failures of the immune system1
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HYPERSENSITIVTY
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Hypersensitivity refers to undesirable(damaging, discomfort-producing andsometimes fatal) reactions produced by the
normal immune system. Hypersensitivity is a process of reactions of
antigen with antibodies or sensitized
lymphocytes that are harmful to the host.
Hypersensitivity refers to processes in whichthe immune response itself isprimarily
responsible for the induction and/or
exacerbation of disease.
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As in all immune responses, hypersensitivity
requires prior sensitization, is antigen-specific, and depends on the participation of
antibodies or lymphocytes. Frequently, a particular clinical condition
(disease) may involve more than one typeof reaction.
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First contact with potential antigen produces
no detectable reaction but it may sensitize.
If sensitized, exposure to same antigen
elicits a reaction. The reaction is highly specific, elicited only
by sensitizing antigen or a structurally
related substance (cross reacting)
Additional exposures to the same antigenmay increase or sometimes decrease the
severity of the reaction
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There are four major types ofhypersensitivity. Three are mediated byantibody, and the fourth is mediated bycellular mechanisms.
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All individuals make an IgE response against
parasitic infections. About 20% of the population,however, are also genetically predisposed to makean IgE response against relatively harmlessenvironmental antigens e.g. grasses, weeds, andcat or dog proteins.
These individuals are called atopic.
a. Common allergens in type I reactions causingrespiratory symptoms include:
. Tree, grass, and weed pollens
. Cat antigen and other animal dander antigens
. Dust mite faecal pellet antigens
. Mold spores
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It is also known as immediate or anaphylactichypersensitivity.
The reaction may involve skin (urticaria and
eczema), eyes (conjunctivitis), nasopharynx
(rhinorrhea, rhinitis), bronchopulmonary tissues(asthma) and gastrointestinal tract
(gastroenteritis).
The reaction may cause from minor inconvenience
to death.
The reaction takes 15-30 minutes from the time of
exposure to the antigen. Sometimes the reaction
may have a delayed onset (10-12 hours)
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Type 1 hypersensitivity is an allergic reactionprovoked by re-exposure to a specific type of
antigen referred to as an allergen
Exposure may be by ingestion, inhalation,
injection, or direct contact. The difference between a normal immune
response and a type I hypersensitive response
is that plasma cells secrete IgE
This class of antibodies binds to Fc receptors
on the surface of tissue mast cells and blood
basophils.
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The mechanism of reaction involves preferentialproduction of IgE, in response to certain antigens(allergens).
IgE has very high affinity for its receptor on mast cellsand basophils.
A subsequent exposure to the same allergen cross
links the cell-bound IgE and triggers the release ofvarious pharmacologically active substances
Cross-linking of IgE Fc-receptor is important in mastcell triggering.
Mast cell degranulation is preceded by increased Ca++ influx, which is a crucial process; ionophores whichincrease cytoplasmic Ca++ also promotedegranulation, whereas, agents which depletecytoplasmic Ca++ suppress degranulation.
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First exposure sensitizes
hostMacrophages and B cells
present epitopes to T h2cells, which produce
interleukin (IL)-4 IL-4 causes class switch to
IgE.
Mast cells and basophils
Bind IgE to high-affinityreceptors.
IgE cross-linking initiatesgranule release.
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Within 12 h of an acuteallergic reaction a late-phase reaction occurs,which is characterized bya cellular infiltrate of
CD4+ cells, monocytesand eosinophils.
The cells also synthesizeProstaglandins andLeukotrienes LTC 4 andLTD 4 which mediatethe late-phase ( 4-6hours later)Inflammatory response.
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The preformed or primarymediators that arereleased from thegranules are:
Histamine.
Heparin
Eosinophil chemotacticfactor A for anaphylaxis
(ECF-A)Neutrophil chemotactic
factor (NCF-A)
Platelet activating factor
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Leukotriene- B4 basophil attractant
Leukotriene C4, D4 - same as histamine but1000x more potent
Prostaglandins D2 - oedema and pain
PAF - platelet aggregation and heparin release:microthrombi
Under normal circumstances, these mediatorshelp orchestrate the development of adefensive acute inflammatory reaction.
In a run away reaction their bronchoconstrictiveand vasodilatory reactions can be lifethreatening.
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Histamine itself is responsible for many of
the immediate symptoms of allergic
reactions including bronchoconstriction,
vasodilatation, mucus secretion and oedema
caused by leakage of plasma proteins from
small vessels.
Tryptase released by mast cells activates
receptors on endothelial cells thatselectively attract eosinophils and basophils.
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In humans, generalized anaphylaxis presents
with itching erythema, vomiting, abdominal
cramps, diarrhoea and respiratory distress.
In severe cases, laryngeal oedema, vascularcollapse and death can occur. Only a timely
intravenous injection of adrenaline to
counter smooth muscle contraction and
capillary dilatation can prevent death.
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Skin (prick and intradermal) tests
Measurement of total IgE and specific IgE
antibodies against the suspected allergens by
a modification of enzyme immunoassay(ELISA)
Increased IgE levels are indicative of an
atopic condition, although IgE may be
elevated in some non-atopic diseases (e.g.,myelomas, helminthic infection, etc.)
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Avoidance of the allergen Antihistamine (Benadryl) to block histamine
receptors
Chromolyn sodium to stabilize mast cellmembranes
Epinephrine to increase intracellular cyclic AMP
Epinephrine to increase bronchial dilation and
increase heart rate to raise blood pressure
Theophylline (xanthines) to block
phosphodiesterase enzyme that breaks down
cyclic AMP
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Immunotherapy by injecting small amounts of
allergen to switch the response from Th2 to
The lymphocyte type, resulting in decreased
IgE production and increased IgG typeCorticosteroids to reduce both inflammation
and production of antibody
f3-Adrenergic agonists-bronchial dilators that
relax smooth muscle in airways, e.g.,albuterol or terbutaline
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The reaction time is minutes to hours. It is
primarily mediated by antibodies ofIgM or
IgG class and complement, Phagocytes and K
cells may also play a role (ADCC).
Either IgG or IgM is made against normal self
antigens as a result of a failure in immune
tolerance or a foreign antigen resembling
some molecule on the surface of host cellsenters the body and IgG or IgM made against
that antigen then cross reacts with the host
cell surface.
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Type II: Antibody-mediated hypersensitivityagainst our own cells orreceptors or membranes.
There are several othermechanisms whichaccount for type IIhypersensitivity.
These include
opsonisation via C3breceptors which also existon surfaces ofmacrophages andresultant phagocytosis.
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Haemolytic disease of the newborn is an
important clinical example of type II
cytotoxic hypersensitivity. In its severest
form it is known as erythroblastosis foetalis.
In the foetus this disease is due to the
transport across the placenta of IgG specific
for one of the Rhesus (Rh) protein antigens
(RhD).
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If a pregnant woman is Rh-ve and the father
is Rh+ve, there is a chance that the foetus
will also be Rh+.
This situation will pose no problem in thefirst pregnancy, as the mother's immune
system will not usually encounter foetal red
blood cell antigens until placental separation
at the time of birth.
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At birth, Rh+ve foetal red blood cells will
enter the maternal circulation and stimulate
a T-dependent immune response, eventually
resulting in the generation of memory B cells
capable of producing IgG antibody against
RhD.
In a subsequent pregnancy with another
Rh+ve foetus, this maternal IgG can betransported across the placenta, react with
foetal Rh+ve red cells, and activate
complement producing haemolytic disease.
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Haemolytic disease of the newborn can be
prevented by treating the Rh-mother with
RhoGAM TM, a preparation of human anti-
RhD IgG antibody, at 28 weeks of gestation
and again within 24 hours after birth.
This antibody effectively eliminates the
foetal Rh+ red cells before they can generate
RhD-specific memory B cells in the mother.Anti-RhD antibody should always be given to
any Rh-ve individual following termination
of any pregnancy.
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Noncytotoxic type II hypersensitivity is alsodue to the production oftissue-specific IgG
autoantibody.
Instead of causing cytotoxic tissuedestruction, however, the antibody in these
cases alters cellular structure or function.
In Graves disease, an IgG autoantibody
against the thyroid-stimulating hormonereceptor mimics the hormone but stays
bound for an excessive length of time,
resulting in hyperthyroidism.
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On transfusion ofmismatched red cells, the
donor red cells are rapidly
coated with the hosts
isohaemagglutinins andsevere reactions ensue,
which utilize complement.
Since IgM is involved, cross
linking of just a fewdeterminants is sufficient
to set off the entire
complement cascade.
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Drugs coupled to the bodys own cells
become antigenic and the humoral immune
system recognizes the drug-cell complex as
foreign, resulting in an antibody attack which
destroys the cells as well.
When the drug is withdrawn, the sensitivity
is no longer evident. With drugs such as
chlorpromazine and phenacetin, red cellsbecome coupling agents and a type II
haemolytic anaemia is seen.
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Goodpasture syndrome: An autoantibodyproduced against the patient's own type
IV collagen present in basement
membranes of kidney and lung.Autoimmune haemolytic anaemia: An
autoantibody produced against the
patient's own red blood cell antigens
(e.g., I antigen).
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Autoimmune thrombocytopenic purpura:An autoantibody produced against the
patient's own platelet integrin.
Hyperacute graft rejection: The recipientof a graft already has pre-formed antibody
against the graft; after receiving the graft
it is rejected within hours.
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With hold allergen drug .
Remove antibodies: by - Exchange
transfusion
- PlasmapheresisUse immunosuppressive agents:
- Corticosteroids
- Cytoxan
- Cyclosporin A
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The reaction may be general (e.g., serum
sickness) or may involve individual organs
including skin (e.g., systemic lupus
erythematosus, Arthus reaction), kidneys
(e.g., lupus nephritis), lungs (e.g.,
aspergillosis), blood vessels (e.g.,
polyarteritis), joints (e.g., rheumatoid
arthritis) or other organs.
This reaction may be the pathogenic
mechanism of diseases caused by many
microorganisms.
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Type III (immune complex) hypersensitivity is
caused by high levels of circulating, soluble
immune complexes containing IgG or IgM
antibody.
The term immune complex disease refers to
a group of diseases whose pathogenesis
involves tissue damage from excessive
antigen-antibody reactions. The reaction may take 3-10 hours after
exposure to the antigen (as in Arthus
reaction).
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This results in systemic, rather than organ-specific, damage, as the circulating immune
complexes overwhelm the ability of the
mononuclear phagocyte system to remove them.
The excess complexes then deposit in varioustissues (e.g., skin, glomeruli, blood vessels,
synovium, lungs) and activate complement.
The antigen may be exogenous (chronic
bacterial, viral or parasitic infections), orendogenous (non-organ specific autoimmunity:
e.g., systemic lupus eythematosus, SLE).
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The subsequent attempt by neutrophils to remove
them results in degranulation and tissue damage.
Example of type III hypersensitivity immune complex
diseases are:
Serum sickness
Hypersensitivity pneumonitis
Post-streptococcal glomerulonephritis
Lupus Rheumatoid arthritis
Certain infectious diseases, e.g., hepatitis B, HIV,
and mycobacterium
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The body may be exposed to excessive
amounts of antigen in a number of
circumstances, such as persistent infectionwith microbial agents, autoimmunereactions and repeated contact withenvironmental agents.
The subsequent attempt by neutrophils to
remove them results in degranulation andtissue damage.
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When antigen and antibody couple to forminsoluble complexes at fixed sites, tissue reaction
and tissue damage occur.
If complement is involved, C3a and C5a, two
potent vasoactive amines, are released; this causesincreased vascular permeability. Increased vascular
permeability leads to deposition of immune
complexes in tissues.
Antigen in complex reacts with IgE on circulatingbasophils, causing platelet clumping, this forms
microthrombi, causes degranulation and the
subsequent release of histamine, serotonin and
other chemotactic factors.
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Chemotactic factors lead to influx ofpolymorphonuclear leukocytes.
This leads to extracellular release of polymorphgranular contents which include proteolytic
enzymes, kinin forming enzymes and otherproteins which will damage tissues and intensifythe inflammatory process.
When large insoluble complexes form, or when
the clearing system is deficient, immunecomplexes are deposited in tissues with resultantdamage. Deposition can occur anywhere in thebody, but some organs such as the kidney areaffected more often than others.
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Diagnosis involves examination of tissue
biopsies for deposits of Ig and complement
by immunofluorescence.
Presence of immune complexes in serum anddepletion in complement level are also
diagnostic.
Treatment includes anti-inflammatory
agents.
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It is also known as cell mediated or delayed
type hypersensitivity.
The classical example of this hypersensitivity
is tuberculin (Mantoux) reaction whichpeaks 48 hours after the injection of antigen
(PPD or old tuberculin).
The lesion is characterized by induration and
erythema.
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Delayed hypersensitivity is a cell mediatedimmune reaction in an individual previouslysensitized to an antigen. DTH gets its namefrom the long time (24 to 96 hours) that it
takes for a skin reaction against the antigento develop.
Antibody and complement play no role inDTH.
Th1 cells recognize the antigenic peptidepresented by an antigen presenting cell andsecrete cytokines (interferon-y) that activatemacrophages.
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Macrophage mediators then produce the damagein tissues.
Th2-type cells producing IL-4 and IL-5 can alsoproduce tissue damage through their ability to
recruit eosinophils. Antigens may be intracellular bacterial
pathogens (Mycobacterium tuberculosis,Mycobacterium leprae), viruses, fungi, orintracellular parasites.
Contact dermatitis is caused by environmentalsubstances (e.g., poison ivy, nickel), which,acting as haptens, enter the skin, attach to bodyproteins, and become complete antigens.
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The best known example of this reaction is
the positive Mantoux reaction (i.e. the
delayed appearance of an indurated and
erythematous reaction that reaches a
maximum at 2448 h and is characterized
histologically by infiltration with
mononuclear phagocytes and lymphocytes.)
where tuberculin is injected into the skin of
an individual, in whom previous exposure toMycobacterium tuberculosis has induced a
state of cell mediated immunity (CMI).
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Poison ivy
Nickel
Formaldehyde
LatexChromium
Dyes in clothing and cosmetics
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The skin rashes of small pox and measles and
the lesions of herpes simplex have been
attributed to delayed type hypersensitivity
reactions with associated cytotoxic T cell
damage to virally infected cells.
Cell mediated hypersensitivity is also evident
in fungal diseases such as candidiasis,
dermatomycosis, coccidioidomycosis and
histoplasmosis and in parasitoses such as
leishmaniasis and schistosomiasis.
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Unlike other forms of hypersensitivity,
delayed hypersensitivity does not involve
antibody and cannot be transferred from a
sensitized individual to a non sensitized
individual with serum antibody.
Continuing provocation of delayed
hypersensitivity by persisting antigen leads to
formation of chronic granulomas.
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Distinctions between different types of
hypersensitivity.
Mechanisms of immune-mediated damages.
Examples of different types ofhypersensitivity and overlap among them.
Diagnostic test for hypersensitivity diseases
and treatments.