What is hypersensitivity?

How is it initiated?

What is the result of a hypersensitive reaction?

This is the inappropriate or heightened inflammatory response to antigen.

It is initiated during the course of either a humoral or cell-mediated immune responses

It can cause tissue damage or death.

What was the experiment that lead to the identification of anaphylatoxins?

Who identified it?

People were reacting violently to stings from portugese man of war jelly fishes. The development of vaccinations using the jelly fish toxins and then boosters to dogs resulted in an "overreaction" of the immune response leading to death.

Discovered by Paul Portier and Charles Richet.

Immediate hypersensitivity : anaphylactic reaction initiated by ab or ag-ab complexes

      e.g peanut allergy

Delayed-type hypersentivity: recognition of the delay of symptoms until days after exposure.

     e.g poison ivy, poison oak...a day later will see welts.

Type I (IgE mediated)

Type II (Ab-mediated mainly IgM and IgG)

Type III (Immune complex-mediated)

Type I Hypersensitive Response

What is the mediator?

What induces the response?

Type I is mediated by IgE

The response is induced by allergens

Allergens: non-parasitic ag capable of stimulating type I hypersensitivity in allergic people.

Type I IgE mediated Hypersentivity

What is atopy?

What chromosomes are found to be affected?

What Ig isotype is increased and what cell type increases?

Atopy: hereditary predisposition to develop immediated hypersensitivity reactions to common environmental antigens

Chromosome 5q: encodes cytokines

Chromosome 11q: encodes beta chains of the high affinity IgE receptor

   - inherited atopy is multigenic

IgE increase production and circulation with incresed eosinophils

Explain the general occurence during the first and second exposure during type I.

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First Exposure: allergen activated B cells which is presented to Th cell and plasma cells secrete IgE, IgE binds to IgE specific Fc receptors on mast cells and basophils (Bound IgE is stable)

Second Exposure: cross linking of bound IgE release chemical mediators, generation of cellular responses.

1. dose and class switch

2. sensitization

3. genetic constitution of the individual

4. presence of an adjuvant

5. relative levels of Th1 and Th2 subsets and cytokines

What chains are found on IgE?

What is the purpose of the additional constant region?

What are the IgE binding receptors specific for what region?Name the Fc regions with high and low affinity.

IgE: 2 heavy Epsilon and 2 light chains and a constant region

Constant region: allows for altered conformation for the Fc portion and its ability to bind to glycoproteins on the surface of mast or basophil cells.

IgE Receptor: specific for Fc region of the epsilon heavy chain

   - FcEpislon RI (high affinity)

   - FcEpsilon RII (low affinity)

1. IgE cross linkage by allergens initiates degranulation

2. IgE cross linkage can be initiated by antibodies

3. Anaphylatoxins such as C3a, C4a, and C5a can initiate degranulation without IgE cross linkage

4. can be initiated by drugs

1. Where are mast cells and basophils found?

2. What do the granules contain?

3. What cytokines are secreted?

4. What are the two classes of Fc episilon receptors and what are their affinities respectively?

1. Mast cells located: connective tissue

basophils located: in the blood, 0.5-1.0% (must be recruited if inflammation is at tissue)

2. Granules contain active mediators

3. IL-4,5,6 and GM-SCF

4. FcEpsilon RI High affinity, FcEpsilon RII low affinity

Explain the intracellular events controlling mast-cell degranulation starting with the cross linkage to the breakdown of PC (step 1 through 4)

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1. X linkage of FcERI activates Lyn, which phosphorylates tyrosines in the ITAMs of the beta and gamma chains. Activation of PTK then phosophorylates phospholipase C, convert PIP2 to DAG and IP3.

2. DAG activated PKC, which with Ca2+ assembles microtubular assembly and the fusion of granules with the plasma membrane. IP3 is a potent moblizer of intracellular Ca2+ stores

3. cross linkage of FcERI also activates an enzyme converting PS to PE. PE becomes methylated to PC by PMT I and II.

4. The accumulation of PC on exterior surface of the plasma membrane causes an increase in membrane fluidity and faciliates the formation of Ca2+ channels Influx of Ca2+ and PTK-activated MAPK activates phospholipase A2, which promotes the breakdown of PC into lyso PC and arachidonic acid.

Explain the intracellular events controlling mast-cell degranulation starting with arachodonic acid to the release of mediators (step 5 through 8)

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5. Arachidonic acid is converted into potent mediators: the leukotrienes and prostaglandins C2

6. Activated MAPK induces secretion by cytokines by increasing transcription of cytokine genes

7. FcERI x linkage also activates the membrane adenylate cyclase, leading to a transient increase in cAMP within 15 secs. A later drop in cAMP levels is mediated by protein kinases and is requred for degranulation to proceed

8. cAMP-independent protein kinase are thought to phosphorylate  the granules membrane proteins, thereby changing the permeablity of the granules to water and Ca2+. The consequent swelling of the granules and for formation of SNARE protein complexes, facilitates the fusion with the plasma membrane and release of mediators.

1^st exposure- B cells produce allergen-specific IgE ab

   ---  tail of IgE Ab reacts with Fc receptors on mast cells, leaving Fab’s directed away from the cell surface

2^nd exposure- allergens enter body, cross-links IgE on mast cell in mucous membranes, skin, and triggers release of chemicals à symptoms

1) Primary infection: histamine, heparin, serotonin, eosinophil, neutrophil and proteases.

2) secondary infection: platelet-activating factor, leukotrienes, prostaglandins, cytokines (IL 2, TNF alpha, IL 4, IL13, IL3, IL5, IL6, IL10, TFG beta and GM CSF)

Describe the reactions of systemic anaphylaxis.

What is the treatment?

• shock-like and often fatal
• rapid onset
• blood pressure drops
• contraction of smooth muscle (GI and bladder) vasodialation (drop in bp), bronchiole constriction (asphyxiation)
• Edema, shock and bronchiole constriction leads to death

TREATMENT: Epinepherine

• relaxes smooth muscles
• decreases vascular permeability
• improves cardiac output

Describe the rections of a localized anaphylaxis.

Include relationship with atopy, the types of localized reactons, and late phase reactions.

• reaction is limited to a specific tissue or organ
• tendency for localized response in inherited (atopy)
• bronchoconstriction
• edema
• mucus
• inflammation

Types

• allergic rhinitis (hay fever)
• asthma
• eczema (atopic dermatitis)
• food allergies

Late Phase Reactions induce localized responses

• localized inflammation following granulation
• develops within 4-6 hours, persists for days.

• avoidance of allergens
• immunotherapy with repeated subcutaneous injections increases doses of allergens (generation of an IgG blocking Ab)
• use of drugs to inhibit biochemical steps leading to degranulation

• histamine: vasodialation
• PGD2: bronchoconstriction
• LTC4: mucus secretion

• IL-4, INF alpha < LTC4: increases endothelial cell adhesion
• PAF, IL 5, ECF: leukocyte migration
• IL4, IL5: leukocyte activation

• cells are sensitized in the GI tract
• if Ag is blood-borne it will cause symptoms like hives or asthma

• antigen stimulation
• IL-4 induced class switch to IgE (TH2 cells and mast cells)
• IFN-gamma reduces IgE production (inhibit type I)

• skin test
• RIST- total serum IgE
• RAST- IgE specific for a single allergen

• avoidance of the Ag
• hyposensitization:  immunotherapy with repeated injection of increasing doses of allergens to reduce the severity of type I reactions or elimate them completely
• Drugs

1. antihistmaines (block receptors)
2. epinephrine (maintain high cAMP and prevent degranulation)
3. Cromolyn: Na+ blocks calcium flux of mast cells

What is Type II hypersentivity?

What does it activate?

What mediates cell destruction?

What acts as an opsonin?

1. IgG-mediated cytotoxic hypersentivity. Antibody mediated destruction of cells.
2. activates complement
3. mediate cell destruction by antibody dependent cell-mediated cytotoxicity (ADCC)
4. antibody serves as an opsonin; phagocytic cells with FcR or C4bR bind an phagocytose coated cells

1. Transfusion reactions
2. hemolytic disease of newborns
3. drug induced hemolytic anemia

Type II hypersensitivity.

What occurs during transfusion reactions?

Include how the reaction is generated.

Antibodies (isohemglutinins) to ABO antigens

- genereted in response to allelic variations in RBC glycoproteins following transfusion

- generated following natural exposure to similar antigen determinants on microorganisms of normal gut flora

- reaction = antibody bind blood cells and mediate lysis by activating complement.

Fetal cells entering mother's blood stream at birth
- maternal memory cells generate IgG antibodies directed again Rh factor expressed on fetal RBC's
- result in mild to severe enemia in second fetus
- treated at first pregnancy with rhogam (24048 hours after delivery, antibodies that clear fetal RBCs from mother)

     - no memory
     - can also treat 2nd pregnancy just in case.

Type II hypersesitivity

Describe the immune complex-mediated hypersentivity generalized immune response.

• large amounts of antigen enter the blood
• formation of circulating immune complexes
• geeration of antibodies to foreign serum proteins
• development of serum sickness, autoimmune disease, drug reaction, infecrious disease.

Type IV Hypersensitivity

What is delayed-type hypersesitivity?

Include how it is initiated and the characteristics.

• Initiated by cytokines secreted by subgroups of Th cells

Characteristics

• delayed onset of response
• large influx of macrophages and langerhand cells
• necessary and detrimental tissue damage

Mycobacterium tuberculosis: tissue damage to lungs cause blood via coughing

Lepercy: gangrenes, massive tissue damage

Candidica albican: thrush, white pustule

Intracellular virus: herpes simplex, open sores

Type IV hypersensitivity

What occurs during sensitization and effector phases of DTH?

Sensitization: being 1-2 weeks after contact with antigen

    - Th cells are activated by APCs (macrophage or langerha cells,   clonally expanded)

Effector phase/ 2nd exposure:

   - Th2 cytokines cytokines recruit and activate resting macrophages

   - leads to recruitment of macrophages to site of infection

   - outcome rapid cleaving of tissue

Contact dermatitis: reaction to pendadecacetechol compound. The complex is internalized and processed and presented to TH1 cells

2nd exposure: induces massive cytokine synthesis. Tissue damage resuls from lytic enzymes realesed from activated macrophages