Ch13 (3)

Clinical Immunology & SerologyA Laboratory Perspective, Third Edition

Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company

Hypersensitivity

Chapter Thirteen

D02 RECORDER


Copyright © 2010 F.A. Davis Company

Hypersensitivity Hypersensitivity reactions can be defined as a

heightened state of immune responsiveness.

Typically, it is an exaggerated response to a

harmless antigen that results in injury to the

tissue, disease, or even death.



Hypersensitivity Figure 13-1



Hypersensitivity In Type I reactions, cell-bound IgE antibody

reacts with antigen to release physiologically

active substances.

Complement is not involved in type I reactions.



Hypersensitivity Type II reactions are those in which free IgG

or IgM antibody reacts with antigen associated

with cell surfaces.

Complement plays a major role in producing

tissue damage in type II reactions.



Hypersensitivity In type III hypersensitivity, free antibody

reacts with soluble antigen to form complexes

that precipitate in the tissues.

Complement plays a major role in producing

tissue damage in Type III reactions.



Hypersensitivity Type IV hypersensitivity differs from the

other three, because sensitized T cells rather

than antibody are responsible for the

symptoms that develop.

Complement is not involved in type IV

reactions.

Refer to Table 13-1 in the text for a summary

of the main characteristics that distinguish

each class.



Hypersensitivity Types I–III have previously been referred to as

immediate hypersensitivity because

symptoms develop within a few minutes to a

few hours.

Type IV hypersensitivity has been called

delayed hypersensitivity, because its

manifestations are not seen until 24–48 hours

after contact with antigen.



HypersensitivityType I Hypersensitivity "heridetary"

The distinguishing feature of type I

hypersensitivity is the short time lag, usually

seconds to minutes, between exposure to

antigen and the onset of clinical symptoms.

The key reactant present in type I, or

immediate sensitivity reactions, is IgE.



HypersensitivityType I Hypersensitivity

Antigens that trigger formation of IgE are

called atopic antigens, or allergens.

Atopy refers to an inherited tendency to

respond to small quantities of naturally

occurring inhaled and ingested allergens with

continued production of a large amount of

IgE.




Although actual antibody synthesis is

regulated by the action of cytokines, the

tendency to respond to specific allergens

appears to be linked to inheritance of certain

major histocompatibility complex (MHC)

genes.




Various HLA class II molecules, especially

HLA-DR2, DR4, and DR7, seem to be

associated with a high response to individual

allergens.

HLA-D molecules are known to play a role in

antigen presentation; thus, individuals who

possess particular HLA molecules are more

likely to respond to certain allergens.




Certain polymorphisms in the gene for the

beta chain of IgE receptors are linked to atopy.

These high-affinity receptors, named FCε-RI

receptors, bind the FC region of the epsilon-

heavy chain and are found on basophils and

mast cells.




Langerhans and dendritic cells internalize and

process allergens from the environment and

transport the allergen-MHC class II

complex to local lymphoid tissue, where

synthesis of IgE occurs.

Binding of IgE to cell membranes increases

the half-life of IgE from 2 or 3 days up to at

least 10 days.




Once bound, IgE serves as an antigen

receptor on mast cells and basophils.

Cross-linking of at least two antibody

molecules by antigen triggers release of

mediators from these cells. (See Fig. 13-2.)







Cross-linking of surface-bound IgE on

basophils and mast cells by a specific allergen

causes changes in the cell membrane that

result in the release of preformed or primary

mediators, include histamine, heparin,

eosinophil chemotactic factor of anaphylaxis

(ECF-A), neutrophil chemotactic factor, and

proteases.




The effect of each of these mediators is

discussed and a summary is presented in

Table 13-2 in the text.

In addition to immediate release of preformed

mediators, mast cells and basophils are

triggered to synthesize certain other reactants

(eg, prostaglandins, leucotrienes) from the

breakdown of P-lipids in the cell membrane.




These products are responsible for a late-

phase allergic reaction seen within 6 to 8

hours after exposure to antigen.

Newly formed mediators include platelet

activating factor (PAF), prostaglandin (PG) D2,

leukotrienes (LT B4, C4, D4, and E4); and

cytokines. Promote prolonged symptoms seen

in asthma.




Anaphylaxis is the most severe type of

allergic response, because it is an acute

reaction that simultaneously involves multiple

organs.

It may be fatal if not treated promptly.

Symptoms depend on such variables as route

of exposure, dosage, and frequency of

exposure.




Rhinitis is the most common form of atopy, or

allergy; food allergies is an other example

which leads to vomiting ,diarrhea, urticaria

Asthma can also result: The airflow obstruction

is due to bronchial smooth muscle contraction,

mucosal edema, and heavy mucous secretion,

triggered by histamine , prostaglandins and

leucotrienes.




Testing for allergies or immediate

hypersensitivity can be categorized as in vivo

or in vitro methods.

In vivo methods involve direct skin testing,

which is the least expensive and most specific

type of testing.




In vitro tests involve measurement of either

total IgE or antigen-specific IgE.

These are less sensitive than skin testing but

usually are less traumatic to the patient.




testing methods involve the use of

immunoassays employing enzyme or

fluorescent labels (see Fig.13-3)

Microarray testing on a microscope slide ,

using anti-IgE with a fluorescent label






Type 1 hypersensitivity Treatments:

1. antihistamines, corticosteroids

2. muscle relaxants eg. bronchodilators

3. epinephrine for systemic anaphylaxis

4. desensitization

5. antibodies against IgE, leucotrienes, etc



HypersensitivityType II Hypersensitivity

The reactants responsible for type II

hypersensitivity, or cytotoxic hypersensitivity,

are IgG and IgM.

The antigens responsible for their formation

may be altered self-antigens or heteroantigens

on a cell surface.




Antibody coats cellular surfaces and

promotes phagocytosis"Fc" by both

opsonization and activation of the complement

cascade.

Macrophages, neutrophils, and eosinophils

have FC receptors that bind to the FC region

of antibody on target cells, thus enhancing

phagocytosis.




Natural killer (NK) cells also have FC

receptors, and if these link to cellular antigens,

cytotoxicity results.

Once activated, complement may coat cells

with C3b, thus facilitating phagocytosis

through interaction with specific receptors for

C3b on phagocytic cells.




Complement may also generate cell lysis if the

cascade goes to completion.

Examples of type II reactions include

transfusion reactions, hemolytic disease of the

newborn (HDN) (see Fig. 13-4 in the text), and

autoimmune hemolytic anemia (including

warm and cold autoagglutinins).




Some type II reactions involve destruction of

tissues because of combination with antibody.

Medications, acting as haptens, may bind to

rbc membranes, leading to antibody and

complement-induced hemolysis.

Other examples include Goodpasture’s

syndrome, Hashimoto’s disease, myasthenia

gravis, and type 1 diabetes mellitus.




The Direct Coombs’ Test can detect in vivo

attachment of antibodies to the patient’s own

red cells.

The Indirect Coombs’ Test can detect in vitro

attachment of antibodies in the patient’s serum

to a panel of reference red cells with known

antigens on their surfaces.



HypersensitivityType III Hypersensitivity

Type III hypersensitivity reactions are similar

to type II reactions since IgG or IgM is

involved and destruction is complement

mediated.

However, in the case of type III reactions, the

antigen is soluble.




When soluble antigen combines with antibody,

immune complexes are formed that precipitate

out of the serum.

Normally such complexes are cleared by

phagocytic cells.

But if the immune system is overwhelmed,

these complexes deposit in the tissues.




There they bind complement, causing damage

to the particular tissue involved.

Precipitating complexes occur in mild antigen

excess, and these are the ones most likely to

deposit in the tissues.




Sites in which this deposition typically occurs

include the glomerular basement membrane,

vascular endothelium, joint linings, and

pulmonary alveolar membranes.

Long-term changes include loss of tissue

elements that cannot regenerate and

accumulation of scar tissue.




The classic example of a localized type III

reaction is the Arthus reaction.

The inflammatory response is caused by

antigen–antibody combination and subsequent

formation of immune complexes that deposit in

small dermal blood vessels.

See Figure 13-5



HypersensitivityFigure 13-5




Complement is fixed, attracting neutrophils

and causing aggregation of platelets.

Neutrophils release toxic products such as

oxygen-containing free radicals and proteolytic

enzymes (see Fig. 13-5).

The Arthus reaction is rare in humans.




Serum sickness is a generalized type III

reaction that is seen in humans, although not

as frequently as it used to be.

Serum sickness results from passive

immunization with animal serum, usually horse

or bovine, used to treat such infections as

diphtheria, tetanus, and gangrene.




Type III hypersensitivity reactions can be

triggered by either autologous or heterologous

antigens.




Systemic lupus erythematosus (SLE) and

rheumatoid arthritis are auto immune diseases

caused by this process.

In SLE, antibodies are directed against

constituents such as DNA and nucleohistones,

which are found in most cells of the body.




Immune complex deposition in SLE involves

multiple organs, but the main damage occurs

to the glomerular basement membrane in the

kidney.

In rheumatoid arthritis, an antibody called

rheumatoid factor is directed against IgG and

forms deposits in the joints causing

complement-induced cytolysis.



HypersensitivityType IV Hypersensitivity

Type IV hypersensitivity differs from the other

three types of hypersensitivity in that

sensitized T cells, usually a subpopulation of

Th1 cells, play the major role in its

manifestations.

Antibody and complement are not directly

involved.




There is an initial sensitization phase of 1–2

weeks that takes place after the first contact

with antigen.

Upon subsequent exposure to the antigen,

symptoms typically take several hours to

develop and reach a peak 48–72 hours after

exposure to antigen.




Th1 cells are activated and release cytokines,

including IL-3, interferon gamma (IFN-γ),

tumor necrosis factor-beta (TNF-β), and tumor

necrosis factor-alpha (TNF-α).

These recruit macrophages and neutrophils,

produce edema, promote fibrin deposition, and

generally enhance an inflammatory response.




Cytotoxic T cells are also recruited, and they

bind with antigen-coated target cells to cause

tissue destruction.

Allergic skin reactions to bacteria, viruses,

fungi, and environmental antigens such as

poison ivy typify this type of hypersensitivity

reaction.




Further examples include contact dermatitis,

hypersensitivity pneumonitis and the

response to the tuberculin skin test that uses a

Mycobacterium tuberculosis antigen that is

injected under the skin (PPD test) .

Preferred testing for TB is the interferon

gamma release assay (IGRA); better

specificity



Hypersensitivity; 13-6Figure 13-6


Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company

Type IV hypersensitivity

Testing for the cause of dermatitis:

1. Patch testing with specific ag

Read after 48 hrs.

2. Intradermal injection with purified ag

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