HS_AndAllergy2023_upload.pptx

Hypersensitivities and Allergy Dr. Gabor Szalai Email: [email protected] Learning objectives 1. Explain how mast cells play a role in adaptive immunity 2. Compare and contrast mast cells and B cells 3. Describe the role of the Fc-epsilon receptors in IgE-mediated immunity 4. Describe the compou...

Hypersensitivities and Allergy Dr. Gabor Szalai Email: [email protected] Learning objectives 1. Explain how mast cells play a role in adaptive immunity 2. Compare and contrast mast cells and B cells 3. Describe the role of the Fc-epsilon receptors in IgE-mediated immunity 4. Describe the compounds secreted by mast cells that mediate responses to helminths and allergic disease 5. Compare and contrast the four different types of hypersensitivity Study of Immunology Immunology: • Defense against infectious diseases • But: immune system can also be activated against:  Non-microbial foreign substances (poison ivy, organ transplant)  Altered self substances (cancer cells)  Unaltered self substances (beta islets) Autoimmunity Hypersensitivit y One sentence: “Kill pathogens, do not harm the host” Inherit ability to differentiate self vs. foreign Introduction to HS The immune response generally provides rapid and regulated responses to infectious agents. Under some circumstances, these responses may arise to some inappropriate stimuli (allergy) or cause tissue damage and possibly death (anaphylaxis, organ failure). These deleterious reactions are known collectively as hypersensitivity. Some of the consequences of hypersensitivity reactions may be severe and life-threatening. Some of the consequences may be simply annoying, such as hay fever. There are four (4) primary types of hypersensitivity reactions. Hypersensitivity Definitions 1. Allergy ⇒ A disease or reaction caused by an immune response to one or more environmental antigens, resulting in tissue inflammation and organ dysfunction; a type of hypersensitivity 2. Allergen ⇒ Any antigen that causes allergy 3. Atopy ⇒ A genetically determined state of hypersensitivity to common environmental allergens, mediated by IgE antibodies 4. Hypersensitivity reaction ⇒ Excessive immune response (often to innocuous antigens) that causes damage 5. Allergic Rhinitis (Hay fever) ⇒ The most common clinical expression of atopic hypersensitivity Hypersensitivity reactions Primary mechanism Examples Type I IgE activating mast cells for rapid release of inflammatory mediators Allergic rhinitis, anaphylaxis, allergic asthma Type II IgG, IgM activating complement or ADCC1 to kill cells hemolytic anemia, Pemphigus (autoimmune disease of the skin) Type III Immune complex deposition in blood vessels leads to inflammation Persistent infections (viral hepatitis) and autoimmune diseases (SLE, RA) Type IV Cell-mediated responses, usually delayed by 2 days or more, where activated lymphocytes and/or macrophages cause tissue damage* Poison ivy; granuloma formation in tuberculosis (DTH) [See Notes] Hypersensitivity reactions Type I Hypersensitivity Immunology for Medical Students, 2 nd Ed., NAIRN, RODERICK, PhDCopyright © 2007, 2002 by Mosby, an imprint of Upon first exposure, an atopic person becomes “sensitized”, which means they have formed IgE antibody which binds to the surface of mast cells and basophils. Subsequent contact with that same allergen will trigger the mast cells to degranulate and release inflammatory mediators. Type I reactions are called “immediate hypersensitivity” because the reaction can typically be seen within minutes of exposure. Type I HS - Sensitization  Note that IgE binds to the Fc RI via its Fc region leaving the Fab regions free to bind allergen (Sensitized) Mak, Tak W., Primer to The Immune Response Copyright © 2014 Copyright © 2014 Elsevier Inc. All rights reserved Type I HS – Effector phase • Subsequent contact with allergen causes cross-linking of Fc RI units, which is needed for mast cell activation • Mast cell activation leads to degranulation with immediate release of mediators (e.g., histamine) • Mast cell activation leads to production of other mediators (e.g., prostaglandins, leukotrienes, cytokines) • In late phase reactions eosinophils, monocytes (macrophages) and neutrophils are also recruited to the site Mak, Tak W., Primer to The Immune Response Copyright © 2014 Copyright © 2014 Elsevier Inc. All rights reserved Type I HS – Summary Mechanisms are involved in anaphylaxis: • IgE binding to mast cells • Allergen triggers mast cell degranulation • Systemic release of inflammatory mediators: Histamine, chemotactic factors, leukotrienes, proteases, cytokines Type I HS – Effector phase sites Local activation of mast cells can lead to local disease (e.g. allergic rhinitis). Systemic mast cell activation, such as a reaction to bee venom, can lead to severe anaphylaxis. The diagnosis of systemic anaphylaxis in a patient observed during an acute attack should be established or suspected as rapidly as possible by the symptoms and physical findings of hypotension, urticaria, angioedema, and laryngeal or bronchial obstruction, or any combination of these. Major clinical features in anaphylaxis Respiratory ⇒ nasal obstruction, ↑ mucus, dyspnea, wheezing Cardiovascular ⇒ hypotension, shock Skin ⇒ urticaria, angioedema, pruritus, erythema Gastrointestinal ⇒ pain, nausea, diarrhea Hematological ⇒ thrombocytopenia, Disseminated intravascular coagulation (DIC) Probable Type I Reactions • A 7-year-old begins sneezing minutes after arriving at a petting zoo . . . • A 3-year-old is brought to the ER with rapid labored breathing. She appears in distress and using accessory muscles of respiration. One parent has a history of hay fever . . . • An 8-year-old male develops urticaria, nausea, vomiting, and labored breathing within 20 minutes of eating cookies that contain peanuts . . . • A 23-year-old medical student comes to the clinic for something stronger than the OTC medicines to relieve symptoms of watery eyes, sneezing, and coughing that occur routinely whenever the neighbor cuts grass . . . Allergy skin test The wheal-and-flare reaction in the skin. A - In response to antigen-stimulated release of mast cell mediators, local blood vessels first dilate and then become leaky to fluid and macromolecules, which produces redness and local swelling (a wheal). Subsequent dilation of vessels on the edge of the swelling produces the appearance of a red rim (the flare). B - Photograph of a typical wheal-and-flare reaction in the skin in response to injection of an allergen. Cellular and Molecular Immunology, Eighth Edition, Abbas, Abul K., MBBS Copyright © 2015, 1991 by Saunders, an imprint of Elsevier Inc. Other (non-IgE) antibodymediated diseases  Type II hypersensitivity – injury caused by antitissue antibody, mainly IgG. Antibodies in type II reactions usually form during autoimmune disease  Type III hypersensitivity immune complexes mediate tissue injury. Immune complex disorders commonly involved the skin, joints, and kidneys Basic Immunology: Functions and Disorders of the Immune System, 4 th Ed., Abbas, Abul K., MBBS, Copyright © 2014, 2001 by Saunders, an imprint of Elsevier Inc. Type II Hypersensitivity Cellular/tissue damage may be caused by the antibody binding, by the activation of complement, or by the recruitment of effector cells. •Characteristics of effector cells include: Macrophages, Neutrophils, Eosinophils, NK cells • Effector cells bind to target antigens on cells using the antibody as a bridge between the two cells • Effector cells mediate target cell lysis (ADCC) and/or release inflammatory mediators Basic Immunology: Functions and Disorders of the Immune System, 4 th Ed., Abbas, Abul K., MBBS, Copyright © 2014, 2001 by Saunders, an imprint of Elsevier Inc. Type II HS clinical situations 1. Incompatible blood transfusion reactions 2. Hemolytic disease of the newborn 3. Autoimmune hemolytic anemias 4. Autoimmune diseases such as Goodpasture’s syndrome, Pemphigus and Myasthenia gravis1 5. Penicillin sensitivity: binds to the surface of red blood cells (RBS) in a *See Notes Type III Hypersensitivity Immune complex mediated HS reaction, damage by neutrophils and active complement, which can also tigger platelet aggregation Basic Immunology: Functions and Disorders of the Immune System, 4 th Ed., Abbas, Abul K., MBBS, Copyright © 2014, 2001 by Saunders, an imprint of Elsevier Inc. Immune Complexes in Type III HS Cellular and Molecular Immunology, 8 th Ed., Abbas, Abul K., MBBS, Copyright © 2015, 1991 by Saunders, an imprint of Elsevier Inc. Immune complex (a.k.a. lattice) formation occurs naturally and constantly as the immune system responds to antigens. Normally immune complexes are taken up by RBCs and eliminated in the liver and spleen. However, in type III hypersensitivity, the immune complexes are formed in excess and tend to deposit in tissue and blood vessel walls triggering inflammatory reactions. Immune Complexes in Type III HSactivate Immune Complex may complement and then bind complement proteins. Characteristics: • can vary greatly in size • activate effector mechanisms  Complement activation  Fc-receptor mediated ADCC  Inflammation • deposit in blood vessel walls or renal glomeruli leading to inflammation and tissue damage, i.e. immune complex Type III HS clinical situations 1. Persistent infection malaria, leprosy 2. Autoimmunity SLE, dermatomyositis 3. Inhaled antigen Farmer’s lung, bronchopulmonary aspergillosis 4. Serum sickness Symptoms: fever, weakness, rashes, edema 7-21 days post antivenin (against snake bite) administration or other immunoglobulin (serum) administration (vaccination). Type III HS clinical situations For Example A 19-year-old female complains of stiff joints in her hands, constant fatigue, and a rash over her face. The rash seems to worsen after exposure to sunlight. Examination revealed confluent symmetrical macular erythema over the malar eminences, with tenderness and swelling in peripheral joints. Laboratory tests revealed high titers of anti-nuclear antibody (ANA) and proteinuria. Type IV Hypersensitivity Type IV HS is a.k.a. Delayed Type Hypersensitivity (DTH) Features: • Cell mediated HS • 2-7 day delay • Usually tissue damage is minimal • Large influx of macrophages • Subtypes depend on T effector cells: Th1, Th2 CD8+ Type IV Hypersensitivity reactions 1. Allergic contact dermatitis 2. Tuberculin skin test 3. DTH associated with autoimmunity 4. Granulomatous disease Common features: all are cell mediated and develop over time 2 - 3 days, or perhaps weeks for autoimmunity or granulomas Type IV Hypersensitivity reactions Reaction time Appearance Antigen Contact 48 – 72 hours Eczema Nickel, poison ivy Tuberculin 48 – 72 hours Local induration Tuberculin; PPD Granuloma 21 – 28 days Focal mass; induration Persistent antigen, e.g. infectious agent Allergic Contact Dermatitis • the dermatitis is characterized by skin inflammation including pruritic papules and vesicles on an erythematous base • upon first contact with an allergen, sensitization may take 10 – 14 days • upon subsequent contact with an allergen, dermatitis may develop in hours to days • 50% of ACD are likely due to one of about 25 chemicals, the most common are  nickel  preservatives, dyes and fragrances  chemicals in rubber gloves Allergic contact dermatitis is fairly common and may become persistent if the offending material is not identified and avoided. Allergic Contact Dermatitis Allergic contact dermatitis begins when a contact allergen enters the skin where it is taken up by antigen-presenting Langerhans cells (special DCs). These cells migrate to regional lymph nodes where they active the allergenspecific T cells (generally Th1). *See Notes Allergy, Fourth Edition, Holgate, Stephen T, CBE BSc MB BS MD DSc CSci FRCP FRCP(Edin) FRCPath FSB FIBMS FMedSci, © 2012, Elsevier Limited. All rights reserved. Allergic Contact Dermatitis Subsequent contact with the same allergen/antigen will stimulate those specific T cells in the skin to release inflammatory cytokines. The proinflammatory cytokines act on keratinocytes, endothelial cells, and other cells to produce the characteristic skin lesions that present as eczema. *See Notes Allergic Contact Dermatitis Skin eruptions appear as erythema, swelling, and vesiculation. Severe cases may show blistering, scaling and weeping. Lesions are typically pruritic. What do you think will happen upon their next exposure to the same antigen? Clinical Dermatology, Sixth Edition, Habif, Thomas P., MD © 2016, Elsevier Inc. All rights reserved. *See Notes Type IV HS, Patch testing The memory response is the basis for the patch testing also. Antigen is applied to the skin. Antigen-specific memory T-cells in the skin are activated. The release of pro-inflammatory cytokines and influx of cells causes the indurated skin lesion that is a positive reaction. Test is read in 48-96 hrs (DELAYED type HS). The skin test can be used to determine sensitization to various contact allergens. Test allergens are placed under a dressing. The skin reaction is read after 48 – 96 hours. *See Notes Tuberculin type hypersensitivity Skin test for exposure to M. tuberculosis PPD test Screening for TB PPD injected intradermally Skin reaction read 48 - 72 hours later Positive test = induration 5 - 15 mm diameter • BCG immunization gives positive result • • • • • *See Notes Tuberculin type hypersensitivity Candida normally lives on the skin and inside the body, in places such as the mouth, throat, gut, and vagina, without causing any problems. Poison Ivy induced CD CDC Website Note the CD8+ CTL response. Mak, Tak W., Primer to The Immune Response Copyright © 2014 Copyright © 2014 Elsevier Inc. All rights reserved *See Notes Hypersensitivity reactions Irritant or allergic contact dermatitis Irritant contact dermatitis is inflammation of the skin (erythema, edema, hyperkeratosis, or vesiculation) that is a nonspecific response to direct chemical damage. This is often an occupational disease. History of contact with the potential chemical is key to diagnosis. There is no diagnostic test. Allergic Irritant Type of reaction Allergen specific Nonspecific Requirement for Sensitization Required Not required Patch testing Positive for the allergen May be used to rule out allergic dermatitis Resolution of symptoms May take some time Follows soon after removal of the irritant Tissue Granuloma • Cell types involved derived from macrophages  Epithelioid cells  Multinucleated giant cells • Tissue damage due to size and location of granuloma • Granulomas often form in diseases with persistent antigen  Tuberculosis  Leprosy Robbins and Cotran Pathologic Basis of Disease, 9th Ed., Kumar, Vinay, MBBS, MD, FRCPath, Copyright © 2015, 1974 by Saunders, an imprint of Elsevier Inc. Tissue Granuloma Mak, Tak W., Primer to The Immune Response Copyright © 2014 Copyright © 2014 Elsevier Inc. All rights reserved Further Reading 1. Hogan, D.J. 2016. Allergic contact dermatitis, Medscape http://emedicine.medscape.com/article/1049216-ov erview 2. Mak, Tak W., Primer to The Immune Response Copyright © 2014 Elsevier Inc. All rights reserved [Library Clinical Key resource] Thank you for your attention!