Download Hypersensitivity Reactions

Hypersensitivity Reactions
 Hypersensitivity is a state of reactivity to Ag that is greater than normal; it denotes
a deleterious rather than a protective outcome.
 Hypersensitivity Reactions are divided into 4 types I, II, III, IV designated by
coombs and Gell.
 Type I:
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IgE-mediated reactions, "immediate hypersensitivity", "allergy".
Reactions are stimulated by binding of IgE "via its Fc region" to IgE specific Fc
receptor "FcRI" on mast cells and basophils.
When cross-linked by Ags, IgE Trigger mast cells and basophils to release
inflammatory mediators leading to allergic reactions, including rhinitis, asthma
and in severe cases anaphylaxis "ana=away from, phylaxis=protection".
Reactions are rapid occurring within minutes after challenge "re-exposure to
Ag".
 Type II:
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Cytolytic or cytotoxic reactions, occurs when IgM or IgG Abs bind to Ag on
the surface of cells and activate complement cascade, culminating in destruction
of cells.
 Type III:
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Immune complex reactions occur when complexes of Ag and IgM or IgG
accumulate in the circulation or in tissue and activate the complement cascade.
Granulocytes are attracted to the site of activation. Damage results from release
of enzymes from granulocytes. Reactions occur within hours of challenge with
Ag.
 Type IV:
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Cell-mediated immunity "CMI" reactions "delayed-type hypersensitivity
"DTH". It is mediated by T cell-dependent effector mechanisms involving both
CD4+ TH1 cells and CD8+ cytotoxic T cells. Abs do not play a role in type IV.
Upon activation TH1 cells release cytokines that cause accumulation and
activation of M which in turn, cause local damage. Reaction may occur days
or weeks after challenge with Ag.
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Type I Hypersensitivity
"Allergic Reactions"
Phases of allergic reactions:
1) The sensitization Phase:
- IgE is produced in response to antigenic stimulus and binds to specific
receptors on mast cells and basophils.
2) The activation phase:
- Re-exposure or challenge to Ag triggers the mast cells and basophils to
respond by release of the contents of their granules.
3) The effector phase:
- A complex response occurs as a result of the effects of the many
inflammatory mediators released by the mast cells and basophils.
- The clinical manifestations of these effector mechanisms include eczema,
asthma and rhinitis.
Sensitization Phase:
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Ig responsible for allergic reactions is IgE.
Sensitization to allergens can occur through any means of contact including skin
contact, ingestion, injection, and inhalation.
Hay fever, a term used to describe the clinical symptoms induced by airborne
allergens.
Atopy refers to IgE-mediated hypersensitivity, atopic refers to affected patient.
IgE responses are genetically controlled by MHC-linked genes on chromosome 6.
Other regulatory genes include FcRI on chromosome II and the TH2 IL-4 gene
cluster on chromosome 5 which contains genes for IL-3, IL-4, IL-5, IL-9, IL-13.
IgE Ab. production is TH2 cell dependent:
 IL-4 and IL-13 cytokines play a role. Anti IL-4 Abs in mice inhibits IgE
production.
 IL-4 levels in allergic individuals are higher than non allergic ones. IgE levels
are also higher in the first group.
 Once exposure to the allergen has been achieved by repeated exposure and IgE
has been produced, the individual is considered to be sensitized. IgE attaches
to mast cells and basophils.
 Mast cells are found around blood vessels in the connective tissue, in the
lining of the gut and in the lungs.
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 Both mast cells and basophils have receptors "FcRI" that bind IgE Fc region
cells will remain sensitized and it will trigger the activation of the cells when
the antigen comes in contact with them.
 Passive sensitization is achieved by transfer of serum that contain IgE Ab to
specific Ag. Prausnitz-Kusner "P-K" test is used to detect Abs responsible for
anaphylactic reaction.
 Allergic person to antigen X  serum "IgE"  inject into nonallergic person
 IgE binds mast cells  injection with Ag X  urticarial reaction.
 Reaction in passively sensitized animals is called "Passive cutaneous
anaphylaxis (PCA)".
Activation Phase:
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The activation phase of allergic reactions begins with the triggering of the mast
cell to release its granules and their inflammatory mediators.
It requires at least two of the receptors of the Fc region of the IgE molecules be
bridged together in a stable configuration.
The physiologic consequences of IgE-mediated mast cell degranulation depend
on the dose of Ag and route of entry.
 Mast cells that degranulate within the gastrointestinal tract "GIT" cause
increased fluid secretion and peristalsis which can result in diarrhea &
vomiting.
 In lungs, decrease in airway diameter and blockage of the airways.
 Degranulation of mast cells in blood vessels causes vascular permeability.
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Fig 14.3 shows various types of cross linking which lead to mast cell
degranulation.
Calcium ionophores leads to rapid influx of Ca++ into the cell leads to its
degranulation.
Anaphylatoxins C3a & C5a, drugs like codeine, morphine, and certain lectins can
also cross link IgE Fc receptors.
Receptor aggregation and changes in membrane fluidity which results from
methylation of phospholipids, leading to transient increase in CAMP followed by
influx of Ca++, which slow down the process of degranulation. Thus activation of
adenylate cyclase controls anaphylaxis.
Degranulated cells regenerate, synthesize the granules and resume their function.
Effector Phase:
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The symptoms of allergic reactions are entirely attributable to the inflammatory
mediators released by the activated mast cells. Two categories of mediators:
Preformed mediators and newly formed mast cell mediators.
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A. Preformed Mediators:
1. Histamine:
 Formed by decarboxylation of histidine and is stored bound by
electrostatic interaction to an acid matrix protein called heparin.
 Two receptors for Histamine H1 receptor on smooth muscles, binding of
histamine results in constriction, and increased vascular permeability.
 H2 receptors involved in mucous secretion and increased vascular
permeability and release of HC1 from stomach mucosa.
 H1 receptors are blocked by antihistamines e.g. Benadryl.
 H2 receptors are blocked by other drugs e.g. cimetidine.
2. Serotonin: similar to histamine in its effect.
3. Cytokines and chemotactic factors:
a)
b)
c)
d)
e)
f)
g)
GM-CSF.
IL-5
TNF.
Eosinophilic chemotactic factors "ECFs".
Platelet-activating factor "PAF".
Leukotrienes.
IL-8-chemotaxis of PMNLs.
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4. Heparin:
 Acidic proteoglycan.
 Inhibits coagulation.
 Not involved directly in anaphylaxis.
B. Newly Synthesized Mediators:
1. Leukotrienes "LTs":
 Metabolite of arachidonic acid "LTB4, LTC4, LTD4, LTE4".
 They cause prolonged constriction of smooth muscles. The cause of much
antihistamine-resistant asthma in humans.
2. Thromboxanes and Prostaglandins:
 They are vasoactive causing bronchoconstriction and are chemotactic for
neutrophils, eosinophils, basophils, and monocytes.
3. Platelet-Activating Factor "PAF":
 Activation leads to release of histamine, serotonin, arachidonic acid
metabolites.
 Potent bronchoconstrictor and vasodilator produces shock.
Late-Phase Reaction:
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Occurs within 48h and persists for several days.
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Clinical consequences of allergic reactions:
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Allergic rhinitis "hay fever".
Food allergics.
Atopic dermatitis.
Asthma.
Clinical Tests:
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Skin-prick test:
 Minute amounts of Ag.
 Wheal and flare response "redness and edema" within 10-15 min.
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Radioallergosorbent test "FAST":
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Covalent coupling of allergen to insoluble matrix.
Dip into a sample of patients serum, allowed to bind specific Ab for allergen.
Wash, radiolabeled Ab specific for IgE is added.
The amount of radioactivity bound Is a measure of the amount of specific IgE
Ab in the serum sample.
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Intervention:
a) Environmental intervention:
 Avoid exposure to known allergen.
b) Pharmacological intervention:
 Bronchodilators e.g. aminophylline.
 Antihistamines.
 Corticosteroids.
c) Immunologic intervention:
 Hyposensitization:
o injecting the patient with increasing doses of allergen.
o IgG level is increased which competes with IgE for allergen.
o Initial increase in levels of IgE followed by prolonged decrease on
continued therapy due to induction of tolerance or to switch from T H2 to
TH1 cells.
o Use of humanized anti IgE monoclonal Ab which does not cross link IgE
bound to mast cells and basophils.
o Use of cytokines "shift from TH2 to TH1 responses".
o Use of anticytokines e.g. IL-4(responsible for IgE class switching in B
cell) to inhibit its production.
o Cytokine receptor antagonists.
o Administration of chemically altered allergen which suppress a primary or
established IgE response.
Protective Role of IgE:
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The immune response to many parasite worms favors the induction of IgE.
Histamine and other mediators associated with anaphylactic response are
released in response to worm Ags cross-linking IgE on the surface of mast cells
and eosinophils. The effects of increased permeability due to histamine release
bring serum components, including IgG Abs, to the site of worm infestation.
The IgG Abs bind to the surface of the worm and attracts the eosinophils, which
have migrated to the area as a result of the chemotactic effects of ECF-A.
The eosinophils then bind to the IgG-coated worm via their membrane receptors
for Fc and release the contents of their granules(fig.14.8).
As eosinophils express the low affinity Fc receptor for IgE,which facilitates the
binding of these cells to IgE-coated worms.
The major basic protein released from the eosinophil granules coats the surface
of the worm and leads, in some unknown way, to the death of the worm and its
eventual expulsion from the body.
All components of the type I reaction combine to perform this protective
function. This beneficial effect suggests that the wide range of responses
involving IgE may have evolved from efforts to combat worm parasitism.
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Type II – Ab-mediated Cytotoxic Reactions
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Cytotoxic reactions occur when IgG or IgM Abs bind to Ag on the surface of cells
and activates complement cascade, culminating in destruction of the cells.
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Many of these cytotoxic reactions are manifestations of Ab-mediated
autoimmunity. Abs are either directed against normal self Ags e.g. cross reactive
Abs elicited following infection or modified self-Ags e.g. drug-induced auto-Abs
elicited following the binding of drugs to certain cell membranes. The targeted cell
is either damaged or destroyed.
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Ab-mediated mechanisms are involved in these cytotoxic reactions:
1. Complement-mediated reactions:
 Ab reacts with cell membrane component, leading to complement fixation.
 Complement cascade is activated.
 Cell may be lysed or opsonization mediated by receptors for FC or C3b. Fig
15.1 p. 216 expressed on M and PMNLs.
 Blood cells are most commonly affected by this mechanism.
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2. Antibody-Dependent Cell-Mediated Cytotoxicity "ADCC":
 It uses FC receptors on many cells "e.g. NK cells, M, PMNLs, eosinophils
as a means of bringing these cells into contact with Ab-coated target cells.
Fig 15.1B p. 216.
o Lysis requires contact but does not include phagocytosis or complement
activation.
o ADCC lysis of target cells is similar to that of TC cells, perforin and
granzymes are released perforins forms pores, granzymes "serine
proteases" activate events leading to apoptosis.
o ADCC reactions involve IgG and IgG FC receptors.
o IgE can also be involved "the mechanism is similar to type I".
3. Ab-mediated cellular dysfunction:
 Cell surface serve as target Ags when auto-Abs bind to such receptors, they
impair function without causing cell injury or inflammation.
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Examples of Cytotoxic
Hypersensitivity Reactions
1. Transfusion Reactions:
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Transfusion of ABO-incompatible blood results in complement-mediated
cytotoxic reactions.
A person with blood group O has in his blood anti A Abs and Anti B Abs
isohemagglutinins of IgM type.
Upon transfusion with blood group A IgM will bind RBCs, activates
complement and hemolysis results. Kidney may be damaged because of the
large quantities of RBCs membranes and the toxic of effects of heme complex.
2. Drug-induced Reactions:
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Certain drugs act as haptens and combine with cells or with other circulating
blood constituents and induce Ab formation.
When Ab combines with cells coated with the drug, cytotoxic damage results.
 e.g. some drugs bind to platelets, causing them to become immunogenic, Ab
response's cause lysis of platelets resulting in thrombocytopenia.
3. Rh incompatibility:
1) Rh- mother pregnancy Rh+ fetus delivery some fetus blood  mother
circulation  anti Rh Abs "IgG".
2) 2nd pregnancy  anti Rh Abs crosses placenta from mother to Rh+ fetus 
destruction of fetus RBCs.
 Administration of anti Rh Abs to the mother within 72 h of delivery
prevents Rh incompatibility.
4. Autoimmune Reactions involving cell Membrane Receptors:
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Myasthenia gravis is an autoimmune disease where antagonistic auto-Abs
reactive with acetylcholine receptors in the motor end plates of skeletal muscles
impair neuromuscular transmission, causing muscle weakness "Fig.15.1C p.
216"
In Grave's disease, auto-Abs serve as agonists, causing stimulation of target
cells.
 Abs against TSH receptor on thyroid epithelial cells, stimulate the cells,
resulting in hyperthyroidism.
5. Autoimmune Reaction involving other cell membrane determinants:
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Some people produce Abs reactive against their own blood cells "autoimmune
hemolytic", binding of anti-RBC auto-Abs shortens their life span or destroys
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them by mechanisms that involve hemolysis or phagocytosis via receptors for
Fc and C3B.
Type III Hypersensitivity
Immune Complex Reactions
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Immune complex reactions occur when complexes of Ag and IgM or IgG
accumulate in the circulation or in tissue and activate the complement cascade.
Normally small amounts of complexes are removed by phagocytic cells.
Complexes bind IgG Fc receptors on phagocytic cells. RBCs with C3b receptors
may bind complexes which are removed in the liver by kupffer cells.
When large amounts of complexes are deposited in tissues, they trigger a variety
of systemic symptoms known as type III hypersensitivity reactions.
Complexes may be deposited in kidneys, skin, joints, choroids plexus and ciliary
artery of the eye.
Ag-Ab complexes may fix complement &/or activate effector cells (e.g.
neutrophils) that cause tissue damage.
C3a, C5a generated by complement activation induce mast cell degranulation M
are stimulated to release TNF- and IL-1, platelets form microthrombi and release
PDGF-platelet derived growth factor.
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Phases of Systemic Immune Complex Disease
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1) Ag-Ab immune complexes form in the circulation.
2) Deposition of immune complexes in various tissues.
3) Occurrence of inflammatory reactions in various tissues.
 Deposition of immune complexes is influenced by the size e.g. small or
intermediate complexes which circulate for longer time tend to be deposited,
while larger complexes are rapidly removed by phagocytic cells.
 The integrity of the mononuclear phagocytic system influence the development
of systemic immune complexes.
- Serum Sickness:
 The prototype of systemic immune complex disease.
 Treatment with horse serum containing Abs to some bacterial toxins.
 2nd injection of horse serum "foreign for human body" may develop serum
sickness "allergic manifestations".
- Rheumatic fever as sequale of group A streptococsal infection:
 It involves inflammation and damage to heart, joints and kidneys.
 Ags in the cell wall and membrane of streptococci cross react with human Ags
found in heart muscle, cartilage, glomerular basement membrane.
 Abs to streptococcal Ags bind to these components and induce inflammatory
reactions.
- Arthus reactions:
 It is the prototype of localized immune complex reactions.
 Local inflammatory response generated after reactivity of Ag with already
formed, Ag-specific IgG.
 Ag-Ab reactions near vessel walls, complexes form and accumulate ending
with the rupture of the vessel wall and hemorrhage, accompanied by necrosis of
local tissue.
Delayed-type hypersensitivity "type IV"
- Cell-mediated immunity "CMI" reactions.
- Mediated by T-cell-dependent effector mechanisms involving both CD4+ TH1 cells
and CD8+ cytotoxic T cells.
- Abs do not play a role in this type.
- TH1 cells-upon activation-release cytokines that cause accumulation and activation
of M which in turn cause local damage.
- Delayed onset.
- Type IV hyper sensitivity reactions can be transferred only with T cells.
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- Ags eliciting this type of response may be foreign tissue "as in allograft reactions",
intracellular parasites "viruses, mycobacteria, fungi, soluble proteins", or chemicals
penetrating skin and couple to body proteins that serve as carrier.
1. Characteristics of DTH:
 Clinical features vary, depending on the sensitizing Ag and the route of Ag
exposure.
 The major events leading to type IV reactions are:
1. activation of Ag-specific inflammatory TH1 cells in a previously sensitized
individual.
2. secretion of cytokines by Ag-specific TH1 cells.
3. recruitment and activation of Ag-nonspecific inflammatory leukocytes.
2. Mechanisms of DTH:
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 DTH reactions also involve CD8+ T cells which are activated & expanded
during the sensitization stage of the response.
 CD8+ T cells damage tissue by cell-mediated cytotoxicity.
 Activation of CD8+ T cells occurs as a consequence of the ability of many lipidsoluble chemicals capable of inducing DTH reactions to cross the cell
membrane.
o e.g. pentadecacatechol, the chemical which induces poison ivy. It is
degraded Within cytoplasm to generate modified peptides that are
translocated to the endoplasmic reticulum "ER" & then delivered to cell
surface in the context of MHC class I modules.
 Cells presenting such modified cell proteins are subsequently damaged or killed
by CD8+ T cell.
- Examples of DTH:
1) Contact sensitivity "contact dermatitis":
 The prototype of contact dermatitis is poison ivy dermatitis.
 The offending substance is contained in an oil secreted by the leaves of the
poison ivy vine and other related plants.
 Oils contain a mixture of catechols "dihydroxyphenols" with long
hydrocarbon side chains.
 They penetrate skin by virtue of their lipophilicity and couple covalently to
cell-associated proteins "Lipid-soluble haptens".
 Various chemicals nickel "Ni" and chromium "Cr" present in Jewelry are
capable of inducing contact sensitivity probably by chelation to skin
proteins.
 Offending allergen is presented by Langerhans cells. Expansion of TH1
clones capable of recognizing the specific contact sensitizer.
 Subsequent contact "challenge" with the sensitizing agent triggers the
elicitation stage of DTH.
 In many cases, sensitizing agent remains for 1 week, when T cells expand,
the Ag that persists serve as the challenging Ag and a reactions will flare
up.
 Test for the presence of contact sensitivity:
o A solution of the suspected Ag is spread on the skin and covered by an
occlusive dressing.
o The appearance within 3 days of an area of induration and erythema,
indicates sensitivity.
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2) Tuberculin-type hypersensitivity:
 Cutaneous inflammatory reactions characterized by red swelling of the skin
in 48-74 hrs after challenge.
 Purified protein derivative "PPD". Mantoux test is used to test if the
individual has been previously sensitized to Ags expressed by M.
tuberculosis as a consequence of infection with this organism.
 The area is infiltrated by monocyte-macrophage series and few
lymphocytes.
 False negative "HIV patients and those who receive high doses of
chemotherapy" due to inhibition of T cells.
 False-positive in vaccinated individuals with BCG.
3) Allograft Rejection:
 Treatment of DTH by corticosteroids topically
Immunosuppressive drugs may be used in severe cases.
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or
systemically.