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Home , Hypersensitivity, Type I hypersensitivity

2/18/2014

Objectives Foundations of Public Health • Describe the reaction to exposure • Identify and explain the similarities and differences in the mechanism of the four types of hypersensitivity reactions Hypersensitivity • Identify selected disorders for each type of hypersensitivity reaction (selected disorders of )

Type I hypersensitivity • Identify and explain the mechanisms of sepsis reactions can be caused by a variety of

Hypersensitivity Hypersensitivity • Normally beneficial immune responses that • Four types of occur in an exaggerated or inappropriate hypersensitivity form • Results in , tissue damage or other problems known as immunopathology • Mechanism of • Hypersensitivity reaction only occur on the immune injury second or subsequent exposure to an is different in • The host must first be sensitized to the allergen!! each type

Characteristics of Hypersensitivity Type I: Immediate Hypersensitivity • Also know as: • • • • Most severe form of Type I reaction • Examples of Type I reactions • • Hay fever • Some food and drug

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Type I Hypersensitivity Type I Reaction cont’d Reaction • Cross‐linking induces • IgE is produced in 1st degranulation of the exposure to an antigen involved mast cells and ‐ on 2nd & later • IgE proteins bind to Fc exposures receptors on mast cells • Mediators are released (on both the connective during degranulation tissue and in the mucosa) • Trigger the symptoms of Type I hypersensitivity and basophils • One mediator released during • Repeat exposure to the this reaction is • , C3a & C5a, antigen then cross‐links also released in complement the IgE molecules cascade triggered by released mediators.

Process of the cross-linking of IgE with the antigen

Type I: Immediate Hypersensitivity • Th2 promote Type I hypersensitivity • Genetic predisposition for allergen which appears to be Human Leukocyte Antigen (HLA)‐linked • Environmental pollutants can promote allergies • These pollutants can act as IgE adjuvants

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Th2 Mediation of Type I Hypersensitivity

Type I: Immediate Hypersensitivity Type I:

• Allergies can be diagnosed by • Occurs when the reacts the Skin Prick Test to proteins in natural rubber latex • “Wheal & Flare” is characteristic • of an allergic reaction An estimated 1 –6% of general population has been sensitized to latex • Common allergens include , foods, dander • 5 – 10% of healthcare workers are • A variety of medication and sensitized! treatments are used to control • Should substitute synthetic gloves allergies for latex • Hyposensitization • Products that commonly cause reactions (Desensitization) therapy included gloves, balloons & condoms • Person is exposed in increasing levels of the antigen until • May also react to rubber bands, erasers, tolerance develops rubber parts of toys, pacifiers, etc.

Ascaris (Roundworm) Type 1: Asthma • Effects of an asthmatic reaction • Strong immune response to larval stage can occur both Ascaris lumbridoides infestation immediately and • Ascaris allergen is the most potent of all allergens over a prolonged or parasitic origin time period • • Results in both an Bronchial asthma, urticaria (), early & late (diffuse swelling and hives) response during an frequently occur with the larval stage parasite asthmatic attack • However, the immune system is frequently from inflammatory response tolerant of adult Ascaris intestinal infestation

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Dracunuliasis Type 2: Cytotoxic Hypersensitivity • Also known as Guinea Worm • With Type 2 reactions, the reaction is against an antigen located on a cell surface • The female worm forms a painful • blister on the skin (usually the The antigen being attacked is an integral part of the cell!! feet) and when the foot is placed • IgM and IgG bind to the cell surface or in water, the female worm tissue in conjunction with complement releases numerous eggs activation • The worm can be removed by • The complement activation results in: winding it slowly around a stick over many days (see photo w/ • Chemotaxis match stick) • Inflammation • If worm ruptures during removal, • Opsonization it will release numerous antigens • Cellular activation & produce a severe allergic reaction.

Type 2 Mediated Immunopathology Type 2: Blood Immunopathologies • Blood transfusion reactions • Hemolytic Disease of the Newborn • RhD factor • Reaction involves IgG • Also called erythorblastosis fetalis

Erythroblastosis fetalis

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Bleeding under the skin due to low platelets. Type 2: Autoimmune Blood Reactions • Spontaneous reactions that destroy erythrocytes • Warm hemolytic anemia involve that attach to and destroy erythrocytes at temperatures above normal body temperature • Cold antibody hemolytic anemia involve autoantibodies that attach to and destroy erythrocytes at temperatures below normal body temperature • (low platelet count)

Type 2: Adverse Drug Reactions • Drug‐induced reactions involving drug‐Ab and erythrocyte antigens • Steven‐Johnson Syndrome (SJS) • Affects people of all ages, but more child cases • If untreated, can result in death • Toxic Epidermal Necrolysis Syndrome • Another form of SJS Toxic Epidermal Necrosis

Type 2: Autoimmune Diseases Type 2: Autoimmune Diseases • Goodpasture’s syndrome • • Involves IgG and complement • • Lungs & kidneys are effected Involves antibodies against • Results in kidney basement chromosome proteins, skin membrane damage and mucous membranes • May be triggered by viral • Results in blistering respiratory infections or inhaling hydrocarbon solvents • Exact cause is unknown • Treat with immunosuppressive • Disease is uncommon, drugs and plasmapheresis (to occurs mostly in middle‐aged remove harmful autoantibodies from the blood) (or older) patients

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Type 2: Autoimmune Diseases Type 3: Immune Complex Hypersensitivity • • With type 3 hypersensitivity, damage occurs to tissues • Involves IgG and at sites of immune complex deposition complement against • Antigens involved in Type 3 reactions are insoluble, acetylcholine receptors small immune complexes which have not been on muscle cell removed by , the liver, or the spleen membranes • Results in muscle • Involves the deposited antigen, antibodies (IgG), weakness and fatigue complement deposition & effector cells • Thymus abnormalities • The antigen‐antibody often present complexes induce • Thymic tumors found in complement activation 10% of patients & result in • Changes in germinal inflammation mediated centers found in 70% of patients by

Factors Contributing to Deposition of Immune Complexes • Complement • Increased vascular deficiencies permeability (due to • Low affinity antibodies vasoactive amines) • Antibody • High blood pressure • Ineffective phagocytois and turbulence (for example in the • Abnormal carbohydrate glomerular capillaries of on antibody molecules the kidneys) • Size of immune complex • Affinity of the antigen and the antibody for specific tissues isotype

Type 3 Hypersensitivity • Three General Groups: • Persistent infection involving microbial antigens and the kidneys • against self antigen • Damage can occur to the kidneys, joints, & arteries etc. • Extrinsic antigens • Inhaled antigen –(mold) lung • •

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Type 3: Autoimmune Disease Types 1 - 3 • Systemic Erythematosus • Antibody Mediated (SLE) Hypersensitivity • Formation of immune complexes cause inflammation & tissue • Different effector injury mechanisms that cause • Affects many parts of the body (joints, skin, kidneys, heart, pathology lungs, brain, blood vessels) • Autoantibodies are • Characterized by periods of illness (flares) & times of health antibodies specific for self (remission) antigens • More common in young women • Damage cells & tissues • Present in excess in many autoimmune diseases (including SLE)

Autoimmune Diseases: Autoantibodies Tests

• Not always a direct • Antinuclear antibody (ANA): may be found in autoimmune hypersensitivity link, but disorders [especially lupus, , Sjorgren’s formation of autoantibodies can syndrome, , certain types of chronic active cause autoimmunity hepatitis] • Graves disease & Hashimoto’s • Anti‐DNA antibody: may be present in lupus thyroiditis are 2 disease where • Titers will decrease when treatment is successful autoantibodies target a single • Usually not found in other autoimmune diseases organ – the thyroid • Antiphospholipid antibody: may be found in lupus and • is a certain other conditions systemic autoimmune disorder – • Associated with miscarriages and clots high levels of circulating autoantibodies target multiple • Rheumatoid factor: often found in blood and joint synovial organs but most commonly affect fluid in rheumatoid arthritis patients the joints

Type 4: Delayed Hypersensitivity Mediated Hypersensitivity • Type 4 reactions are regulated by cell‐mediated reactions • Type 4 reactions usually take longer than 12 hours to develop due to mediation via T‐cells Granuloma formation around a schistosome • Protective does not egg (center) destroys always occur with Type 4 the liver tissue. reactions • Three varieties of Type IV Hypersensitivity: • Contact hypersensitivity • Tuberculin type hypersensitivity • Granulomatous hypersensitivity Wristwatches may stimulate contact hypersensitivity reactions.

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Contact Hypersensitivity • With contact hypersensitivity, penetrate the epidermis and conjugate with protein (which acts as a carrier for the ) • Examples of possible haptens include nickel, poison ivy, chromate, DNCB, etc. • CD4+ T‐cells and macrophages Examples of are involved in contact contact hypersensitivity reaction hypersensitivity • There is down regulation of reactions to the reaction by cytokines poison ivy.

Contact Hypersensitivity • The reaction involves both sensitization and elicitation phases • Maximal reaction occurs at 48 to 72 hours • The reaction produces an eczematous reaction of the skin

Type 4 Contact Hypersensitivity Tuberculin Type Hypersensitivity • Examples of tuberculin type hypersensitivity reactions include the tuberculin skin test and the intradermal tuberculin injection • CD4+ T cells and macrophages are involved in tuberculin type hypersensitivity • With previous exposure to the antigen, a localized induration occurs at the site of the injection • A maximal reaction occurs at 48 to 72 hours

• The induration usually resolved within 5 to 7 Example of + days PPD test

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Granulomatous Hypersensitivity • Persistent antigen and can be considered “Pathologic CMI” • Chronic inflammation can produce these reactions • Reactions result from secretory epithelioid and giant cells, macrophages, and lymphocytes • Granulomatous hypersensitivity produces hardening or fibrosis of tissue • These reactions may take 21 to 28 days or longer to develop • Diseases that may exhibit granulomatous hypersensitivity include Tuberculosis, Leprosy, Schistosomiasis, Sarcoidosis Enlarged liver and spleen occurs in schistosomiasis due to granuloma formation, blocking abdominal circulation.

Summary of Delayed Hypersensitivity Reactions

Innate Hypersensitivity: SIRS Systemic Inflammatory • SIRS represents a continuum of Response Syndrome (SIRS) disease: • Bacteremia –bacteria in the bloodstream • Effects of a systemic activation of the innate immune • Sepsis –SIRS due to an infection regardless of infecting organism response without regard to the cause (bacterial, viral, fungal) • The body produces an exaggerated response to the • Severe sepsis –Sepsis associated with at least one acute organ dysfunction, poor stimulus perfusion, or low blood pressure • Everyone is potentially at risk for SIRS (hypotension) • Septic shock –Sepsis‐induced • However, certain individuals are at greater risk including hypotension persists despite adequate critically ill patients and immunocompromised patients fluid replacement • MODS (Multiple organ dysfunction • Factors contributing to increased mortality from sepsis syndrome) –Presence of altered function • underlying disease in two or more organs in an acutely ill patient • older age • Death

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In Summary • Hypersensitivity • Mechanisms of Types I –IV hypersensitivity • Examples of each type • Associated autoimmune diseases • Autoantibodies • Sepsis

Self-Test Questions • Describe the 4 types of hypersensitivity. How do the cells, mechanisms of action, and times for each reaction differ? • Name 2 examples of autoimmune diseases associated with each type of hypersensitivity. • What are autoantibodies? What are some tests that can be used to identify these antibodies? • Name 4 factors that contribute to immune complex diseases. • What is the fundamental difference between Type 4 hypersensitivity & the other 3 types? • What are the 3 types of delayed hypersensitivity reactions? Name an allergen or example of each type. • What is SIRS? Why is SIRS like adaptive hypersensitivity diseases? Who is at risk? Is there a specific stimulus that causes it?

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