TYPE IV Hypersensitivity

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