Type IV Hypersensitivity Flashcards
Type IV hypersensitivity
delayed, T-cell mediated hypersensitivity
24-72 hours delayed nature due to stepwise sensitization - response progression
antigent presentation by APCs > naive T cell recognition > t cel migration, macrophages migration, response
Type IV sensitivity, unlike types I, II & III cannot be adoptively transferred
by serum but only with sensitized T cells. The T cells that produce delayed hypersensitivity (DTH) are cells that have been specifically sensitized by antigen due to previous exposure.
These T cells (TDTH) act by recruiting other cells to the site of reaction.
contact hypersensitivity
Peaks at 48-72 hours
Characterized by edema at site of antigen contact
Antigens: haptens, poison ivy, poison oak (antigen urushiol, plant must be
injured to release it. Smoke from burning plants can cause severe dermatitis), nickel, chromate, chemicals in latex
Cells: Langerhans’ cells & Dendritic cells are principal APC
Sensitization phase: 0-14 days in man
Elicitation: 4-8 hr mononuclear cells, 48-72 hr peak infiltration of cells
(mainly CD4+ but some CD8+ present).
Mechanism: Langerhans’ & Dendritic cells present hapten-protein as
peptide-MHC complexes to CD4+ memory T cells
Cytokine release follows (IL-2, IL-3, IFNγ, GM-CSF) T cells express IL-2
receptors.
By 48 hr IFNγ induces MHC class II on keratinocytes.
Keratinocytes release IL-1, IL-6, GM-CSF
Reaction begins to wane between 48-72 hours
Macrophages produce prostaglandin which inhibits IL-1 and IL-2 and
down regulates the response
Tuberculin type DTH
Primarily a defense mechanism against intracellular bacteria (Listeria or
mycobacteria), viruses, intracellular parasites or intracellular fungi.
Classical animal model for DTH is the response of an immunized guinea
pig to antigen applied to the skin or by intradermal injection
Four hours after antigen is injected or applied, neutrophils accumulate
around the postcapillary venules at the injection site. By 12 hours T cells
and blood monocytes appear.
Endothelial cells become plump and leaky to plasma macromolecules.
Fibrinogen escapes into tissue and changes to fibrin. Fibrin, T cells and
blood monocytes collect around injection site causing swelling and
hardening (induration)
Induration is detectable at 18 hr, is maximal at 24-48 hr. DTH is
transferable by sensitized CD4+ T cells.
Three phases of DTH
Cognitive, Activation and Effector.
Effector phase
o Inflammation o Resolution
Langerhans’ cells are important in initial sensitization
Macrophages are important APC’s in DTH
Endothelial cells lining the post-capillary venules also serve as APCs
T cells, once activated, produce lymphokines
Cytokines involved
IL-2 autocrine and paracrine proliferation of activated T cells. Augment
synthesis of cytokine by CD4+ T cells including IL-2, IFNγ, TNF & lymphotoxin.
IFNγ induces increased MHC class II on APC’s & activates monocytes
infiltrating inflammatory site to eliminate antigen. It is the most important cytokine in DTH
TNF and lymphotoxin act on venular endothelial cells, enhancing binding
and activation of leukocytes in inflammation
Venular endothelial cells and inflammation
Regulate the infiltration of leukocytes in the inflammatory reaction
Under the influence of TNF and other cytokines, they produce prostacyclin
(PGI2) a vasodilator which increases blood flow and the delivery of leukocytes to sites of inflammation.
Causes the expression of new adhesion molecules which facilitate the
adhesion of leukocytes and increase the residence time of leukocytes in the endothelium
Adhesion molecules
ELAM-1 (endothelial leukocyte adhesion molecule) binds neutrophils
ICAM-1 binds lymphocytes via LFA-1
VCAM-1 (vascular cell adhesion molecule) binds monocytes &
lymphocytes. The ligand is VLA-4 (very late antigen). The sequential changes in the endothelial cell surface caused by TNF
lead to the sequential adhesion of, first neutrophils, then lymphocytes &
finally monocytes.
TNF and IFN-gamma
TNF causes endothelial cells to secrete IL-8 and monocyte chemotactic
protein (MCP-1) which increases mobility of leukocytes.
TNF and IFNγ cause endothelial cells to undergo shape changes and
basement membrane remodeling that favor leakage and extravasation of
cells
Resolution and Activated Macrophages
Macrophages activated by IFNγ kill microorganisms. They stimulate acute
inflammation through the secretion of short-lived inflammatory mediators (platelet activating factor PAF, prostaglandin and leukotrienes).
They act as an endogenous surgeon to cauterize the wound, leading to
elimination of the antigen and resolution of the DTH reactions. Activated macrophages become more efficient antigen presenting cells Their products, cytokines, progressively modify the local tissue
environment. Initially there is tissue destruction and later there is
replacement by connective tissue.
Cytokine Actions
ACUTE: TNF, IL-6, IL-1 augment cell mediated immunity by acting on T
cells, inflammatory leukocytes and endothelial cells. This causes tissue damage.
CHRONIC: Stimulate fibroblast proliferation and collagen production. Slow
action of cytokines and transforming growth factor produce chronic activation of macrophages in tissue which leads to replacement of the differentiated tissue with fibrous tissue
In chronic DTH activated macrophages can also undergo changes that
give them the appearance of epithelial cells (epithelioid). The epithelioid cells fuse to form multinucleated cells (giant cells) in
granulomas.
Granulomatous Hypersensitivity
Clinically, this is the most important form of DTH
Causes many of the pathological effects in the diseases which involve T
cell mediated immunity Characterized by persistence of microorganisms or particles within
macrophages. The characteristic cell in the granulomatous hypersensitivity is the
epithelioid cell. (large flattened) Giant cells: Multinucleated giant cells are found in this reaction; they have
many off centered nuclei, and little cytoplasmic reticulum. Granuloma are found in granulomatous hypersensitivity. The granuloma
has a core of epithelioid cells, macrophages, and sometimes giant cells. Examples:
o Tuberculosis o Leprosy o Sarcoidosis o Schistosomiasis
In a disease like tuberculosis, the central core of the granuloma might
have a zone of necrosis & destruction of all cellular architecture The macrophage epithelioid core is surrounded by a lymphocyte cuff and
considerable fibrosis.
