Overview

• 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

• 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.
  — Under direction from IL-1, IL-6, and IL-23, cells of subset Th17 are produced.
• In turn, these Helper T cells release cytokines that recruit and activate inflammatory cells:
  — Th1 Helper T cells release interferon-gamma, which recruits macrophages; show that, upon activation, macrophages induce tissue damage and fibrosis.
  — Alternatively, show that Th17 Helper T cells release IL-17 and IL-22, which recruit and activate neutrophils; show that neutrophils cause inflammation.

Examples:

• Tuberculosis is characterized by the formation of granulomas, aka, tubercles, which comprise special populations of epithelial cells and macrophages that gather around the M. tuberculosis bacteria. In a more magnified view, label a giant cell, which formed from macrophages that merged together.
• 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.
  — In our image, we can see that a positive test result shows induration, which is caused by macrophage activities, and, erythema, which is caused by neutrophil-induced inflammation.

Cytotoxic T Cell

• Destruction of host tissues is more direct:
  — 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.
  — Indicate that, in an affected islet, we would see infiltration of destructive lymphocytes.

Additional Disorders

Helper T cell-mediated damage

• 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; show that the fingernails become thick and broken, with a yellowish tint.
• Multiple sclerosis is a demyelinating disorder caused by inflammatory cell destruction of myelin sheaths.
  — We can see areas of periventricular white matter lesions in a radiograph.
  — In a histological sample, we can see perivascular cuffing, which is characterized by aggregation of lymphocytes and macrophages around the blood vessels.
• Rheumatoid arthritis is caused by inflammation and tissue erosion.
  — Indicate neutrophil and macrophage destruction of the cartilage and bone of a synovial joint of the hand; rheumatoid arthritis tends to affect the bones of the hands and feet, first.
  — In an x-ray, we can see how tissue erosion has led to deformation of the hands.

Cytotoxic T cell-mediated damage

• Contact dermatitis is 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 the related, more severe Toxic Epidermal Necrolysis (TEN), are 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, and 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.