The Hypersensitivity Reactions,2010,Immunology lecture

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The Hypersensitivity Reactions

Immunology Lecture

CLS 311

Specific Lecture Objectives:

At the completion of the lecture, the student will be able to:

1. State the principle characteristics of the types I through IV

hypersensitivities as outlined by Gell and Combs.

2. Compare the immunoglobulin classes, the involvement of complement and host

cells, the chemical mediators present, and the antigens involved in each type of

reaction.

3. Interpret the type of hypersensitivity response given various hypothetical

clinical situations.

The Hypersensitivity States

I. Classification System

A. Older system

1. Immediate (immunoglobulin mediated)

2. Delayed (T-cell or lymphokine mediated)

B. Gell and Coombs system - emphasizes the kind of immunopathological

damage done.

1. Type I: Immediate hypersensitivity

2. Type II: Cytotoxic hypersensitivity

3. Type III: Immune Complex

4. Type IV: Delayed type hypersensitivity

II. Type I Immediate hypersensitivity

A. Demonstrated 1921 by Prausnitz and Kustner

1. Hallmark: ability to be passively transferred from sensitive individual to

non-sensitive individual via serum

F{Kustner allergic to fish, Prausnitz injected serum, waited 24

hrs, then injected fish extract wheal and flare reactions}

2. Antibodies involved found to be IgE, referred to variously as

Prausnitz-Kustner antibodies (P-K antibodies), reagins, reaginic antibodies or

anaphylactic antibodies

a. IgE has non-specific affinity for mast cells and basophils (attaches via the

Fc portion of the molecule), antibodies with this affinity are called cytotropic

antibodies

B. Combining of antigen (allergen) and IgE on mast cell in presence of

calcium ions and regulated by intracellular levels of cAMP (high levels inhibit

release of granules, low levels stimulate degranulation) results in

degranulation of cell and release of histamine and other mediators

C. Mediators of Type I hypersensitivities

1. Mediators include

a. Histamine

b. Slow-reacting substance of anaphylaxis (SRS-A)

c. Eosinophilic chemotactic factor of anaphylaxis

(ECF-A)

d. Platelet activation factor (PAF)

e. Serotonins

f. Bradykinins

g. Possibly other kinins

2. Resulting changes due to mediators

a. Changes in capillary permeability, vessel dilation, smooth muscle

contraction and mucous membrane responses

{General effects: Smooth muscle contraction

Vasodilation

Increased vascular permeability

Increased mucous secretions}

b. Effects may be systemic (anaphylactic shock) or localized (atopic

allergies)

D. Systemic anaphylaxis

1. Usually develops suddenly, most common precipitating events are

the injection of drugs or antisera or the sting of an insect (wasps, bees,

hornets etc.)

Reactions include:

a. Reddening of skin (erythema)

b. Hives (urticaria) and itching

c. Severe respiratory difficulties due to the accumulation of fluids and cells

in lung tissue and constriction of respiratory bronchioles; smooth muscle spasms

d. Airway obstruction from laryngeal edema

e. Hypotension (shock resulting from vascular permeability and collapse)

{vasodilation and leakage of intravascular fluids}

f. Abdominal cramps, vomiting and diarrhea

2. Countermeasures to Anaphylaxis include:

a. Avoidance of known precipitating substances

b. Administration of epinephrine to counteract the effects of

histamine and other vasoactive mediators

c. Maintenance of an airway

d. Drugs to maintain adequate blood pressure whenever shock occurs

E. Local anaphylaxis (atopic allergy) may occur in specific target organs

1. Respiratory system, resulting in hay fever or asthma

2. Skin, resulting in urticaria, atopic dermatitis (eczema)

3. GI tract, resulting in abdominal cramps and diarrhea

Most common allergens: pollen, mold spores, foods, animal hairs, danders

(sloughed skin cells of animals), feathers, dust, wool, insect bites and stings

and some antibiotics

F. Clinical Diagnosis and Treatment of atopic allergies

1. Diagnosis

a. Family history - hereditary predisposition to atopic allergies. If

both parents atopic, 75% of children will be, if one parent atopic, 50% of

children will be

b. Skin testing either directly or passively (cutaneous anaphylaxis

method (P-K))

c. Basophil degranulation test (measures release of histamine from

leukocytes)

d. Determination of serum level of IgE. In normal serum, very

little IgE presents, so little that extremely sensitive methods must be used for

detection. Normal levels in non-atopic individuals is usually less than 20

IU/ml. In atopic individuals generally none are less than 20 IU/ml, many have

greater than 100 IU/ml.

1. RIST (radioimmunosorbent test) measures total IgE, most

sensitive of methods available

2. RAST (radioallergosorbent test) quantitates a specific

IgE. Avoids exposing patient to potentially dangerous skin testing.

2. Treatment of Atopic Reactions

a. Avoidance of identified allergen whenever possible

b. Inactivation of released mediators or inhibition of their

release. The most common drugs used are:

1. Antihistamines to block the effect of histamines

2. Epinephrine and isoproterenol to stimulate the synthesis

of cAMP, also act to dilate bronchiolar smooth muscles

3. Methylxanthine (theophylline) to inhibit degradation of

cAMP, also a muscle relaxer and bronchodilator, but also has a diuretic effect

4. Disodium cromoglycate group: Suppresses mediator-release

by trapping calcium ions at the surface of mast cells, thereby preventing the

influx necessary for granule release. Usually administered by inhalation

therapy

c. Desensitization - Theory: If antigen (allergen) is introduced via

muscular or subcutaneous route, more likely to stimulate immunoglobulins other

than IgE. These non-cytotrophic antibodies may function as blocking antibodies,

combining with the allergen and preventing further reactions with cell-bound IgE

III. Type II Cytotoxic, Cytolytic Hypersensitivity Reactions

A. Cell damaging and cell destroying reactions in which an

antigen-antibody reaction occurs on a cell surface. Occurs within minutes to

hours.

1. Cell can be destroyed by phagocytosis or lysis

2. Complement system frequently involved

3. Antibodies are usually of IgG and / or IgM types

B. Conditions under which cytolytic reactions take place

1. Antigen structural component of cell membrane or an extrinsic

antigen that has attached to cell

2. Antigenic determinant on host cell that is identical or very

similar to foreign antigen originally evoking antibody production

3. New antigens that have occurred on cell surface as a result of

drug-induced changes

4. Antigen-antibody complexes that have formed in circulation and

subsequently attached to red blood cells. This leads to red cell destruction.

C. Diseases resulting from cytolytic reactions are generally in the

category of hematological cytolytic diseases

1. Cells that are destroyed are usually patients cells, but may be

translocated or transfused cells as in Rh incompatibility or red blood cell

transfusion reactions

2. Cell types primarily destroyed

a. Red blood cells

b. White blood cells of the granulocytic type

c. Platelets (thrombocytes)

d. Vascular endothelial cells

D. Examples of Disease

1. Autoimmune hemolytic anemia

2. Autoimmune thrombocytopenia purpura

3. Autoimmune neutropenia

4. Transfusion reactions Type III Immune Complex Hypersensitivity

A. Reactions occur when soluble antigen and corresponding antibody unite

and activate complement. The Ag-Ab complexes form in blood and tissue spaces

and are deposited in the walls of blood vessels, in basement membranes, and in

joint synovia.

B. Arthus reaction demonstrated by Maurice Arthus in 1903.

1. Artificially induced in laboratory.

2. Induced localized inflammatory skin reaction in previously

sensitized rabbit (to horse serum) by intradermal injection of cognate Antigen.

Inflammation grossly visible after several hours

a. Longer time than Type I, but shorter than Type IV.

Classified as immediate because responsible antibodies can be passively

transferred via serum.

b. Ag-Ab complexes form and adhere to vascular endothelium;

complement system activated and some of its chemotactic intermediates attract

neutrophils to site. Anaphylatoxins degranulate mast cells with resultant

release of histamine that causes constriction of arterioles and retards blood

supply to area. Platelets stimulated by the immune complex initiate the

coagulation cascade, resulting in fibrin deposits. Eventually vessels become

clogged with thrombin and accumulated cells, causing an exudate into the

surrounding tissue (edema). Deprivation of blood supply to area results in

ischemic necrosis.

c. Only precipitating (multivalent) antibodies can elicit the

Arthus reaction (mainly IgG). Relatively large amounts of antigen required.

d. Reverse passive Arthus possible (Ab from sensitized animal

injected intradermally, Ag IV or at site).

C. Human lung hypersensitivities (Immune complex pneumonitis, allergic

pneumonitis, hypersensitivity pneumonitis)

1. Natural counterpoint of artificially induced Arthus reaction

2. Farmers lung, pigeon breeder's lung, mushroom workers lung etc.

3. Inhalation of allergen (fungal spores, animal danders, excretory

products etc.) sensitizes. Further exposure elicits IgE and IgG

D. Serum Sickness

Occurs in patients receiving large doses of foreign serums (horse

antitoxin against tetanus, antilymphocyte serum for immunosuppression of tissue

transplant, serum therapy for pneumococcal infection pre-antibiotics). 7-10

days following initial exposure to foreign serum patient develops malaise,

fever, nausea, vomiting, edema, lymphadenopathy, muscle and joint pains and

hives. Massive dose of antigen serves as challenging dose to stimulate Ab

production and as reactive dose. More chronic and less lethal than IgE mediated

anaphylaxis.

In general, findings of cryoglobulinemia (abnormal globulin that

precipitates at 4 degrees C and redissolves on warming) and/or decreased

complement levels suggest presence of immune complexes.

5. Rh incompatibility

IV.

V. Type IV Delayed Hypersensitivity (cell-mediated

hypersensitivity;DTH-Delayed T-cell Hypersensitivity)

A. Usually requires 24-72 hours to reach a maximum reactivity (as

compared to immediate which occur in minutes). Do not depend on antibodies but

on T-lymphocyte cells and their products. Cannot be passively transferred by

serum, but can be transferred by sensitized T cells.

1. First described by Koch 1891. Observed that if tubercle

bacilli were injected into skin of Guinea Pigs previously infected with tubercle

bacilli, an intense area of inflammation would develop in 1-2 days at the site

of injection. Uninfected controls negative.

2. How does T cell accomplish immunity? T cell responsible for the

specific recognition event, but often other cells bring about the final effect

on the antigen or on the host's tissue. Sensitized T-cells release lymphokines,

which, unlike antibodies, are not specific for antigens. T cells sensitized to

a given antigen infiltrate the area where the antigen is located. Other cell

types, especially macrophages, are recruited and activated thru the intervention

of released lymphokines. The recruited cells come to constitute as much as 95%

of the cell infiltrate of the affected area. These recruited cells, not the T

lymphocyte, ultimately are the final effectors of the response.

3. Protective assignments of T cells include

a. Immunity against those infective agents that have an

intracellular habitat (viruses, TB bacilli, Leprosy, Brucella)

b. Recognition and elimination of aberrant " self " cells, namely

cancer cells

c. Recognition and elimination of foreign cells and tissues

such as those which occur in graft rejection

4. DTH is an inflammation mediated by soluble, biologically active

factors released by activated TDTH cells and macrophages. Such

lymphocyte-released factors are given the general name lymphokines.

5. Sequence:

a. Antigen, coupling protein and TDTH cells react on

macrophage surface. Macrophage releases a soluble lymphocyte activating factor

(LAF) called interleukin I (IL-1). This, together with the antigen, stimulates

T cell to synthesize and release a variety of lymphokines.

b. These lymphokines are produced in minute quantities and act

locally. They have been difficult to purify and identify chemically, therefore

they have been named according to their biologic activity. 50-100 have been

named. Action of most lymphokines is on cells: macrophages, other T cells,

eosinophils, neutrophils and basophils.

c. In general, lymphokines stimulate cell proliferation, influence cell

motility, and induce cytocidal or cytostatic activities in macrophages. Can

also influence lymphocyte differentiation and function

6. Examples of lymphokines:

a. Macrophage - activating factor: Macrophages activated by

this lymphokine are larger, have more lysozymes than non-activated, secrete

enzymes involved in inflammation and have increased phagocytic activity. Have

increased killing capacity over resting cells because they release relatively

large amounts of hydrogen peroxide and superoxide ion, both of which help to

destroy microorganisms and possible tumor cells.

b. Migration inhibitory factor: Migration of macrophages out

of area is inhibited when sensitized lymphocytes and their corresponding antigen

are allowed to react. (MIF) keeps lymphocytes localized in area of inflammation.

Also, there is a migration inhibiting factor for leukocytes (LIF)

c. Chemotactic factors: produce lymphokines that attract

macrophages, neutrophils, lymphocytes, eosinophils, basophils and fibroblasts

(collectively referred to as lymphocyte-derived chemotactic factors (LDCF).

Some are specifically named for cell type attracted

Others: Specific Macrophage-arming factor (SMAF)

Osteoclast-activating factor (OAF)

Lymphocyte-transforming factor (LTF)

Colony-stimulating factor (ICSF)

Interferon- inhibits maturation of monocytes

into mature macrophages

B. Allergic Contact Dermatitis

1. Skin contact with a variety of simple chemicals can cause.

Allergens found in cosmetics, industrial chemicals, dyes, ointments, plant

materials and topically applied chemotherapeutic agents. These compounds act as

haptens, coupling with proteins of skin. ACD allergies sometimes referred to as

nonatopic allergies to distinguish from immediate type.

2. Poison Ivy is classic ACD. Typical reaction 18-24 hours after

contact with allergen. A group of catechols found in sap of poison ivy called

urushiol (u-roishe-ol). These are oxidized to guinones, which couple to skin

proteins and become sensitizing antigens. Catechols are also present in poison

oak and poison sumac

3. Control of DTH

a. No clear immunological rational exists for desensitization of

T cells. Steroids and other anti-inflammatory substances are sometimes used,

but are not always effective.

hypersen.doc

3/30/2010 10:45 AM