- Briefly describe Type IV Hypersensitivity
- Type IV hypersensitivity is T-cell mediated hypersensitivity.
- Activated T-cells release cytokines that activate macrophages or kill cells directly.
- Type IV hypersensitivity is useful against intracellular organisms (viruses, fungi, parasites, some bacteria).
- Here it results in inflammation, cell destruction, and granuloma formation
- What are the Types of Type IV Hypersensitivity reactions
- Delayed-type Hypesensitivity (DTH)
- CD4+ T cells secrete cytokines, activating macrophages, can lead to granulomatous inflammation
- Direct cell cytotoxicity
- CD8+ T cells kill target cells
- Delayed-type Hypesensitivity (DTH)
- Describe the pathogenesis of delayed-type Type IV Hypersensitivity reactions
- Initial exposure (Sensitization)
- Mechanism of exposure:
- Contact sensitization with chemicals and environmental antigens
- Intradermal or subcutaneous injection of protein antigens
- Microbial infection
- APCs (DCs and Macrophage) uptake antigen, are activated and secrete IL-12, IL-1, IL-6, and IL-23
- The phagocytosed mocs are presented to naive CD4+ T-cells via MHC II
- Naive CD4+ T-cells are activated:
- Secrete IL-2: Autocrine growth factor that stimulates proliferation of the antigen responsive t-CELLS
- APCs secrete IL-12 which converts CD4+ T-cells to Th1 subset
- APCs secrete IL-1, IL-6 and IL-23 which convert CD4+ T-cells to Th17 subset
- Effector Th1 and Th17 cells enter circulation and join the pool of memory T-cells which persist for long periods, sometimes even years
- Mechanism of exposure:
- Re-exposure (Effector T-cell function)
- On repeat exposure Th1 secrete IFN-y
- IFN-y activates macrophages via the classical pathway in order to eliminate the offending antigen
- Ability to phagocytose and kill micro-organisms is enhanced
- Express more class II MHC molecules on the surface enhancing antigen presentation
- Secrete TNF, IL-1 and chemokines which promote inflammation
- Produce more IL-12, amplifying the Th1 response
- Activate Th17 cells secrete IL-12, IL-22, chemokines and other cytokines
- Function to recruit neutrophils and monocytes to the reaction promoting inflammation
- Recruited macrophages and neutrophils cause tissue destruction via lysosomal enzymes and reactive oxygen species
- Prolonged inflammation causes granulomatous inflammation whereby macrophages are activated to become epitheloid or they fuse to form giant cells
- Granuloma formation
- Microbe or foreign body persists within macrophages that the cell is unable to destroy
- Sustained Th1 activation and IFN-y production causes macrophages to undergo morphologic transformation into epitheloid cells with large abundant cytoplasm
- Some Macrophages fuse to form giant multinucleated cells
- Examples
- Infections: Leprosy, Tuberculosis, Schistosomiasis
- Non-infectious conditions: Sarcodiosis, Crohn disase
- Foreign body reaction: Berylliosis, Talcosis, Silicosis
- Direct cell cytotoxicity – CD8+ mediated Hypersensitivity
- CTLs recognize antigens on surface cells.
- Initial exposure (Sensitization)
- Give examples of Delayed Type Hypersensitivity reactions (DTH)
- CD4+ Mediated
- Mantoux test
- Brucellosis
- Lepromin test
- Frei’s test in Lymphogranuloma Venerium
- Tuberculin (PPD) reaction
- Contact Dermatitis (Urushiol poison ivy)
- Autoimmune diseases (Rheumatoid Arthritis, Psoriasis, Multiple sclerosis, IBD – Crohn)
- Granuloma formation (Leprosy, Tuberculosis, Schistosomiasis, Sarcodiosis, Crohn disease, Berylliosis, Talcosis, Silicosis
- CD8+ mediated
- Type I Diabetes Mellitus
- Graft Rejection
- CD4+ Mediated
- Briefly describe contact dermatitis
- Contact dermatitis is a DTH reaction when skin comes into contact with chemical substances or drugs (poison, hair dyes, cosmetics, soaps, neomycin).
- These substances enter the skin as small molecules (haptens) attached to proteins to form immunogenic substances.
- Urushioll: antigenic component of poision ivy or poison oak
- Mechanism
- Occurs from topical exposure to chemicals and environmental antigens
- Haptens penetrate the skin and combine with tissue proteins to form neo-antigens
- Langerhan cells are the principle APCs in recognition of hapten-tissue protein complexes and presentation to T-cells
- DTH leads to : eczema, rash, vesicular eruption
- Briefly describe the Tuberculin skin test (PPD)
- PPD is injected intradermally in sensitized persons.
- A local area of induration appears at the injection site 48-72 hours later due to the accumulation of macrophages and lymphocytes.
- Similar reactions in:
- Brucellosis
- Lepromin test in Leprosy
- Frei’s test in Lymphogranuloma venereum
- Morphology: Accumulation of mononuclear cells (Mainly CD4+ T-cells and Macrophages around venules producing perivascular cuffing
- What is the mechanism behind the Tuberculin Skin Test (PPD)
- Occurs in individuals who have been exposed to M tuberculosis (Infection, Vaccination?)
- Delayed Type Hypersensitivity evolves over 24-48 hours
- 4 hours after injection in sensitized individuals neutrophils accumulate around the post-capillary venules at the injection site
- 12 hours after the injection T cells and blood monocytes infiltrate the area
- Endothelial cells lining these venules become enlarged and the vessels leak plasma macromolecules
- Fibrinogen escapes from the blood vessels into the surrounding tissue where it is converted into fibrin
- Deposition of fibrin, edema and accumulation of mononuclear cells within the extravascular tissue space around the injection produces an area of induration (swollen and firm)
- Describe the procedure and interpretation of the Mantoux test (Tuberculin Skin Test, PPD)
- Inject 0.15mL of 5 TU PD solution intradermally on the volar surface of the lower arm using a 27G needle and tuberculin syringe
- Produce a wheal 6-10mm diameter
- Note the arm in which the test was administered
- Read the skin the skin test 48-72 hours after administration
- Note the are of induration (not erythema) in millimeters in the axis perpendicular to the long axis of the arm
- Interpretation
- 5mm – Immunosuppressed
- 10mm – Individuals with risk factor to TB Endemic individuals, Injection drug users MTB lab personnel, Children younger than 4, infants, children and adolescents exposed to high-risk individuals
- 15mm – Individuals with no known risk factors for TB
- Describe the procedure and interpretations of the Lepromin test
- Procedure is same as the one for the Mantoux test
- Read 48 hours = Fernandez reaction
- Read 3-4 weeks = Mitsuda reaction
