Type IV Hypersensitivity

Introduction

Sensitisation phase: Type IV hypersensitivity-Brian Catchpole RVC 2008

Type IV hypersensitivity-Brian Catchpole RVC 2008

Cell mediated hypersensitivity:

Type IV hypersensitivity, also known as delayed hypersensitivity, involves cytokines being secreted from the Th-I cells, which causes the activation of macrophages and other T cells.

• CD4+ (helper) mediated:
  • Abnormal activation of macrophages in healthy tissues.
  • Macrophage production of inflammatory mediators and MMP (matrix metalloproteinase) enzymes cause tissue damage.

• CD8+ (cytotoxic) mediated:
  • Cytotoxic T lymphocytes (CTLs) kill healthy cells mistakenly thinking they are infected by a virus.

Exposure to antigen causes CD4+ T helper cells to be activated leading to colonal expansion (takes 1-2 weeks). On subsequent exposure with the same antigen sensitised CD4+ T helper cells secrete cytokines which attract and activate macrophages. The macrophages have an increased ability to phagocytose pathogens, which is very important for the clearance of intracellular pathogens. However if antigen exposure persists, the lytic products of the macrophages can damage healthy tissues.

2 types:

1. Contact

• Involves simple chemicals (antigens) which bind to skin proteins:
  • Nickle
  • Rubber
  • Poison ivy

Distinguishing contact from immediate hypersensitivity

	Atopic dermatitis	Contact dermatitis
Pathogenesis	Type I	Type IV
Time	20 mins	24-48 hours
Distribution	face, nose, eyes, feet, perineum	hairless regions
Antigens	foods, pollens, fleas, inhaled allergens	chemicals, dyes
Diagnosis	"prick" test	patch test for delayed hypersensitivity
Pathology	mast cells, eosinophils	mononuclear cells

2. Granulomatous

• Intense activation of T cells, cytokine release and macrophage activation cause necrosis of surrounding tissue, granuloma formation leading to destruction of host tissue.
• Composed of epithelial cell, giant cells and macrophage in response to infection, for example:
  • Mycobacterium tubercle
  • Schistosome eggs
• Granulomas can obstruct normal organ function:
  • Lungs: fills up with cells leading to impaired function
  • Brain/liver: very severe

Tuberculin test

• Injection of intradermal antigen into the skin.
• A skin reaction (infiltration of lymphocytes and Monocytes) peaking at 48-72 hours indicates prior exposure to the antigen or ongoing infection.
• It is used for TB testing cattle; the antigen is purified protein derivative-PPD from Mycobacterium tuberculosis.
• Presently in the UK the animal is culled if it has a positive skin reaction.

From Pathology

• Delayed hypersensitivity
• Haptens bind to carrier proteins (mainly epidermal)
• Mediated by sensitised T-cells -> release cytokines +/- recruit lymphocytes
• Used in diagnosis of tuberculosis, histoplasmosis and coccidiomycosis
• Perivascular mononuclear cell accumulation

Originally funded by the RVC Jim Bee Award 2007