HYPERSENSITIVITY REACTIONS

Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system Hypersensitivity reactions require a presensitized (immune) state of the host
www.similima.com 2

CLASSIFICATION

TYPE I IMMEDIATE, ATOPIC, ANAPHYLLACTIC TYPE II ANTIBODY DEPENDANT TYPE III IMMUNE COMPLEX TYPE IV CELL MEDIATED / DELAYED TYPE OF HYPERSENSITIVITY TYPE V - STIMULATORY
www.similima.com 3

Type 1: Immediate Hypersensitivity Reaction

Mediated by IgE antibody to specific antigens

Mast cells stimulated and release histamine

Reaction within one hour of exposure Examples

Anaphylaxis (e.g. Penicillin) Urticaria Angioedema Atopic Allergy

www.similima.com 4

Type 2: Cytotoxic Antibody Reaction

Mediated by IgG and IgM to specific antigens Examples Transfusion Reaction Rhesus Incompatibility (Rh Incompatibility) Mycoplasma pneumoniae related cold agglutinins Hashimoto' Thyroiditis Good pasture's Syndrome Delayed transplant graft rejection

www.similima.com 5

Type 3: Immune Complex Reaction

Antigen-antibody complexes deposit in tissue Reaction within 1-3 weeks after exposure Examples

Systemic Lupus Erythematosus Erythema Nodosum Polyarteritis nodosa Arthus Reaction (e.g. Farmer's Lung) Rheumatoid Arthritis Elephantiasis (Wuchereria bancrofti reaction) Jarisch-Herxheimer Reaction Serum Sickness
www.similima.com 6

Type 4: Delayed-Type Hypersensitivity

Mediated by T-Lymphocytes to specific antigens

Involves major histocompatibility complex (MHC) Reaction within 2-7 days after exposure Mantoux Test (PPD) Allergic Contact Dermatitis (e.g. Nickel allergy)
www.similima.com 7

Examples

Other allergy mediated reactions

Stimulatory Hypersensitivity Humoral antibody activates receptor sites Example: Thyrotoxicosis (TSH autoantibodies) Fas/Fas ligand-induced apoptosis Example: Stevens Johnson Syndrome T-Cell activation Example: Sulfonamide induced Morbilliform rash

www.similima.com

TYPE I HYPERSENSITIVITY REACTION

Type 1 hypersensitivity is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen Exposure may be by ingestion, inhalation, injection, or direct contact The difference between a normal immune response and a type I hypersensitive response is that plasma cells secrete IgE This class of antibodies binds to Fc receptors on the surface of tissue mast cells and blood basophils
www.similima.com 9

The mechanism of reaction involves preferential production of IgE, in response to certain antigens (allergens). IgE has very high affinity for its receptor on mast cells and basophils. A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances Cross-linking of IgE Fc-receptor is important in mast cell triggering. Mast cell degranulation is preceded by increased Ca+ + influx, which is a crucial process; ionophores which increase cytoplasmic Ca++ also promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress degranulation.
www.similima.com

10

www.similima.com

11

Pharmacologic Mediators of Immediate Hypersensitivity

Preformed mediators in granules Histamine - bronchoconstriction, mucus secretion, vasodilatation, vascular permeability Tryptase proteolysis Kininogenase - kinins and vasodilatation, vascular permeability, edema ECF-A (tetrapeptides)attract eosinophil and neutrophils
www.similima.com 12

Newly formed mediators

Leukotriene- B4 basophil attractant leukotriene C4, D4 - same as histamine but 1000x more potent prostaglandins D2 - edema and pain PAF - platelet aggregation and heparin release: microthrombi
www.similima.com 13

Diagnostic tests for immediate hypersensitivity include skin (prick and intradermal) tests measurement of total IgE and specific IgE antibodies against the suspected allergens Total IgE and specific IgE antibodies are measured by a modification of enzyme immunoassay (ELISA) Increased IgE levels are indicative of an atopic condition, although IgE may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.)
www.similima.com

14

Intradermal skin test with multiple positive allergen responses

www.similima.com

15

TYPE 2 HYPERSENSITIVITY REACTION

Mechanism Either 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 and IgG or IgM made against that antigen then cross reacts with the host cell surface.
www.similima.com 16

The binding of these antibodies to the surface of host cells then leads to: opsonization of the host cells whereby phagocytes stick to host cells by way of IgG, C3b, or C4b and discharge their lysosomes
www.similima.com

17

Opsonization During Type-II Hypersensitivity, Step-1

The Fab of IgG reacts with epitopes on the host cell membrane. Phagocytes www.similima.com Fc portion bind to the

18

Opsonization During Type-II Hypersensitivity, Step-2

Phagocytes binding to the Fc portion of the IgG and discharge their lysosomes causing cell lysis.
www.similima.com

19

IgG reacts with epitopes on the host cell membrane. Phagocytes then bind to the Fc portion of the IgG and discharge their lysosomes.

www.similima.com

20

activation of the classical complement pathway causing MAC lysis of the cells

www.similima.com

21

MAC Lysis During Type-II Hypersensitivity, Step-1

IgG or IgM reacts with epitopes on the host cell membrane and activates the classical complement pathway. Membrane 22 www.similima.com attack complex (MAC) then causes lysis of the cell.

MAC Lysis During Type-II Hypersensitivity, Step-2

Membrane attack complex (MAC) then causing lysis of the cell.

www.similima.com

23

IgG or IgM reacts with epitopes on the host cell membrane and activates the classical complement pathway. Membrane attack complex (MAC) then causes lysis of the cell.

www.similima.com

24

ADCC destruction of the host cells whereby NK cells attach to the Fc portion of the antibodies. The NK cell then release pore-forming proteins called perforins and proteolytic enzymes called granzymes. 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.
www.similima.com 25

ADCC-Induced Apoptosis by NK Cells During Type II Hypersensitivity, Step-1

www.similima.com

26

ADCC-Induced Apoptosis by NK Cells During Type II Hypersensitivity, Step-2

www.similima.com

27

ADCC-Induced Apoptosis by NK Cells During Type II Hypersensitivity, Step-3

www.similima.com

28

ADCC Destruction During Type-II Hypersensitivity

www.similima.com

29

ADCC Apoptosis by NK Cells During Type II Hypersensitivity

www.similima.com

30

Type II Hypersensitivity Reaction

Type II hypersensitivity affects a variety of organs and tissues The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples The reaction time is minutes to hours Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement Phagocytes and K cells may also play a role (ADCC)
www.similima.com

31

www.similima.com

32

Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence.
www.similima.com 33

The staining pattern is normally smooth and linear, such as that seen in Good pasture's nephritis (renal and lung basement membrane)
www.similima.com 34

pemphigus (skin intercellular protein, desmosome)

www.similima.com

35

THANK YOU

www.similima.com

36