hypersensitivity types & features

8/6/2019 Hypersensitivity Types & Features

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Hypersensitivity: Types & Features

Under some circumstances, immune responseproduce damaging or fatal results.

Such deleterious reactions are known collectivelyas Hypersensitivity. IR are damaging rather thanhelpful to the host.

Inappropriate/overreaction/immunopathology



Types

Coombs and Gell (1960): Reactions 4 types:

Type I > 2-30 min IgE Abs mediated

Type II 5-8 hr Abs (IgG & IgM) +

Complement (cytotoxic)

Type III 2-8 hr Ag/Ab Immune Complex

Type IV 24-72 hr T-cell mediated (DTH)



Type I: Ig E-Mediated Hypersensitivity

Most common type of hypersensitivity reaction.

Mediated by IgE & causes hay fever to life

threatening (bee stings) clinical manifestations.

Reactions are stimulated by binding of IgE (viaits Fc region) to high affinity IgE specificreceptors (FcRI) expressed on mast cells &basophils.



When cross linked by Ags, IgE triggers mast cells & basophils to release inflammatorymediators that lead to clinical features

(allergic reactions) eg. rhinitis, asthma,allergy, hay fever, bee sting, etc.

These reactions are very rapid, occur within

min after challenge-that is re-exposure to Ag.

Allergic reactions are called ITH or Type Ihypersensitivity.



Sequence of Events involved:

Sensitization Phase = Activation Phase =

Effector Phase



Sensitization Phase

Initial exposure to an allergen (Ag) induces IgEformation, following the primary antibodymediated immune response.

IgE binds via Fc portion to specific receptors onbasophils (in blood) and mast cells (in tissues),

(both cell types have histamine granules)

(No effect on mast cells directly up to this stage)



Activation Phase

Second and subsequent exposure to sameallergen (specific Ag):

-allergen (specific Ag) binds to V region of Fab and crosslinks two adjacent IgEs onmast cell/basophil surface.



Effector Phase

Crosslinking of two adjacent IgEs on mast

cell/basophil surface triggers these cells to

degranulate immediately and release histamine

and many other mediators.

Immediate response (min after exposure)

mediators release due to an increase in cGMPlevels and/or decrease in cAMP levels

Leads to clinical manifestations, allergy,

asthma, etc.



Sensitization-skin contact, ingestion, injection,inhalation.

~50% generates IgE response to airborne

Ags but ~20% develops clinical symptoms(those with high IL-4).

Low levels of IgE in non-allergic due tosuppressor effect of IFN- (Th1 produced)

dowregulates Th2.



Key Mediators

Histamine preformed molecules in granules.

-binds receptors on target cells (lungs, skin, bloodvessels)

-causes vasodilation, capillary permeability, smooth

muscle constriction

-antihistamines block histamine receptors.

Prostaglandins from mast cells, causes bronchial

constriction, edema.

Leukotriene adhesion of leukocytes to capillaryvenules, degranulation.



SRS-A (Slow Reacting Substance of Anaphylaxis)

-produced after exposure to allergen, nor preformed

-slow release

-bronchoconstricton: implicated in asthma

ECF-A (Eosinophil Chemotactic Factor of Anaphylaxis)

-preformed in mast cell granules

-quick release

-attracts eosinophils which release histaminase and

arylsulfate from their granules

-histaminase degrades excess histamine



Major Basic Protein destructive effects(from eosinophils granules)

Acid Hydrolases (mast cells); superoxide,nitric oxide, Tumor necrosis Factor (all frommacrophages)



Treatment: Chronic Allergies

Antihistamines block histamine receptors ontarget cells

Corticosteroids block degranulation of mast

cells Cromolyn sulfate blocks degranulation fast

acting but not permanent, must administerwhen exposed or risk at exposure to allergen

NSAIDs: Non steroid Anti Inflammatory drugs(Aspirin)



Treatment Acute allergies (anaphylactic shock)

Epinephrine (EpiPen) inject directly,increases camp levels which decreases

mediator release.

-immediate action

-short effect (~20 min)-followed by intravenous antihistamines



Type-II Reactions

Hypersensitivity resulting from Abs mistakenly reactingwith normal self-Ags on body cells.

Binding of Abs to these normal cells result in immunedestruction.



Mechanism

Either IgG or IgM made against normal self-Ags as aresult of a failure in immune tolerance or a foreign Agresembling some molecules on the surface of host

cells enters the body and IgG or IgM made against that Ag then cross-reacts with the host cell surface.



Binding of IgG/IgM to host cell surface leads to:

Opsonization of host cell.

Activation of classical complement pathway causing

MAC mediated lysis of cells.

ADCC destruction of host cells: NK cells attachment >

release pore-forming proteins perforins & proteolytic

enzymes granzymes. Granyzymes pass throughpores & activates enzymes that leads to apoptosis of infected cell by means of destruction of its structuralcytoskelton proteins & by chromosomal degradation.



Ab & Rh blood group reactions.

Autoimmune diseases (Graves/multiple sclerosis)

Good pastures disease, auto Ab to lung & kidney

basement membrane cause hemorrhage at site of

binding.

Breakdown of tolerance to self:

Abs to Ach receptors, loss of receptors, reducing orinhibiting nerve impulses across neuro-muscular

junctions (myasthenia gravis).



Hypersensitivity Reactions III

Normally Immune complexes removed byphagocytic cells & there is no tissue damage.

However, when large amounts of I.Cs.persists in tissues they activate complement cascade and cause damage to tissues.(Arthus reaction).

Ags responsible: Microbial Ags, auto Ags,foreign serum components.



Removal of Ag Ab Complex

Ag-Ab complex binds to Fc receptors of IgG,RBCs have C3b receptors, binds tocomplexes, that have fixed complement &transport them to liver, where complexes areremoved by phagocytic kupffer cells.

Ag-Ag complexes are clusters of interlocking

Ags-Abs; rapidly removed by blood stream byMacrophages (spleen), kupffer cells (liver).



When large quantities of ICs of a certain sizeare formed in circulation, they can bedeposited in tissues and trigger a variety of pathogenic events, called hypersensitivityreactions- III. (Kidneys, skin, joints, eye).



Ag-Ab complex activates classicalcomplement pathway. This may causeMassive inflammation: complement proteinC5a.

Influx of neutophils: Due to complement protein C5a, neutrophils discharge theirlysosomal enzymes & cause tissue damage,further inflammation.

MAC lysis of surrounding tissue cells. Aggregation of platlets: Blockage of

capillaries.



Under some circumstances ICs continue tocirculate, and eventually become trapped intissues of kidneys (glomerulonephritis), liver,skin (skin lesions), joints (thematoid arthritis),blood vessels & lead to inflammation & tissuedamage.



Localized: inhaled> bacterial fungal spores,pigeons serum (farmers lung disease).Systemic: Micobes (Streptococcus)Streptococcal nephritis. Serum sickness(fever, skin eruption, lympadenopathy.



Type-IV- Delayed Type of Hypersensitivity DTH

Mediated by T-cells together with dendriticcells, macrophages & cytokines.

The normal events associated with cell-

mediated immunity are a crucial mode of immunologic reactivity for protection against intracellular parasites (bacteria, viruses etc).However, the nature of reaction and its

mediators also cause DTH reactions.



When activated by contact with an Ag presented byantigen-presenting cell the responding T cells releaseinappropriately large amount of cytokines, some of which attract and activate other mononuclear cells

that are not antigen specific (such as monocytes andmacrophages).

Recruitment and activation of these antigen-

nonspecific mononuclear cells are mainly responsiblefor the eventual damaging outcome of the reactions.



Major events: 3 steps

Activation of antigen-specific inflammatory Th- 1cells in a previously sensitized individual.

Elaboration of proinflammatory cytokines by the

antigen-specific Th-1 cells.

Recruitment and activation of antigen non-specificinflammatory leukocytes.

These events typically occur over a period of several days (24-72 hrs) hence known as DTH



Causative Agents

Skin contact, small molecules (chemicals,plant molecules).

Contact Sensitivity (contact dermatitis): eg.

some cosmetics, Formaldehyde.

Poison Ivy Dermatitis: Offending substance iscontained in an oil secreted by leaves of

poison-ivy vine & other plants. Theypenetrate skin & cause blister formation.



Mantoux or PPD Test

Small amounts of purified protein derivative(PPD) of tuberculin derived from M.tuberculosis organisms injected into skin &site examined after 72 hrs. +ve skin test Ist red swelling, maximal at 48-72 hrs post injection. This is caused by influx of T-cells &macrophages at site of injection.

PPD test is useful for public healthsurveillance of TB.

hypersensitivity types & features

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