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TYPE IV HYPERSENSITIVITY
Group 3 Medicine 2C
Clinical Summary
Gigi, a 2 year old girl was brought for consult at the Out-patient department because of poor weight gain. She also has a history of recurrent cough and colds occurring at least monthly. The physicians at the OPD suspected a primary tuberculosis and suggested a tuberculin skin test (purified protein derivative or PPD). After administering the PPD on Gigi’s right volar forearm, she was advised to come back after 2 days to check for the presence of induration on the injection site.
Guide Questions
1. What type of hypersensitivity reaction does tuberculin skin testing exemplify?
The tuberculin reaction is a classic example of a cell-mediated (delayed) hypersensitivity. When a small amount of tuberculin is
injected into the epidermis of a patient previously exposed to Mycobacterium tuberculosis, there is little immediate reaction; gradually, however, induration and redness develop and reach a peak in 24–72 hours.
Mononuclear cells accumulate in the subcutaneous tissue, and there are inflammatory CD4 Th1 cells in abundance.
Guide Questions
2. Give other examples of this type of reaction. Contact hypersensitivity is another example of
cell-mediated hypersensitivity. It occurs after sensitization with simple chemicals ,
plant materials, topically applied drugs some cosmetics, soaps, and other substances. In all cases, small molecules enter the skin and then, acting as haptens, attach to body proteins to serve as complete antigen.
Cell-mediated hypersensitivity is induced, particularly in skin. When the skin again comes in contact with the offending agent, the sensitized person develops erythema, itching, vesication, eczema, or necrosis of skin within 12–48 hours.
Guide Questions
3. The primary cells involved in delayed hypersensitivity reactions are monocytes and T-cells
Cytokines
IL 12 – produced by macrophages, differerentiation of naïve CD4 helper Tcells to Th1 cells, produce cytokines
IFN gamma –key mediator, activates macrophages, produce more Class II molecules, secrete PDGF, secrete TNF, IL1 and chemokines
IL 2 – autocrine and paracrine proliferation of tcells and CD4 and helper tcells
TNF & lymphotoxin – increases prostacyclin, increases P E selectins, secretion of chemokines
Type IV hypersensitivity
Repeated exposure
Sensitized CD4 cells accumulate in dermis
Migrate towards epidermis (where antigen is )
Continuation…
Release cytokines that damage keratinocytes
Separation of these cells
Intraepidermal vesicle
•TST•Multipuncture Tests (MPTs)•Interferon-γ Release Assays (IGRAs)
Other DIAGNOSTIC TESTS
not as accurate as TST because the exact dose of tuberculin antigen introduced into the skin cannot be controlled.
• No longer used in pediatric practice.
Multipuncture Tests (MPTs)
The tuberculin skin test is performed to evaluate whether a person has been exposed to tuberculosis. If there has been a prior exposure, antibodies are formed and remain in the body. During the skin test, the tuberculosis antigen is injected under the skin and if antibodies are present, the body will have an immune response. There will be an area of inflammation at the site of the injection.
Tuberculin Skin Test
The Mantoux test itself is a delayed hypersensitivity reaction. Thus, 48-72 hours following the intradermal administration of purified M. tuberculosis protein derivative (PPD), patients who have been exposed to the bacteria develop a delayed hypersensitivity reaction manifested by inflammation and edema in the dermis.
Tuberculin Skin Test / Mantoux Test
0.1 mL of 5 tuberculin units of PPD stabilized with Tween 80
Tuberculin Skin Test
Type IV: Cell- Mediated (Delayed)
Hypersensitivity
In a previously exposed individual to Mycobacterium tuberculosis:
injection of small amt of tuberculin → little immediate reaction → (24-72 hrs) indurations and redness develop
Tuberculin Skin Test
Mononuclear cells accumulate in subcutaneous tissue
Abundance of CD4 TH1
(+) Skin Test = individual infected with agent +/- presence of current disease
(-) →(+) Skin Test = recent infection + possible current activity.
Type IV: Cell- Mediated (Delayed)
Hypersensitivity
≥ 5mm close contact with known/ suspected contagious people with TB; suspected to have TB; immunosuppressive therapy / conditions
≥10mm increased risk of disseminated TB; increased exposure to TB
≥15mm without any risk factors
TST Results
Limitations of TST
Lack of mycobacterial species specificityDue to large number of proteins in this product that are highly conserved in the various species
Subjectivity of the skin-reaction interpretation, deterioration of the product & batch-to-batch variations
Interferon-γ Release Assays (IGRAs)
Both tests have
internal controls
(similar to placing a Candida skin test for the PPD).
Detect interferon- γ generation by the patient’s T cells in response to specific M. tuberculosis antigens (ESAT-6 and CFP-10).
T-SPOT.TB QuantiFERON-TB Gold (FDA)
Interferon-γ Release Assays (IGRAs)
Theoretical and
Practical Advantag
es
As sensitive as TST for
active tuberculosis
Logistical convenience Lack of cross reaction with BCG
vaccination & nontuberculous mycobacteria.
Absence of boosting ( ↑ rxn to the TST with serial testing)
Avoidance of unreliable & subjective measurements such as skin induration
Interferon-γ Release Assays (IGRAs)
Cellestis Ltd., Carnegie, Australia
Whole blood enzyme-linked immunosorbent assay (ELISA) for measurement of IFN- γ
Oxford Immunotec, Oxford , UK
Enzyme-linked immunospot (ELISpot) assay
May work best when used in combination with a PPD to increase sensitivity.
Lower rate of indeterminate results & higher degree of diagnostic sensitivity
QuantiFERON-TB Gold T-SPOT.TB
Pharmacologic Treatment
Varies depending on the severity of the disease
Avoid offending antigen
Corticosteroids (over the counter, prescription, injectable and oral), Burrow solution
Rarely needed (response is short lived and self limited)
Topical corticosteroids
Axillary lymphadenopathy and fever: aspirin and ibuprofen
Contact Dermatitis Tuberculin Skin Test
Pharmacologic Treatment
Have anti-inflammatory properties and cause profound and varied metabolic effects
Modify the body's immune response to diverse stimuli
Triamcinolone: Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability
Corticosteroids Corticosteroids
Pharmacologic Treatment
Mometasone: May depress formation, release, and activity of endogenous chemical mediators of inflammation.
Prednisone: May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity
Corticosteroids Corticosteroids
Pharmacologic Treatment
Cimetidine H2 receptor blocker, acts as a reverse
antagonist and may augment cell-mediated immunity
COMPARISON OF DIFFERENT TYPES OF HYPERSENSITIVITY
Characteristics I II III IV
Antibody IgE IgG, IgM IgG, IgM None
Antigen Exogenous Cell surface Soluble Intracellular
Response time 15-30 minutes Minutes to hours 3-8 hours 48-72 hours
Appearance Wheal and Flare Lysis and necrosis Erythema and Edema
Erythema and induration
Histology Basophil,eosinophil Ab and complement PMN and complement
Monocytes and lymphocytes
Examples Hay fever, asthma Pernphigus, Good pasture
Farmer’s lung, SLE TB test, poison Ivy, granuloma