish, dairy products)
• Certain drugs (penicillin)
• Latex

• Rhinitis (“hay fever”)
• Allergic asthma
• Food allergies
• Skin reactions (Urticaria (“hives”), angioedema, eczema) - Wheal and flare
• Systemic anaphylaxis - A potentially fatal reaction, and associated with IgA-deficient patients

- aka hives
- caused by an immediate hypersensitivity rxn to a medication

- a condition that causes swelling in the deeper layers of the skin due to fluid leaking from small blood vessels
- the example shown here is caused by a yellow jacket sting on the right hand just above the middle finger

• Avoidance of allergens
• Drug therapy
- Antihistamines, bronchodilators, mast cell stabilizers, corticosteroids, epinephrine
• Monoclonal anti-IgE antibody
• Allergy immunotherapy (AIT) - administer gradually, increasing doses of
allergen

- Percutaneous or intradermal
- Process:
-- Apply a panel of allergens to separate sites on the skin.
-- Wait 15 to 20 minutes.
- Positive test = wheal and flare at the site of application

Used to detect IgE to a specific allergen in patient serum

is used to detect the total concentration of IgE in patient serum

- aka antibody-mediated cytotoxic hypersensitivity

- IgG and IgM directed AGAINST a cell surface antigen
- Effects:
• Cell destruction
• Inhibition of cell function
• Increase in cell function

- activation of classical pathway of complement and cell lysis
- opsonization and phagocytosis of the cell
- antibody-dependent cell-mediated cytotoxicity (ADCC)

- transfusion rxns
- hemolytic disease of the newborn (HDN)
- autoimmune hemolytic anemia: warm reactive abs, cold agglutinins, paroxysmal cold hemoglobinuria
- anti-GBM (glomerular basement membrane) disease
- Hashimoto's disease

- pregnant women produces antibodies to Rh antigens (usually RhD) on fetal RBC's
- usually occurs when the female is Rh- and baby is Rh+
- first exposure may be ok with treatment if caught early, but second exposure is fatal
- there are treatments for this

- Direct Antiglobulin Test (DAT)
- Detects RBCs coated with complement components or IgG antibody
- Patient RBCs are incubated with a poly-specific anti-human Ig directed against IgG and C’
- If positive (agglutination), the test is repeated with mono-specific anti-IgG, anti-C3b, and anti-C3d

- Coombs’ test
- Tests patient serum for antibodies to RBC antigens.
- Process
• Incubate reagent RBCs with patient serum at 37C; wash to remove excess.
• Add anti-human globulin.
- Positive test = RBC agglutination

- immune complex-mediated hypersensitivity

- IgG and IgM directed AGAINST a soluble antigen

- Small antigen–antibody complexes precipitate out and deposit in tissues.
- Complement binds; vasodilation and vasopermeability increase.
- Macrophages and neutrophils migrate to the affected areas and release their lysosomal enzymes, resulting in tissue damage.

1. Arthus Reaction
2. Serum Sickness
3. Some autoimmune (SLE and RA)
4. Reactions to bee stings
5. Drug reactions (e.g. penicillin)
6. Sequelae to infections (e.g. post-streptococcal glomerulonephritis)

- Type III skin reaction
- localized inflammation characterized by redness and edema
- peaks at 3-8 hours

- Generalized Type III reaction
- Caused by passive immunization of humans with animal serum
- Produces antibodies against the foreign animal proteins in patients.
- Causes immune complexes to form and deposit in tissues.
- Symptoms: headache, fever, nausea, joint pain, rashes, and lymphadenopathy

• Testing for ANAs
• Fluorescent staining of tissue sections to detect deposited immune complexes
• Testing for rheumatoid factor (an anti-IgG)
• Testing complement levels - may be decreased in the serum during periods of high disease activity.

cell-mediated hypersensitivity

--> APCs present antigen to naïve T helper cells, which differentiate into Th1 cells.
--> Th1 cells release cytokines that attract and activate macrophages.
--> Macrophages induce inflammation.
--> Cytotoxic T lymphocytes are recruited and destroy target cells.
--> Hypersensitivity peaks 48 to 72 hours after antigen exposure

1. Infections with intracellular pathogens
2. Contact dermatitis
3. Hypersensitivity pneumonitis

• Mycobacterium tuberculosis
• Mycobacterium leprae
• Pneumocystis carinii
• Leishmania species
• Herpes simplex virus

- allergic disease of the lungs
- caused by inhalation of bacterial and fungal spores
- example: Farmer's lung disease, bird breeder's lung disease, and humidifier lung disease

- Low-molecular-weight compounds contact the skin and act as haptens to sensitize Th1 cells.
- Examples include poison ivy, poison oak, nickel salts, materials in cosmetics and hair dyes, and latex.
- Skin eruptions with erythema, swelling, and papules are produced.

1. Patch test
2. Skin testing for immunodeficiency
3. Mantoux Method

- antigen applied to skin surface
- test for contact dermatitis
- Positive test = redness with papules or tiny blisters

inject common antigens intradermally

- antigen injected intradermally
- test for tubervulosis exposure (PPD) or T cell function
- positive test = induration (thickening and hardening of skin)

under Type IV
1. Measure production of IFN-gamma
2. Quantiferon TB Gold Plus Assay
3. T-SPOT-TB Test

- measure production of IFN-gamma by patient T cells stimulated with MTB antigens

- patient blood is incubated in special tubes with MTB antigens
- plasma is tested for IFN-gamma by ELISA

- patient mononuclear cells are incubated with MTB antigens and tested for IFN-gamma by ELISpot