Failures of the Immune System1

7/31/2019 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.

Failures of the Immune System1

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