group ii immunovirology

8/6/2019 Group II Immunovirology

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ASSIGNMENT OFIMMUNOVIROLOGY

GROUP II

Q2.What is Hypersensitivity?

With examples, discuss the differenttypes of Hypersensitivities.


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The different types of hypersensitivity

reactions are distinguished by (1) their time

course, and (2) whether antibodies or T

cells are involved. Hypersensitivitiesmediated by antibodies are the immediate

and subacute hypersensitivities. T cells

cause delayed hypersensitivity.


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There are four Types of Hypersensitivities

1. Type I: Immediate Hypersensitivity. Anaphylacticreactions mediated by IgE antibodies binding to

mast cells.2. Type II: Antibody-Dependent Cellular Cytotoxicity

3. Type III: Immune complex reactions

4. Type IV: Cell-mediated immunity (DTH- delayed type

hypersensitivity)NB: Types I, II and III are antibody mediated and Type

IV is cell mediated


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Type I: Immediate hypersensitivity (Allergy):

Type I hypersensitivity manifests itself in tissue reactionsoccurring within seconds after the antigen combines with thematching antibody. It may take place as a systemic anaphylaxis(e.g., after administration of heterologous proteins) or as alocal reaction (e.g. an atopic allergy such as hay fever).

The general mechanism of immediate hypersensitivity involves

the following steps. An antigen induces the formation of IgEantibody, which binds firmly by its Fc portion to a receptor onmast cells and eosinophils. Sometime later, a second contact ofthe individual with the same antigen results in the antigen'sfixation to cell-bound IgE, cross-linking of IgE molecules, and

release of pharmacologically active mediators from cells withinseconds to minutes. Cyclic nucleotides and calcium areessential in the release of mediators. There may also be asecond "late phase" that lasts for several days and involvesinfiltration of tissues with leukocytes, particularly eosinophils.


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Type I Hypersensitivity Pharmacological

Mediators Released from Mast cells

EFFECTOR ACTIVITY

Histamine (pre-formed) Vasoactive amine, smooth muscle contraction,

vascular permeability of endothelial cells

Eosinophil Chemotactic

Factor (ECF)

Attracts eosinophils to site

Leukotrienes C4 & D4 Prolonged smooth muscle contraction,

increased vascular permeability

Prostaglandins vasoactive, bronchoconstriction, chemotactic for

leukocytes

Platelet Activating Factor

(PAF)

Releases stores of histamine from platelets

Cytokines: IL-3, 4, 5,

GM-CSF & TNF-

Amplify Th2 IgE response, promote eosinophil

prodn, inflamm, increase adhesion molecules on

endothelium


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Clinical Examples

Allergic rhinitis (hay fever)

Allergic Asthma

Urticaria (hives)

Eczema (itchy rash)

Systemic anaphylaxis

Clinical Diagnosis

Skin testing: Intradermal

injection of allergen -> Wheal

and Flare reaction

Erythema: Vascular dilation

Edema: Vascular permeability

Symptoms manifest in 10-15

minutes

Wheal: edema (fluid in tissue)

Flare: erythema (redness)

Positive Test indicates presence

of allergen-specific IgE on mast

cells in tissues


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Clinical Intervention: Allergen Avoidance

Allergen-specific Immunoth

erapy (Hyposensitization): Administration of very low doses of allergen over

months to induce blocking IgG (e.g. allergy shots for

grass allergies) and possibly regulatory T cells

Desensitization: Administration of very low doses ofallergen every 10-15 minutes to slowly trigger all mast

cells via IgE (e.g., desensitization to penicillin is done in

ICU: intensive care unit)

Mast cell Stablization: drugs that block degranulation

of mast cells and basophils (sodium cromoglycate

Mediator antagonists: antihistamines, epinephrine


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Immunosuppressants: corticosteroids - work

by blocking arachidonic acid pathway forsynthesis of leukotrienes

Anti-IgE Monoclonal Antibodies: Omalizumabbinds Fc portion of IgE to block IgE from

binding to Fc receptor.

Eosinophils and mast cells provide the mosteffective immune response to worm parasites

How??? Release of granule contents


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Type II: Hypersensitivity

Foreign antigen on cell induces IgG antibodyformation then the binding of IgG antibodies tocell surface antigens or extracellular matrix

molecules. Antibody directed at cell surfaceantigens can activate complement (or othereffectors) to damage the cells. The antibody (IgGor IgM) attaches to the antigen via the Fab region

and acts as a bridge to complement via the Fcregion. The result may be complement-mediatedlysis, as occurs in hemolytic anemias, ABOtransfusion reactions, and Rh hemolytic disease.


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Clinical Examples

Drugs such as penicillin can attach to surface proteins on red

blood cells and initiate antibody formation. Such autoimmuneantibodies may then combine with the cell surface, with

resulting hemolysis. Certain pathogens (eg, Mycoplasma

pneumoniae) can induce antibodies that cross-react with red

cell antigens, resulting in hemolytic anemia. In rheumaticfever, antibodies against group A streptococci cross-react with

cardiac tissue. In Goodpasture's syndrome, antibody forms

against basement membranes of kidney and lung, resulting in

severe damage to the membranes through activity of

complement-attracted leukocytes. In some cases, antibodiesto cell surface receptors alter function without cell injuryfor

example, in Graves' disease, an autoantibody binds to the

thyroid-stimulating hormone (TSH) receptor and by

stimulating the thyroid causes hyperthyroidism.


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Transfusion reactions : pre-formed natural anti-

ABO, anti-Rh and otheranti-RBC Abs Erythroblastosis fetalis: Rh incompatability

induces anti-Rh antibodies in mother-IgG crosses

placenta in subsequent child

Autoimmune hemolytic anemia: autoimmune

response against RBCgenerally after an infection

Hyperacute graft rejection: preformed Abs to

transplantation antigens

cause immediate, severe and non-reversible

damage to graft


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Clinical Diagnosis

History and clinical signs(decr. renal func.; lunginfiltrates, hemolysis, anti-

RBC Abs) Presence of Abs against the

appropriate antigen

Detection of Abs andcomplement on affected

tissue

Clinical Intervention

Blood cross-matching

Rhogam for RH(-) mothers

Supportive plasmapheresis

and Immune suppressants


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Type III: Immune Complex Hypersensitivity

When antibody combines with its specific antigen,

immune complexes are formed. Normally, they arepromptly removed, but occasionally they persist and

are deposited in tissues, resulting in several disorders.

In persistent microbial or viral infections, immune

complexes may be deposited in organs (eg, the

kidneys), resulting in dysfunction. In autoimmune

disorders, "self" antigens may elicit antibodies that

bind to organ antigens or are deposited in organs and

tissues as complexes, especially in joints (arthritis),

kidneys (nephritis), and blood vessels (vasculitis).

Finally, environmental antigens such as fungal spores

and certain drugs can cause immune complex

formation with disease.


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Wherever immune complexes are deposited, they activatethe complement system, and macrophages and neutrophilsare attracted to the site, where they cause inflammationand tissue injury. There are two major forms of immunecomplex-mediated hypersensitivity. One is local (Arthusreaction) and typically elicited in the skin when a low dose

of antigen is injected and immune complexes form locally.IgG antibodies are involved, and the resulting activation ofcomplement leads to activation of mast cells andneutrophils, mediator release, and enhanced vascularpermeability. This typically occurs in about 12 hours. Asecond form of type III hypersensitivity involves systemicimmune complex disease. There are several examples,including diseases such as acute poststreptococcalglomerulonephritis.


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Acute poststreptococcal glomerulonephritis is awell-known immune complex disease. Its onsetoccurs several weeks after a group A-hemolyticstreptococcal infection, particularly of the skin,and often occurs with infection due tonephritogenic types of streptococci. Thecomplement level is typically low, suggesting an

antigen-antibody reaction with consumption ofcomplement. Lumpy deposits of immunoglobulinand complement component C3 are seen alongglomerular basement membranes stained byimmunofluorescence, suggesting antigen-antibodycomplexes. It is likely that streptococcal antigen-antibody complexes are filtered out by glomeruli,that they fix complement and attract neutrophils,and that the resulting inflammatory process

damages the kidney.


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Three types of Immune

C

omplexes:Cause Antigen Sites of complex

Cause Antigen

deposition

Persistent

infection

Microbial

antigen

Infected organ(s),

kidney

Autoimmunity Self antigen Kidney, joints,

arteries, skin

Extrinsic Environmental

antigen

lung


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Clinical Examples ofType III Hypersensitivity

Serum Sickness: Formation of immune complexes due to Ab

response to passive immunotherapy with foreign protein.

Rheumatoid Arthritis: Rheumatoid Factor (IgM specific for IgG

Fc)

Infectious Diseases: malaria, persistent viral infections, leprosy Occupational Diseases: Ab to soluble environmental antigen

(e.g. Farmers lung-- reaction due to spores in moldy hay--

pneumonitis)

Arthus Reaction: repeated injection of antigen, local formationof immune complexes in tissue next to blood vessel, FcR on

tissue mast cells binds to immune complex and degranulates

causing inflammatory cells to be attracted to site. Vessel

occlusion and/or rupture may occur.


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Clinical Diagnosis

Presence of Ags and Abs

Urticarial rash

Clinical Treatment

Immunosuppressants to

prevent further antibody

production Supportive until the

antigen


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Type IV: Cell-Mediated (Delayed) Hypersensitivity

Cell-mediated hypersensitivity is a function not

of antibody but of specifically sensitized T

lymphocytes that activate macrophages tocause an inflammatory response. The response

is delayedie, it usually starts 23 days after

contact with the antigen and often lasts fordays.


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Contact Hypersensitivity

Contact hypersensitivity occurs after sensitization with simplechemicals (eg, nickel, formaldehyde), plant materials (poisonivy, poison oak), topically applied drugs (eg, sulfonamides,neomycin), some cosmetics, soaps, and other substances. In allcases, small molecules enter the skin and then, acting as

haptens, attach to body proteins to serve as complete antigen.Cell-mediated hypersensitivity is induced, particularly in skin.When the skin again comes in contact with the offendingagent, the sensitized person develops erythema, itching,vesication, eczema, or necrosis of skin within 1248 hours.Patch testing on a small area of skin can sometimes identifythe offending antigen. Subsequent avoidance of the materialwill prevent recurrences. The antigen-presenting cell in contactsensitivity is probably the Langerhans cell in the epidermis,which interacts with CD4 TH1 cells that drive the response.


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Tuberculin-Type Hypersensitivity

Delayed hypersensitivity to antigens of microorganismsoccurs in many infectious diseases and has been used as anaid in diagnosis. It is typified by the tuberculin reaction.When a small amount of tuberculin is injected into theepidermis of a patient previously exposed to

Mycobacterium tuberculosis, there is little immediatereaction; gradually, however, induration and rednessdevelop and reach a peak in 2472 hours. Mononuclearcells accumulate in the subcutaneous tissue, and there areCD4 TH1 cells in abundance. A positive skin test indicatesthat the person has been infected with the agent but doesnot imply the presence of current disease. However, arecent change of skin test response from negative topositive suggests recent infection and possible currentactivity.


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A positive skin test response assists in

diagnosis. For example, in leprosy, a positive

skin test indicates tuberculoid disease, with

active cell-mediated immunity, whereas a

negative test suggests lepromatous leprosy,

with weak cell-mediated immunity.


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Clinical Examples of DTH:

Tuberculin skin test:

When purified tuberculin is injected into the skin, memory DTH cellsattract macrophages and granulocytes and cause induration anderythema

Positive test indicates exposure to M. Tuberculosis and production ofAb, does not necessarily indicate infection;

Granuloma:

Tubercules found in the tissues of patients with TB are granulomasformed around the slow-growing Mycobacteria through influence ofDTH T cells. Valley Fever (Coccidioidomycosis). Crohns Disease

Treatment

Patients require treatment with an aggressive regimen ofantimycobacterial drugs.


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REFERENCES

Book: Jawetz, Melnick, & Adelberg's MedicalMicrobiology, 24th Edition by Vishal

Mac Sween R.N; and Whaly K.(Murs Textbook ofpathology); 13th edition,Arlond.1997.

Kumar V.;Abbas A.; and Fausto N.(Robbin and Cortan,Pathologic basis of disease).7th edition. Elsevier Sounder.2004.

Rosal J. (Ackerman's surgical pathology); 9th

edition.Mosby.2003. Walts J.B.,Talbot L.c.(general pathology ); 7th edition

,Churchill Livingstone; 1996 .

Krishna V. (Text book of pathology); Orient LongmanPrivate limited. 2004.

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