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Hypersensitivity
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A situation when the immune systems cause harm to the body is referred to as
a hypersensitivity
There are two categories of hypersensitivities:
1. Immediate hypersensitivity and
2. Delayed hypersensitivity.
Immediate hypersensitivities refer to humoral immunity
(antigen/antibody reactions) causing harm;
Delayed hypersensitivities refer to cell-mediated immunity
(cytotoxic T-lymphocytes, macrophages, and cytokines) leading to harm.
Hypersensitivity - general characteristics
characteristics
type-I
(anaphylactic)
type-II
(cytotoxic)
type-III
(immune
complexes)
type-IV
(delayed type
antigen
exogenous
cell surface
soluble
tissues &
organs
response time
15-30 minutes
minutes – hours
3-8 hours
48 - 72 hours
appearance
weal & flare
lysis and
necrosis
erythema and
edema, necrosis
erythema,
enduration
histology
basophils and
eosinophils
antibody and
complement
complement and
lymphocytes
monocytes &
lymphocytes
transferred with
antibody
antibody
antibody
T-cells
examples
allergic ashtma,
hay fever
erythroblastosis
fetalis,
Goodpasture`s
nephritis
SLE, farmer`s
lung disease
tuberculin test,
poison ivy,
garanuloma
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
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GENERAL CHARACTERISTICS:
the most common type of hypersensitivity, seen in about 20-40% of
the population.
IgE is made in response to an allergen
levels of IgE may be thousands of times higher than in those without
allergies.
level of IgE due to a higher number of Th2 cells which produce IL-4,
a cytokine that can increase production of IgE and a lower number of
Th1 cells that produce gamma-interferon, a cytokine that decreases
IgE production
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
Mechanism
The allergen enters the body
and is recognizedby sIg on a B-Ly
The B-lymphocyte then proliferates
and differentiates into plasma cells.
The plasma cells produce and secrete
IgE which binds to receptors on mast
cells and basophils (FcεRI) –
sensibilisation
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
Allergen cross reacting with IgE
on mast cell
The next time the allergen enters the body,
it cross-links the Fab portions of the IgE
bound to the mast cell. This triggers the mast
cell to degranulate - release histamine and other
inflammatory mediators - bind to receptors on
target cells which leads to dilation of blood
vessels, constriction of bronchioles, excessive
mucus secretion, and other symptoms of allergy.
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
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Inflammatory mediators
platelet-activating factor, leukotreins,
bradykinins, prostaglandins, and cytokines
The early phase appears
within min. after exposure to the Ag
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
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The Late phase appears
several hours after exposure to Ag
It is thought that basophils play a major role
here.
Cell-bound IgE on the surface of basophils of
sensitive individuals binds a substance called
histamine releasing factor (possibly produced by
Ma and B-Ly) causing further histamine release.
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
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The inflammatory mediators released or produced
cause the following:
a. dilation of blood vessels.
This causes local redness (erythema) at the site of allergen delivery. If
dilation is widespread, this can contribute to decreased vascular
resistance, a drop in blood pressure, and shock.
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b. increased capillary permeability.
This causes swelling of local tissues (edema). If widespread, it can
contribute to decreased blood volume and shock.
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
c. constriction of bronchial airways.
This leads to wheezing and difficulty in breathing.
d. stimulation of mucous secretion.
This leads to congestion of airways.
e. stimulation of nerve endings.
This leads to itching and pain in the skin.
Immediate Hypersensitivity
1. Type I (IgE-mediated or anaphylactic-type)
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Systemic anaphylaxis, the allergin is usually
picked up by the blood and the reactions occur
throughout the body.
Examples: severe allergy to insect stings,
drugs, and antisera.
Localized anaphylaxis, the allergin is usually
found localized in the mucous membranes or
the skin.
Examples: allergy to hair, pollen, dust, dander,
feathers, and food.
Immediate Hypersensitivity
Type II (Antibody-Dependent Cytotoxicity)
The Fab of IgG reacts with epitopes
on the host cell membrane.
Phagocytes bind to the Fc portion.
Phagocytes binding to the Fc portion
of the IgG and discharge their
lysosomes causing cell lysis.
Immediate Hypersensitivity
Type II (Antibody-Dependent Cytotoxicity)
IgG or IgM reacts with epitopes on the host
cell membrane and activates the classical CP.
MAC then causes lysis of the cell.
Immediate Hypersensitivity
Type II (Antibody-Dependent Cytotoxicity)
The Fab portion of Ab binds to epitopes on the "foreign" cell.
NK cell binds to the Fc portion of Ab
NK cell releases
pore-forming proteins – perforins (cell lysis)
proteolytic enzymes – granzymes (apoptosis), and
chemokines.
Immediate Hypersensitivity
Type II (Antibody-Dependent Cytotoxicity)
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Examples include:
1. AB and Rh blood group reactions;
Immediate Hypersensitivity
Type II (Antibody-Dependent Cytotoxicity)
2. autoimmune diseases such as:
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rheumatic fever - Ab result in joint and heart valve damage;
idiopathic thrombocytopenia purpura - Ab result in the destruction
of platelets;
myasthenia gravis – Ab bind to the acetylcholine receptors on muscle
cells causing faulty enervation of muscles;
Goodpasture's syndrome – Ab lead to destruction of cells in the
kidney;
Graves' disease - Ab are made against thyroid-stimulating hormone
receptors of thyroid cells leading to faulty thyroid function;
multiple sclerosis –Ab are made against the oligodendroglial cells
that make myelin, the protein that forms the myelin sheath that
insulates the nerve fiber of neurons in the brain and spinal cord; and
3. some drug reactions,
4. early transplant rejections participation
Immediate Hypersensitivity
Type III (Immune complex mediated)
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caused when soluble antigen-antibody
(IgG or IgM) complexes, which are
normally removed by macrophages in the
spleen and liver, form in large amounts
and overwhelm the body.
Immediate Hypersensitivity
Type III (Immune complex mediated)
Large quantities of soluble Ag-Ab
complexes form in the blood and
are not completely removed by Ma
These Ag-Ab complexes lodge in the
capillaries between the endothelial cells
and the basement membrane.
Immediate Hypersensitivity
Type III (Immune complex mediated)
These Ag-Ab complexes
activate the CCP leading
to vasodilation.
The C proteins and Ag-Ab
complexes attract Le to
the area.
The Le discharge their
killing agents and promote
massive inflammation.
This can lead to tissue death
and hemorrhage
Immediate Hypersensitivity
Type III (Immune complex mediated)
Examples include
1. serum sickness, a combination type I and type
III hypersensitivity;
2. autoimmune acute glomerulonephritis;
3. rheumatoid arthritis;
4. systemic lupus erythematosus;
5. some cases of chronic viral hepatitis; and
6. skin lesions of syphilis and leprosy
Delayed Hypersensitivity
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Delayed hypersensitivity is cell-mediated
rather than antibody-mediated.
Mechanism: Delayed hypersensitivity is the
same mechanism as cell-mediated immunity.
T8-lymphocytes become sensitized to an
antigen and differentiate into cytotoxic Tlymphocytes while Th1 type T4lymphocytes become sensitized to an
antigen and produce cytokines.
CTLs, cytokines, and/or macrophages then
cause harm rather than benefit.
Delayed Hypersensitivity
Binding of the CTL to a cross-reacting normal cell triggers the CTL to release
pore-forming proteins called perforins, proteolytic enzymes called granzymes,and
chemokines. Granzymes pass through the pores and activate the enzymes that lead
to apoptosis of the infected cell by means of destruction of its structural cytoskeleton
proteins and by chromosomal degradation. As a result, the cell breaks into fragments
that are subsequently removed by phagocytes.
Delayed Hypersensitivity
Delayed Hypersensitivity
5 tuberculin units of liquid tuberculin admistered intradermally
The Mantoux skin test, the patient's arm is examined 48 to 72 hours
after the tuberculin is injected.
Delayed Hypersensitivity
Examples:
1. Cell or tissue damage done during diseases like tuberculosis, leprosy,
smallpox, measles, herpes infections, candidiasis, and histoplasmosis;
2. Skin test reactions seen for tuberculosis and other infections;
3. Contact dermatitis like poison ivy;
4. Type-1 insulin-dependent diabetes where CTLs destroy insulin-producing
cells;
5. Multiple sclerosis, where T-lymphocytes and macrophages secrete cytokines
that destroy the myelin sheath that insulates the nerve fibers of neurons;
6. A major role in chronic transplant rejection as a result of CTL destruction of
donor cells (host versus graft rejection) or recipient cells (graft versus host
rejection).
Cyclosporin A or FK-506 (Tacrolimus) are given in an attempt to prevent
rejection. Both of these drugs prevent T-lymphocyte proliferation and
differentiation by inhibiting the transcription of IL-2.