Group II Immunovirology
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Transcript of 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.