Type IV Hypersensitivity
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Involves immune responses initiated primarily by T cells (Th1 response) – cell-mediated immunity
Transferred from a sensitized to non-sensitized individual by T cells (not serum antibody)
Reactions develop within 24-72 hours – delayed-type hypersensitivity (DTH)
Plays an important role in defense against intracellular pathogens and contact antigens
Can cause extensive tissue damage in some cases
Antigens that elicit a DTH response
- Allografts (foreign tissue)
- Intracellular parasites (viruses, mycobacteria, fungi)
- Soluble proteins
- Chemicals or drugs (haptens) capable of penetrating skin and coupling to body proteins
Mechanism of DTH
- Consists of two main phases
 Sensitization phase
o Lasts 1-2 weeks after primary contact with antigen
o Th cells recognize antigen with help of MHC class II molecules
 Th cells are mostly of Th1 type (though Tc cells can induce a DTH response)
o Th cells become activated and clonally expanded
 Effector phase
o Requires subsequent exposure to antigen
o Th 1 cells secrete cytokines that are responsible for the recruitment and activation of
macrophages and other inflammatory cells
o DTH response normally does not become apparent until 24 hours after secondary antigen
contact and peaks between 48-72 hours
 Delayed onset reflects the time required for cytokines to induce localized influxes of
macrophages
o Macrophages are the principal effector cells
 At peak DTH response, only 5% of participating cells are T cells
o Generally, the influx and activation of macrophages effectively clear the pathogen
o Prolonged DTH response can lead to a destructive inflammatory response – granulomatous
reaction
 Granuloma can form due to continuous activation of macrophages, which adhere
closely to each other to form multinucleated giant cells that displace normal tissue cells
and release high concentrations of lytic enzymes that destroy surrounding tissue,
damage blood vessels, and cause caseous necrosis (all in attempts to wall of inciting
stimulus with fibrous CT)
o After 24 hours, erythema (redness) and induration (hard, raised thickening) appear
Important Cytokines of DTH
Cytokine
Functional Effect
Chemokines Recruit monocytes and macrophages to site of antigen deposition
IFNγ
Activation of macrophages
TNFα
Increases expression of adhesion molecules on endothelial cells and facilitates extravasation of
monocytes; causes local tissue damage
TNFβ
Increases expression of adhesion molecules on endothelial cells and facilitates extravasation of
monocytes; causes local tissue damage
Mechanisms of Drug-Induced DTH
How do T cells recognize drugs or chemicals?
- Recognition of small molecules (such as drugs) by B and T cells can be explained by the hapten-carrier concept
 Haptens are small molecules (< 1000 Da) that are chemically reactive and able to undergo stable,
covalent binding to a larger protein or peptide carrier
o Modification of this protein or peptide makes it immunogenic
o Example – Penicillin G is a hapten that tends to bind covalently with lysine groups within
soluble or cell-bound proteins, thereby modifying them and eliciting T cell reactions (also B
cells)
 Haptens may also bind to peptide presented by MHC molecules
 Haptens may also alter the MHC molecules directly
Detection of the DTH Reaction
- The presence of a DTH reactions can be measured experimentally by injecting antigen intradermally and
observing whether a characteristic skin lesion develops at the injection site
- Example – to determine whether an animal has been exposed to Mycobacterium tuberculosis, a purified protein
derivative (PPD) from the cell wall of the mycobacterium is injected intradermally. Development of a slightly
red, swollen, firm lesion at the injection site within 48-72 hours indicates that the animal either currently has
Mycobacterium tuberculosis infection or was exposed to it in the past
 Blood vessels become leaky and fibrinogen leaks out and gets converted to fibrin. Accumulation of
cells causes the tissue to swell and harden (induration)
Protective Role of the DTH Response
- Though the initial DTH response often results in significant damage to healthy tissue (due to destruction of
cells harboring intracellular pathogens by lytic enzymes released by macrophages), it is the price the body pays
for the elimination of pathogens
- The vitally-important role of the DTH response in protecting the host is illustrated in AIDS patients, who
develop fatal infections due to depleted Th cells and loss of the DTH response
Examples of DTH
- Infections
 Body fails to eliminate pathogen (i.e. Mycobacterium tuberculosis)
 Antigens provoke a chronic DTH reaction
o Persistent release of cytokines and chemokines from Th cells leads to the accumulation of large
numbers of macrophages, epithelioid cells, and giant cells
o Proliferating immune cells, fibrosis, and necrosis within tissue results in chronic granuloma
- Contact dermatitis
 Caused by substances that can complex with skin proteins to form hapten-carrier complexes
o Poison ivy, picric acid, dyes, plant resins, oils, topical medications
 Hapten-carrier complexes are internalized by APCs of the skin (Langerhans cells), processed and
presented by MHC class II molecules
 Activation of sensitized Th1 cells induces cytokine production
 Cytokines caused macrophage accumulation at site
 Macrophages release of lytic enzymes, causing redness and blister formation associated with reaction
to initial substance (i.e. poison oak)
- Allograft rejection
 If an animal receives cell, tissue, or organ grafts from an allogeneic donor (genetically different animal
of same species), tissue is initially accepted and vascularized
 After vascularization, a Th1 response is induced against alloantigens
o Invasion of the graft by a mixed population of antigen-specific lymphocytes and non-specific
monocytes through blood vessel walls
 Monocytes transform into macrophages
 Inflammatory reaction leads to the destruction of vessels, necrosis, and breakdown of grafted tissue
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Autoimmune reactions
 Type I diabetes (T1D)
o Although there is clear evidence in humans, it is unknown as to whether T1D is
immunologically-mediated in dogs
o Atrophy of islets of Langerhans
 In some cases, islets are infiltrated by lymphocytes
o Loss of β cells
 In some cases, Tc cells, antibodies, and/or complement may cause β cell destruction
 Equine polyneuritis
o Progressive neurological disease of the peripheral nerves (sacral and coccygeal nn.)
o Necropsy shows chronic granulomatous inflammation in the region of extradural nerve roots
o Histology of nerves shows loss Myelination, infilration by macrophages, lymphocytes, giant
cells, plasma cells, and deposition of fibrous materials in peritoneum
o Affected horses have circulating antibodies for a protein found in peripheral myelin
(autoimmunity)
o Horse shows progressive paralysis of tail, rectum, and bladder
 Multiple sclerosis (MS)
o Affects the CNS of humans
o Autoreactive T cells destroy myelin sheath of nerve fibers
o Inflammatory lesions and breakdown of myelin leads to vast neurologic dysfunction