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Type IV Hypersensitivity

Notes

Type IV Hypersensitivity

Sections






Type IV reactions are T cell mediated.

Because of the time it takes to recruit and activate T cells and their products, these reactions are delayed – they occur 1-3 days after antigen exposure; in contrast, recall that the other types of hypersensitivity reactions occur within minutes to hours after exposure.

CD4+/Helper T cells induce hypersensitivity reactions via cytokine recruitment of inflammatory cells.

CD8+/Cytotoxic T cells directly destroy tissues.

CD4+ T Cell

Mechanism of Damage:

CD4+ T cells are activated when they recognize and interact with cells displaying the antigen-MHC II complex.

As a result, CD4+ cells proliferate and differentiate:

Under direction from interferon-gamma and IL-12, Helper T cells of the Th1 subset are produced.
Th1 Helper T cells release interferon-gamma, which recruits macrophages.
Upon activation, macrophages induce tissue damage and fibrosis.

Under direction from IL-1, IL-6, and IL-23, cells of subset Th17 are produced.
Th17 Helper T cells release IL-17 and IL-22, which recruit and activate neutrophils; show that neutrophils cause inflammation.

Examples:

Tuberculosis
Characterized by the formation of granulomas, aka, tubercles, which comprise special populations of epithelial cells and macrophages that gather around the M. tuberculosis bacteria.

The tuberculin reaction test uses TB antigens, called Purified Protein Derivatives, to determine whether an individual has been previously exposed to the M. tuberculosis bacteria.
A positive test result shows induration, which is caused by macrophage activities, and, erythema, which is caused by neutrophil-induced inflammation.

Cytotoxic T Cell

Mechanism of Cell Damage:

Direct destruction of host tissues:
When the cytotoxic T cell recognizes the antigen-MHC I complex, it releases granzymes and other harmful molecules into the tissues.

Example:

Type I diabetes mellitus can be caused by insulitis:
Cytotoxic T cells target beta cells of the Islet of Langerhans; recall that beta cells are responsible for insulin secretion.
In an affected islet, we would see infiltration of destructive lymphocytes.

Additional Helper T Cell-Mediated Disorders

Psoriasis
Involves macrophage release of Tumor Necrosis Factor (TNF) and subsequent destruction of the epidermis; thus, dead skin cells build up to form scaly, flaky plaques, often on the hands and feet, scalp, and places where the skin folds, such as elbows and knees.
The nails can also be affected; we that the fingernails become thick and broken, with a yellowish tint.

Multiple sclerosis
A demyelinating disorder caused by inflammatory cell destruction of myelin sheaths.
We see periventricular white matter lesions in brain imaging.
We see perivascular cuffing, which is characterized by aggregation of lymphocytes and macrophages around the blood vessels, in histological samples.

Rheumatoid arthritis
Caused by inflammation and tissue erosion.
RA is by neutrophil and macrophage destruction; we show this happening to the cartilage and bone of a synovial joint of the hand; rheumatoid arthritis tends to affect the bones of the hands and feet, first.
Tissue erosion leads to deformation of the hands.

Additional Cytotoxic T Cell-Mediated Disorders

Contact dermatitis
Characterized by itching, redness, and blisters.
Common causes of contact dermatitis include: Urusiol oil, found in poison ivy.
Heavy metal; many people are allergic to nickel, which is a common component of jewelry and clothing. For example, we show that the nickel buttons on denim pants causes a characteristic umbilical rash in susceptible individuals.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
Potentially life-threatening disorders that can be triggered by drugs, especially some antibiotics.
Cytotoxic release of granzymes causes severe blistering.
SJS is characterized by blistering of less than 10% of the skin.
TEN is characterized by blistering of more than 30% of the skin.

Early recognition is key for effective treatment; causative agents, such as drugs, must be removed immediately.

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Image References

  • Tuberculosis Granuloma (Mark Braun, MD: http://medsci.indiana.edu/c602web/602/c602web/toc.htm).
  • Insulitis (Mark Braun, MD: http://medsci.indiana.edu/c602web/602/c602web/toc.htm).
  • Epidermis (Mark Braun, MD: http://medsci.indiana.edu/c602web/602/c602web/toc.htm).
  • TB reaction (https://www.healthline.com/health/what-does-a-positive-tb-test-look-like#images).
  • Contact dermatitis (Nunyabb, 2006).
  • Arthritis X-ray (http://theconversation.com/fight-against-rheumatoid-arthritis-may-unlock-secrets-to-heart-disease-and-depression-24871; Photo Credit: JoJo).
  • Perivascular cuffing (CDC/Dr. Daniel P. Perl).