GENERAL IMMUNOLOGY PHT 324 Dr. Rasheeda Hamid Abdalla Assistant Professor E-mail rasheedahamed12@hotmail.com

Hypersensitivity

Objectives Types of Hypersensitivity General features of antigens and antibodies reaction

Hypersensitivity Hypersensitivity (Immunological reaction) refers to undesirable immune reactions produced by the normal immune system to repeated exposure to an antigen. Hypersensitivity reactions: four types; based on the mechanisms involved and time taken for the reaction, a particular clinical condition (disease) may involve in more than one type of reaction.

Types of Hypersensitivity Hypersensitivity diseases have been grouped into four major categories: 1.) Immediate (type I) hypersensitivity. 2.) Antibody-mediated (type II) hypersensitivity. 3.) Immune complex-mediated (type III) hypersensitivity. 4.) Cell-mediated (type IV) hypersensitivity.

Classification of Hypersensitivity Type I Type II Type III Type IV ___________________________________ Type I, II and III Antibody Mediated. Type IV Cell Mediated.

Classification of Hypersensitivity

Immediate Type I An allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. (i.e. House dust, Pollens, Cosmetics, Insects, Clothing and Drug). Exposure may be by: Ingestion Inhalation Injection Direct contact.

Pathophysiology In type 1 hypersensitivity, B-cells are stimulated to produce IgE antibodies specific to an antigen. The difference between a normal infectious immune response and type 1 hypersensitivity response is that in type 1 hypersensitivity the antibody is IgE instead of IgA, IgG, or IgM.

During sensitization (the immune system has come into contact with an allergen), the IgE antibodies bind via Fc receptors onto the surface of tissue mast cells and blood basophils. Resulting in the secretion of active mediators such as histamine, leukotriene, that act on the surrounding tissues. The principal effects of these products are vasodilation and smooth-muscle contraction.

Type I (Anaphylactic) Reactions

Type 1 hypersensitivity can be further classified into -an immediate and -late-phase reaction. The immediate hypersensitivity reaction occurs minutes after exposure whereas the late-phase reaction occurs 2–4 hours after exposure. The reaction may be either -local or -systemic. Symptoms vary from: mild irritation to sudden death from anaphylactic shock.

Treatment usually involves adrenaline (epinephrine), antihistamines, and corticosteroids. If the entire body gets involved, then anaphylaxis can take place, which is an acute, systemic reaction that can prove fatal Examples Allergic asthma. Allergic conjunctivitis. Allergic rhinitis ("hay fever"). Penicillin and Cephalosporin allergy. Food allergy.

Antibody-mediated (type II) Type II hypersensitivity (or cytotoxic hypersensitivity) the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces. The antigens recognized in this way may either be intrinsic ("self" antigen: innately part of the patient's cells) or extrinsic (adsorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen).

These cells are recognized by macrophages or dendritic cells, which act as antigen-presenting cells. This causes B cell response, wherein antibodies are produced against the foreign antigen. IgG and IgM antibodies bind to these antigens to form complexes that activate the classical pathway to eliminate cells presenting foreign antigens.

That is, mediators of acute inflammation are generated at the site and membrane attack complexes cause cell lysis and death. The reaction takes hours to a day. Type II reactions can affect healthy cells. Examples include Red blood cells in Haemolytic Anaemia.

ABO Blood Group System Table 19.2

Hemolytic Disease of the Newborn Figure 19.4

Another form of type II hypersensitivity is called antibody-dependent cell-mediated cytotoxicity (ADCC). Here, cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognized by natural killer cells (NK) and macrophages which in turn kill these tagged cells. https://en.wikipedia.org/wiki/Type_II_hypersensitivity

Immune complex-mediated (type III) Type III hypersensitivity occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. Such reactions progressing to the point of disease produce immune complex diseases. The reaction may take 3-10 hours after exposure to the antigen (as in Arhus reaction).

Mechanism of Type III Hypersensitivity Antigens combines with antibody within circulation and form immune complex. Wherever in the body they deposited. They activate complement system. Polymorphonuclear cells are attracted to the site. Result in inflammation and tissue injury.

Hypersensitivity Type III Reactions Local Reactions Systemic Reactions Arthus Reaction: It is named for Dr. Arthus. Inflammation caused by the deposition of immune complexes at a localized site. Clinical Manifestation is : Hypersensitivity Pneumonitis Serum Sickness: Systemic inflammatory response to deposited immune complexes at many areas of body. Few days to 2 weeks after injection of foreign serum or drug it results in : Fever, Urticaria, Artheralgia, Eosinophila, Spleenomegally, and Lymph adenopathy

Immune Complex Diseases Hypersensitivity Pneumonitis Glomerulonephritis Rheumatoid Arthritis Systemic Lupus Erythematosus

The crippling distortion of joints characteristic of rheumatoid arthritis

The characteristic facial rash of systemic lupus erythematosus

Cell-mediated (type IV) Type 4 hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response. CD4+ helper T cells recognize antigen in a complex with MHC2. The antigen-presenting cells in this case are macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ Th1 cells.

CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other cytokines, thus mediating the immune response. Activated CD8+T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

If T-cell function is abnormal, the patient presents with opportunistic infections, including infection with mycobacteria, fungi, parasites, and, often, mucocutaneous candidiasis. Undesirable consequences of delayed-type hypersensitivity (DTH) reactions include illness such as contact dermatitis. Examples of DTH reactions are contact dermatitis (eg, poison ivy rash), tuberculin skin test reactions, granulomatous inflammation (eg, sarcoidosis, Crohn disease), allograft rejection, graft versus host disease.

The tuberculin response An injection of tuberculin beneath the skin causes reaction in individual exposed to tuberculosis or tuberculosis vaccine. Used to diagnose contact with antigens of M. tuberculosis: No response when individual not infected or vaccinated. Red, hard swelling develops in individuals previously infected or immunized.

A positive tuberculin test

Hypersensitivity Reactions Conclusion:

Antigen-Antibody reaction

General features of antigens and antibodies reaction The reaction is specific- antigen can combine only with homologous antibody and cross reaction may occur due to similarity. Entire molecule react not the fragments. There is no denaturation of antigen or antibody during the reaction. The combination occur in the surface. The combination is firm but reversible.

Agglutination Qualitative agglutination test Can be used to assay for the presence of an antigen or an antibody. The antibody is mixed with the particulate antigen and a positive test is indicated by the agglutination of the particulate antigen. Examples (Slide test): a patient's red blood cells can be mixed with antibody to a blood group antigen to determine a person's blood type. RPR / Rapid Plasma Reagin/ card test: for syphilis.

Quantitative agglutination test Can be used to quantitate the level of antibodies to particulate antigens. (tube test). In this test one makes serial dilutions of a sample to be tested for antibody and then adds a fixed number of particulate antigen and determines the maximum dilution which gives agglutination. Example-Widal test for typhoid.

The titre of the patient serum using Widal test antigen suspensions is the highest dilution of the serum sample that gives a visible agglutination. The sample which shows the titre of 1:100 or more for O agglutinations and 1:200 or more for H agglutination should be considered as clinically significant (active infection). Example: In the figure, titre is 160.

Enzyme linked immunosorbent assays (ELISA) It is so named because it involve the use of immunosorbent (absorbing material specific for antigen or antibody which may be cellulose or polystyrene or discs of polyacrylamide). It is done by using 96-well microtitre plate.

Radioimmunoassay(RIA)

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