Hypersensitivity By Me-1

1. 2. 3. 4. 5. 6. 7. 8.

Review questions What is hypersensitivity? How can you classify hypersensitivity? What are the different types of hypersensitivity? What are the differences between cytotoxic & immune complex mediated hypersensitivity? What are the mechanisms of hypersensitivity? Which hypersensitivity is called delayed hypersensitivity? Why it is so called? Write pathogenesis of type 1 hypersensitivity? Wrote about immunological intervention of Type 1 hypersensitivity What desensitization?

Definition:

¤ When the immune systems cause harm to the body, it is referred to as a hypersensitivity . Or ¤ Excess or inappropriate immune response to an antigenic stimulus in a pre sensitized person leading to tissue damage is known as hypersensitivity.

Classification: Hypersensitivity can be classified by different ways: A. Coomb’s and Gel classification. B. On the basis of mechanism of action. C. On the basis of onset of action.

Classification: A. Coombs & Gel: a) Type-1 or anaphylactic hypersensitivity b) Type-II or cytotoxic hypersensitivity c) Type-III or immune complex hypersensitivity d) Type-IV,

Delayed

or

Cell

mediated

hypersensitivity e) Type-V or Stimulatory hypersensitivity

Classification: A. Based on onset of action:

Immediate hypersensitivity. Delayed hypersensitivity. B. Based on mechanism of action: Antibody mediated: Type I, II, III & V Cell mediated: Type IV

Type I or Anaphylactic hypersensitivity •The term ‘ana’ means ‘away from’ and ‘phylaxis’ means ‘protection’. •So

`anaphylaxis`

protection

and

means is

away opposite

from of

‘prophylaxis.’ •This was the first example response can cause harm.

that immune

Sequence of events of Type I hypersensitivity Type I hypersensitivity reaction has 3 phases 1. Sensitization phase 2. Activation phase 3. Effector phase.

Type-I Hypersensitivity

The allergen enters the body and is recognized by Ig on B-lymphocyte. The B-lymphocyte then proliferates and differentiates into plasma cells.

Type-I Hypersensitivity

The plasma cells produce and secrete IgE which binds to receptors on mast cells and basophils.

Type-I Hypersensitivity

Allergen cross reacting with IgE on mast cell.

Binding of IgE on the mast cell surface and degranulation.

Type I hypersensitivity Mechanism: •This is the most hypersensitivity.

common

type

of

•IgE is made in response to an allergen. •In allergic individuals, the levels of IgE may be thousands of times higher than in those without allergies.

Type I hypersensitivity •The Fc portion of IgE binds to the surface of mast cells and basophils. • Reexposure to that antigen causes crosslinking the Fab portions of the mast cellbound IgE.

Type I hypersensitivity •Causes degranulation of mast cell and release of pharmacologically active molecule. •These cause the early phase of reactions, appears within minutes after exposure to antigen.

Chemical mediators released Preformed 1. Histamine. 2. Serotonoin. 3. Eosinphil chemotactic factor. 4. Neutrophil chemotactic factor.

Chemical mediators released Preformed5. Platelet activation factor 6. Heparin. 7.Tryptrase Newly formed1. Leukotriens (LT): LTC4, LTD4, LTE4 2. Prostaglandin. 3. Thromboxanes

Actions of Chemical mediators 1. Histamine– constriction of smooth muscle – Increase vascular permeability – Vasodilatation 1. Serotonin – Increase vascular permeability

1. Eosinophil chemotactic factor (ECFA) 2. Neutrophil chemotactic factor – attracts neutrophils 3. Platelet activation factor – formation of microthrombi 4. Heparin - anticoagulant 5. Tryptase - proteolysis

Action of Chemical mediators Leukotriens (LT): Early inflammatory response. Constriction of bronchial smooth muscle. Increase vascular permeability. Prostaglandin's, Thromboxanes: Late inflammatory response. Constriction of bronchial smooth muscle. Vasodilatation with edema and mucus secretion

Summary of actions of Chemical mediators a. Dilation of blood vessels: This causes local redness (erythema) at the site. If dilation is widespread, this can contribute to decreased vascular resistance, a drop in blood pressure, and shock . b. Increased capillary permeability: This causes swelling of local tissues (edema). If widespread, it can contribute to decreased blood volume and shock.

Summary of actions of Chemical mediators c. Constriction of bronchial airways. This leads to wheezing and difficulty in breathing. d. Stimulation of mucous secretion. This leads to congestion of airways. e. Stimulation of nerve endings. This leads to itching and pain in the skin.

Clinical aspects of anaphylaxis Respiratory symptoms: Sign/symptoms are similar to that of bronchial asthma. Gastrointestinal symptoms :Sign/symptoms are similar to that of gastroenteritis like abdominal pain, diarrhea, vomiting along with skin rashes and some times bronchospasm.

Skin

Type I Hypersensitivity Reaction

Systemic manifestations In systemic anaphylaxis, the allergen is usually picked up by blood and reactions occur throughout the body. Examples include severe allergy to insect stings, drugs, and antisera.

Local reaction With a localized anaphylaxis, the allergen is usually

found

localized

in

the

mucous

membranes or the skin. Examples include allergy to hair, pollen, dust, dander, feathers, and food.

Diagnosis of Type I hypersensitivity • Skin test: The purified form of allergen injected intradermally, hypersensitivity reactions in the form of erythema and oedema are observed within 20-30 minutes. • Immunoassays for serum IgE: -Radioimmunosorbent test. -Radioallergosorbent test (RAST)

Type I Hypersensitivity: Detecting allergies

Management: A. Environmental interventions: • Avoidance of allergens • Use of masks, filters etc. B. Pharmacological interventions. C. Immunological interventions.

Pharmacological intervention Epinephrine: Relaxes smooth muscle, constricts blood vessels, and stimulates the heart. It is used for severe systemic reaction. Antihistamine: Block the binding of histamine to histamine receptors on target cells. Steroids: Potent anti-inflammatory agents. Sodium cromolyn, Montelukast: Prevents mast cells from histamines releasing.

Immunological interventions Desensitisation: • Acute desensitisation:– Very small amounts of Ag injected at 15 min intervals to form Ag-IgE complex on small scale which will not degranulate mast cell.

Immunological interventions • Chronic desensitisation:- Small doses of allergens injected at weekly intervals where IgG is produced & blocks the Ag and do not allow the Ag to reach the mast cell bound IgE .

Immunological interventions Monoclonal Ab block the attachment of IgE to mast cell: A new experimental approach to treat & prevent Type-I hypersensitivity involves giving the person with allergies injections of monoclonal antibodies that have been made against the Fc portion of human IgE.

Immunological interventions Monoclonal Ab block the attachment of IgE to mast cell: This, in turn, blocks the attachment of IgE to the Fc receptor on mast cell and basophil & the subsequent release of histamine by those cells upon exposure to allergen.

Use of monoclonal Ab to block the attachment of IgE to mast cell

Type II (Antibody-dependent cytotoxicity) IgG or IgM is made against normal self antigens as a result of a failure in immune tolerance or a foreign antigen resembling some molecule on the surface of host cells enters the body.

Type II (Antibody-dependent cytotoxicity) Cross reacts with the host cell surface. The binding of these antibodies to the surface of host cells then & to cytotoxicity by various mechanisms.

Mechanisms of Type II ● Activation of the classical complement pathway causing MAC lysis of the cells. ● Opsonization of the host cells whereby phagocytes stick to host cells by way of IgG, C3b or C4b and discharge their lysosomes.

Mechanisms of Type II.. ADCC destruction of the host cells: NK cells attach to the Fc portion of the Ig & release: Pore-forming protein – perforin. Proteolytic enzyme - granzyme. Granzyme activate the enzymes & lead to apoptosis.

Examples of Type II hypersensitivity

1. Mismatched ABO blood group transfusion. 2. Rh incompatibility reactions. 3. Auto immune hemolytic anemia. 4. Hashimoto’s thyroiditis. 5. Rheumatic fever. 6. Myasthenia gravis. Etc.

Opsonization During Type-II Hypersensitivity

The Fab reacts with the host cell membrane & Phagocytes to the Fc portion.

Opsonization During Type-II Hypersensitivity, Phagocytes binds to the Fc portion of the IgG and discharge

their

lysosome & lysis of cell .

Type II Animation showing lysis of cells during Type-II hype

Type II MAC Lysis During Type-II Hypersensitivity

•IgG or IgM reacts with epitopes on the host cell membrane •Activates the classical complement pathway. •Membrane attack complex causes lysis of the cell.

Type II MAC Lysis During Type-II Hypersensitivity

Type II ADCC-Induced Apoptosis by NK Cells

Type II ADCC-Induced Apoptosis by NK Cells

Type III (Immune complex-mediated) ●Soluble antigen-antibody (IgG or IgM) complexes, normally removed by macrophages in the spleen and liver.

Type III or immune complex mediated ●Sometime

circulates and deposits in the

endothelial cells of blood vessels - especially those in the skin, joints, and kidneys – resulting in cell damage. • Two types: a. Arthus reaction. b. Serum sickness.

Type III or immune complex mediated hypersensitivity Mechanism: ●Massive inflammation. ●Influx of neutrophil and cause tissue destruction. ●MAC lysis. ●Aggregation of platelets→ microthrombi formation → blocks capillaries → tissue injury.

Type III or immune complex mediated hypersensitivity a. Arthus reaction - when immune complex is formed in excess of antibody: fermer’s lung, cheese-workers lung, woodworkers lung. b. Serum sickness- when immune complex is formed in excess of antigen: Glomerulonephritis, Rheumatoid arthritis, SLE.

Type-III Hypersensitivity

Large quantities of soluble antigen-antibody complexes form in the blood and are not completely removed by macrophages.

Type-III Hypersensitivity

These antigen-antibody complexes lodge in the capillaries between the endothelial cells and the basement membrane.

Type-III Hypersensitivity

These antigen-antibody complexes activate the classical complement pathway leading to vasodilation.

Type-III Hypersensitivity

The complement proteins and antigen-antibody complexes attract leukocytes to the area.

Type-III Hypersensitivity

The leukocytes discharge their killing agents and promote massive inflammation. This can lead to tissue death and hemorrhage.

Animation showing inflammation and tissue death .

Delayed Hypersensitivity(Type IV) • Onset is slow (1–3 days). • Delayed hypersensitivity is cell-mediated rather than antibody-mediated. • Cytokines from activated TC are the mediators of the inflammatory response • Antihistamines are ineffective and corticosteroid drugs are used to provide relief

Delayed Hypersensitivity (Type IV) - Examples 1.

The cell or tissue damage done during diseases like tuberculosis, leprosy, smallpox, measles, herpes infections, candidiasis, and histoplasmosis;

1.

The skin test reactions seen for tuberculosis and other infections;

2.

Contact dermatitis like poison ivy;

3.

Type-1 insulin-dependent diabetes where CTLs destroy insulin-producing cells;

1.

Multiple sclerosis, where T-lymphocytes and macrophages secrete cytokines that destroy the myelin sheath that insulates the nerve fibers of neurons;

Delayed Hypersensitivity (Type IV)Clinical importance Delayed hypersensitivity also plays a major role in chronic transplant rejection as a result of CTL destruction of donor cells (host versus graft rejection) or recipient cells (graft versus host rejection). Immunosuppressive drugs such as cyclosporin A or FK-506 (Tacrolimus) are given in an attempt to prevent rejection. Both of these drugs prevent Tlymphocyte proliferation and differentiation by inhibiting the transcription of IL-2.

Fig. 1:Cytotoxic T-lymphocyte (CTL)-Induced Apoptosis of a CrossReacting Normal Cell during Type IV Hypersensitivity, step-1

Binding of the CTL to a cross-reacting normal cell triggers the CTL to release pore-forming proteins called perforins, proteolytic enzymes called granzymes, and chemokines. Granzymes pass through the pores and activate the enzymes that lead to apoptosis of the infected cell by means of destruction of its structural cytoskeleton proteins and by chromosomal degradation. As a result, the cell breaks into fragments that are subsequently removed by phagocytes.

Type IV Hypersensitivity Reaction