Session 7 Immunity PDF

Hypersensitivity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to: 1. Define the four types of hypersensitivity 2. Explain the mechanisms behind the four types of hypersensitivity 3. Describe the clin...

Hypersensitivity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to: 1. Define the four types of hypersensitivity 2. Explain the mechanisms behind the four types of hypersensitivity 3. Describe the clinical presentations of the four types of hypersensitivity Immune System Module Definition • Injurious consequences in the sensitized host, following subsequent contact with specific antigens. Immune System Module Gell and Coombs Classification Type- I Type- II Type- III Type- IV Immune response altered Humoral Humoral Humoral Cell mediated Immediate or delayed Immediate Immediate Immediate Delayed 2-8 hrs 24 to 72 hrs Duration between 2min to 30 min 5-8 hrs appearance of symptoms & antigen contact Immune System Module Gell and Coombs Classification Type- I Type- II Type- III Type- IV Antigen Soluble Cell surface bound Soluble Soluble or bound Mediator IgE IgG Ag-Ab complex TDTH cell Effector mechanism Mast cell degranulation 1. ADCC 2. Complement mediated cytolysis Complement activation and inflammatory response Macrophage activation leads to phagocytosis or cell cytotoxicity Immune System Module E E Gell and Coombs Classification Typical manifestations Type- I Type- II Type- III Type- IV 1.Anaphylaxis 2.Asthma 3.Atopic dermatitis 1.Transfusion reactions 2.Rh incompatibility 3.Hemolytic anemia 1.Arthus reaction 2.Serum sickness 3.Glomerulonephtiritis 4.Rheumatoid arthritis 1.Tuberculin test 2.Granuloma formation in tuberculosis, leprosy, etc 3.Contact dermatitis Immune System Module Gell and Coombs Classification Immune System Module • Occur immediately, within few minutes to few hours of Immediate antigen contact, as aHypersensitivity result of abnormalReactions exaggerated humoral response (antibody mediated). Further classified into three types: o Type- I hypersensitivity reaction o Type- II hypersensitivity reaction o Type- III hypersensitivity reaction Immune System Module Delayed Hypersensitivity Reaction • Occurs after few days of antigen contact, as a result of abnormal cell-mediated immune response. • Also called as type- IV hypersensitivity reaction. e Immune System Module Type- I Hypersensitivity Reaction • Hallmark - Production of IgE by sensitized B cells following a contact with an allergen which in turn induces mast cell degranulation. • These changes ultimately lead to: o Localized response (called atopy) o Systemic response (called anaphylaxis). Immune System Module Common Allergens Food Nuts, egg, peas, sea food, beans, milk Plants & pollens Rye grass, rag weed, timothy grass Proteins Foreign serum, Vaccines Drugs Penicillin, sulphonamides, local anesthetics and salicylates Insect bite products Venom of Bee, Wasp, Ant, Cockroach calyx and Dust mites Others Mold spores, animal hair and dander Immune System Module Mechanism of type I hypersensitivity • Sensitization phase • Effector phase o Both occurring with an interval of 2-3 weeks. Immune System Module Sensitization phase • Sensitisation is most effective - allergen is introduced parenterally but may occur by any route, including ingestion or inhalation. • In susceptible individuals, very minute doses can be sufficient to sensitize the host. • Allergen is processed by the antigen presenting cells and the antigenic peptides are presented to the CD4+ helper T cells. Immune System Module Sensitization phase • Activated TH cells are differentiated into TH2 cells which in turn secrete interleukin 4 induces the B cells to differentiate into IgE producing plasma cells and memory cells. • Secreted IgE migrate to the target sites, and coat on the surface of mast cells and basophils. • Fc region (the CH3 and CH4 domains) of IgE binds to high affinity Fc receptors (e.g. FcεR1) present on mast cell surface. • Such sensitized mast cells (coated with IgE) will be waiting for interaction with the subsequent antigenic challenge. Immune System Module • When the same allergen is introduced subsequently (shocking dose), it directly encounters with the Fab region of IgE coated on Effector phase mast cells. • IgE cross linkage initiates degranulation: Allergen bound to IgE triggers the mast cells (and basophils) activation and degranulation. Granules in turn release a number of pharmacologically active chemical mediators that lead to the various manifestations of type-1 reaction. • The memory B cells further differentiate into plasma cells that supply the IgE. Immune System Module Effector phase • Degranulation in two phases: o Primary mediators- The preformed chemical mediators which are already synthesized by mast cells, are immediately released. Primary Mediators Histamine, Heparin and Serotonin Eosinophil chemotactic factor (ECF-A) Neutrophil chemotactic factor (NCF-A) Proteases Immune System Module Action ↑Vascular permeability ↑Smooth-muscle contraction Eosinophil chemotaxis Neutrophil chemotaxis Bronchial mucus secretion; Degradation of blood-vessel basement membrane o Secondary mediators are those which the mast cells synthesize and release Effector phase Secondary Mediators Platelet-Activating Factor (PAF) Action Platelet aggregation and degranulation; Contraction of pulmonary smooth muscles Leukotrienes (slow-reacting substance ↑ Vascular permeability; Contraction of pulmonary smooth of anaphylaxis, SRS-A) muscles Prostaglandins ↑Vasodilation; Contraction of pulmonary smooth muscles; Platelet aggregation Bradykinin Cytokines (IL-1 and TNF-α) ↑Vascular permeability; Smooth-muscle contraction Systemic anaphylaxis; ↑ Expression of cell adhesion molecules (CAMs) on venular endothelial cells Immune System Module Effector phase • Pharmacological actions: o Chemical mediators - ↑bronchial and other smooth muscle contraction, ↑increased vascular permeability and vasodilation. • Symptoms: Breathlessness, hypotension and shock, leading to death at times. Immune System Module Mechanism of type I hypersensitivity reaction Immune System Module Manifestations of Type-I ReactionImmediate Manifestations • Systemic anaphylaxis: o Acute medical emergency condition, characterized by severe dyspnea, hypotension, and vascular collapse leading to death. o Occurs within minutes of exposure to allergen and unless treated promptly, may lead to fatality. o Epinephrine (adrenalin) is the drug of choice for systemic e anaphylactic reactions. Immune System Module • Reaction is limited to a specific target tissue or organ, mostly the epithelial surfaces at the entry sites of allergen. Localized anaphylaxis (atopy) • These allergies afflict more than 20% of people. • Almost always run in families (i.e. inherited) • Examples include: o Allergic rhinitis (or hay fever): Most common atopic disorder. Affects 10% of the population. Results from exposure to airborne allergens with the conjunctiva and nasal mucosa leading to appearance of various symptoms such as ↑watery secretions of the conjunctiva, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing. Immune System Module o Asthma: Second most common atopic manifestation. e Differs from hay feveranaphylaxis in involvement of(atopy) lower respiratory Localized mucosa, resulting in contraction of the bronchial smooth muscles and airway edema, ↑mucus secretion; all together leading to bronchoconstriction and dyspnea. The stimulus may or may not be an allergen. Accordingly asthma can be classified as❖ Allergic asthma- Induced by airborne or blood-borne allergens, such as pollens, dust, fumes, insect products, or viral antigens. ❖ Intrinsic asthma- It is independent of allergen stimulation; induced by exercise or cold. Immune System Module o Food allergy Localized(allergic anaphylaxis o Atopic dermatitis eczema)(atopy) o Drug allergy- Various drugs (such as penicillin, sulphonamides, etc.) may produce type-I hypersensitivity responses which may be either local reactions or even sometimes produce systemic anaphylaxis. e Immune System Module Manifestations of Type-I ReactionLate Manifestations The immediate phase of type I reaction is followed, 4-6 hours later, by an inflammatory response. This phase lasts for 1-2 days and leads to tissue damage. • Mediators: They released in acute phase along with cytokines (IL-3, IL-5, IL-8) and ECF and NCF induce recruitment of various inflammatory cells, such as neutrophils, eosinophils, macrophages, and lymphocytes, etc. Among the infiltrates, eosinophils and neutrophils predominate; each accounting for 30% of the total inflammatory cells influx. Immune System Module Manifestations of Type-I ReactionLate Manifestations • Eosinophil influx: o Favoured by ECF (eosinophil chemotactic factor), IL-5 and GM-CSF. o Eosinophils express Fc receptors for IgG & IgE and thus bind directly to antibody-coated allergens. o Causes release of toxic granules from eosinophils which contribute to the chronic inflammation of the bronchial mucosa that characterizes persistent asthma. Immune System Module Manifestations of Type-I ReactionLate Manifestations • Neutrophil infiltration: o Induced by NCF (neutrophil chemotactic factor), and other cytokines such as IL-8. o Activated neutrophils release various mediators which further potentiates inflammatory tissue damage and thickening of basement membrane. Immune System Module Factors influencing type I hypersensitivity 1. Genetic Makeup Host genetic factors play an important role in mounting an immune response against an allergen. • Some individuals mount a normal response whereas some mount an exaggerated immune response. Allergen to one individual may not be to another one. • There are several gene loci identified which encode proteins that are involved in the regulation of immune responses toward allergens. • It is also observed that if both parents are allergic, there is 50% chance that the child will be allergic and when only one parent is allergic, the chance of the child being allergic drops down to 30%. Immune System Module Factors influencing type I hypersensitivity 2. Allergen Dose The dose of the allergen has a definite impact on the type of immune response produced. It is observed that repeated small doses of allergen induce a persistent lgE response in mice; while higher dosage lead to transient IgE response with a shift towards IgG response. Immune System Module Factors influencing type I hypersensitivity 3. TH1 vs TH2 Response The balance between TH1 and TH2 response determines the response of an individual towards an allergen. • TH1 response produces interferon-γ, which is inhibitory to type I hypersensitivity; whereas TH2 response produces IL-3, IL-4 and I L-5, which promote lgE mediated allergic response. • Hence, accordingly atopic and non-atopic individuals would demonstrate a predominant TH2 and TH1 response to an allergen respectively. Immune System Module Detection of Type I Hypersensitivity 1. Skin Prick Test Small amounts of suspected potential allergens are introduced at different skin sites either by intradermal injection or by superficial scratching. ❖ If a person is already sensitized to the allergen, a local wheal and flare response develops within 30 minutes at the inoculation sites. ❖ ™Advantage: Skin test is relatively inexpensive and allows screening of a large number of allergens at one go. ❖ Disadvantage: It may occasionally sensitize the individual to new allergens and in some rare cases may induce late-phase reaction or even systemic anaphylactic shock. Immune System Module Skin testing by intradermal testing of allergens into forearm Immune System Module 2. Total Serum IgE Antibody Quantitative detection of total serum IgE. 3. Allergen-specific IgE Detection of allergen-specific IgE is more specific than total IgE detection. Immune System Module 1. Avoidance of contact with known allergens: The first and foremost step is identification and avoidance of contact with known allergens such as dusts, Treatment house pets, allergic food, etc. However, it is not practically possible to avoid all allergens especially air born allergens, such as pollens. 2. Hyposensitization: Repeated exposure to increased subcutaneous doses of allergens can reduce or eliminate the allergic response to the same allergen. This occurs probably due to either (1) a shift of lgE response towards lgG or (2) a shift of TH2 response towards TH1 response, which secrete IFN-γ that in turn can suppress the lgE response. Here, the lgG acts as blocking antibody, because it competes with lgE for binding to the allergen. The lgG-allergen immune complex can be removed later by phagocytosis. Immune System Module Treatment 3. Monoclonal anti-IgE antibodies: Humanized monoclonal anti-IgE antibodies can bind and block the lgE; but useful only if the lgE is not already bound to high affinity Fc receptors. 4. Drugs: Several drugs are useful in suppressing type 1 response through various mechanisms. Immune System Module Treatment Drugs Mechanism of action Antihistamines Block H1 receptors on target cells; hence antagonise the effects of histamine released Epinephrine (adrenaline) Stimulates cAMP production in mast cells; thereby prevents mast cell degranulation Cortisone Blocks conversion of histidine to histamine and stimulates cAMP levels in mast cells Theophylline Prolongs high cAMP levels in mast cells Cromolyn sodium Blocks Ca2+ influx into mast cells Immune System Module Type II Hypersensitivity Reaction In type II reactions, the host injury is mediated by antibodies (IgG or rarely IgM) which interact with various types of antigens, such as: ❖ Host cell surface antigens (e.g. RBC membrane antigens like blood group and Rh antigens). ❖ Extracellular matrix antigens. ❖ Exogenous antigens absorbed on host cells (e.g. a drug coating on RBC membrane). After Ag-Ab binding occurs, the Fc region of antibody initiates the type II reactions by the following three broad mechanisms. Immune System Module 1. Complement-dependent reactions The Fc region of antibody (bound with antigen) can activate the classical pathway of complement system. Activation of classical pathway leads to host cell injury which is mediated by the following three mechanisms: A. Complement-dependent cytolysis: The membrane attack complex (C5-C9) formed by the activation of classical pathway can produce pores which lead to lysis of the target cells. Immune System Module B. Complement-dependent inflammation: The byproducts of complement pathways such as C3a and C5a are chemoattractants; hence can induce inflammatory response leading to tissue injury. C. Opsonization: By-products of complement pathway, such as C3b and C4b act as opsonins. They deposit on the target cells. Phagocytes, such as macrophage and neutrophil can engulf such C3b and C4b coated target cells via complement receptors. Immune System Module Immune System Module 2. Antibody-dependent cellular cytotoxicity (ADCC) IgG antibodies can coat on the target cells by interacting with the surface antigens through Fab region. The Fc portion of IgG in turn binds to Fc receptors on various effector cells such as NK cells which result in destruction of the target cells. ❖ ADCC is involved in destruction of the targets that are too large to be phagocytozed, e.g. parasites, tumors or graft rejection. ❖ Although ADCC is typically mediated by IgG antibodies, in certain instances (e.g. eosinophil-mediated killing of parasites) IgE antibodies are used. Immune System Module 3. Autoantibody Mediated (Antibody-dependent cellular dysfunction or ADCD) In this condition, the host produces certain autoantibodies which bind and disturb the normal function of human self-antigens. ❖ Anti-receptor Ab: Antibodies may be directed against human receptors, resulting in either inhibition or excessive activation of the receptors leading to host injury. ▪ Activation of receptor, e.g. Graves’ disease: Here, the autoantibodies produced are called LATS (long-acting thyroid stimulators), which stimulate the thyroid cells to upregulate the production of thyroid hormones. ▪ Inhibition of receptor, e.g. myasthenia gravis: In this condition, anti-acetylcholine (ACh) receptor antibodies are produced; which block the ACh receptors, leading to profound muscular weakness. Immune System Module ❖ Other examples of ADCD: ▪ Goodpasture syndrome (antibody produced against type IV collagen). ▪ Pernicious anemia (antibody directed against intrinsic factor). ▪ Rheumatic fever (antibody against streptococcal antigens cross reacting with heart). ▪ Myocarditis in Chagas disease. Immune System Module Immune System Module Type- III Hypersensitivity Reaction • Occurs as a result of excess formation of immune complexes (Ag-Ab complexes) which initiate an inflammatory response through activation of complement system leading to tissue injury. • Antigen involved- Immune complexes can involve exogenous antigens such as bacteria and viruses or endogenous antigens such as DNA. Immune System Module Type- III Hypersensitivity Reaction • Removal of immune complexes o Under normal circumstances, immune complexes are rapidly cleared by activation of complement system. o Immune complexes coated with complements are either directly phagocytosed by macrophages/ monocytes or are bound to RBCs and carried to liver and spleen where they are phagocytosed. Immune System Module Soluble vs. Insoluble Immune Complexes • Balance between level of antigen and antibody decides the nature of the immune complex that is going to be formed. o Antibody excess or antigen-antibody equivalence, immune complexes formed are large & insoluble; which tend to localize near the site of antigen administration to produce a localized type III reaction. o If antigen is in excess (particularly monovalent antigens), small soluble complexes are formed which tend to travel through blood and get deposited in various sites producing a generalized type III reaction. Immune System Module Mechanism of tissue injury – Classical complement pathway activation • Ag-Ab-immune complexes stimulate the classical pathway of complement; products of which mediate the tissue injury in type III reaction. o Anaphylatoxins o Chemoattractants o Role of neutrophils- Neutrophils fail to phagocytose large immune complexes Immune System Module Mechanism of tissue injury – Platelet activation • Immune complexes bind to the Fc receptors on platelets leading to their activation. • Platelet aggregation (leads to microthrombi formation) and vasoactive amines released from activated platelets. • Cause tissue ischemia leading to further tissue damage. Immune System Module Mechanism of tissue injury – Activation of Hageman factor- • Activation of Hageman factor leads to activation of kinin, which in turn causes vasodilation and edema. Immune System Module Types of type-III hypersensitivity reaction • Localized • Generalized. Immune System Module Localized or Arthus reaction • Defined as localized area of tissue necrosis due to vasculitis resulting from acute immune complex deposition at the site of inoculation of antigen. o The reaction is produced experimentally (N.M. Arthus,1903) by injecting an antigen into the skin of a previously immunized animal, e.g. rabbit. o Circulating antibodies bind with the antigen in the dermis and form immune complexes fix the complement localized immune complex mediated inflammatory response. Immune System Module Arthus Reaction • In skin- i) following insect bites or ii) during allergic desensitization treatment wherein repeated injections of the same antigen is given for long periods. • In lungs, following inhalation of bacteria, fungi, spores or proteins may produce intrapulmonary lesions. Examples include conditions causing extrinsic allergic alveolitis such aso Farmer’s Lung o Bird-Fancier’s Disease Immune System Module Generalized or Systemic type III Reactions • Formation of small sized soluble Ag-Ab complexes- following entry of a large dose of antigen in to the body. • Deposition of the immune complexes in various tissues, thus initiating an inflammatory reaction in various sites throughout the body such as: o Blood vessels (vasculitis) o Glomerular basement membrane (glomerulonephritis), o Synovial membrane (arthritis). Immune System Module • Seen following serum therapy i.e. administration of foreign Serum Sickness serum e.g., horse anti-tetanus serum, to treat tetanus cases. seen in the past • Horse serum proteins being foreign induce antibody formation in the host, leading to formation of large number of immune complexes • Typically, after 7-8 days, the individuals begin to show various manifestations which are collectively called serum sickness. Immune System Module Mechanism of systemic type III hypersensitivity reaction Immune System Module Diseases associated with generalized type III hypersensitivity reactions Immune System Module Type- IV Hypersensitivity Reaction • Type IV hypersensitivity reactions differ from other types in various wayso Delayed type (occurs after 48-72 hours of antigen exposure) o Cell mediated-Characteristic cells called TDTH cells (delayed type of hypersensitivity T cells) are the principal mediators. o Tissue injury occurs predominantly due to activated macrophages. Immune System Module Mechanism of Type IV Reactions 1. Sensitization Phase This is the initial phase of 1–2 weeks occurring following antigenic exposure. ❖ During this period, the antigen presenting cells (APCs) process and present the antigenic peptides along with MHC-II to the helper T cells. TH cells are differentiated to form TDTH cells. ❖ Most T DTH cells are derived from TH1 cells; but occasionally other T cells, such as CD8+ T cells and CD4+ TH17 can also act as TDTH cells. 2. Effector Phase The TDTH cells, on subsequent contact with the antigen, secrete variety of cytokines which attract and recruit various inflammatory cells (e.g. macrophages) at the site of DTH reaction. Immune System Module Mechanism of delayed type hypersensitivity Immune System Module Immune System Module Role of DTH: protective vs tissue damage response • Protective response o Under normal circumstances, the pathogens are usually cleared with little tissue damage; mediated by the enhanced microbicidal potency of activated macrophages. • Tissue damage response o When the intracellular microbes escape the macrophage killing mechanisms enhanced phagocytic activity and release of various lytic enzymes by the activated macrophages in an attempt to kill the pathogen leads to non specific tissue destruction. Immune System Module Pathology of DTH reaction (granuloma formation) • Initial TH cell infiltrate is progressively replaced by macrophages in 2 to 3 weeks. Macrophages transform into two type of cells: o Large, flat, and eosinophilic; denoted as epithelioid cells. o Epithelioid cells occasionally fuse (induced by IFN-γ) to form multinucleated giant cells. • Granuloma consists of an inner zone of epithelioid cells, typically surrounded by a collar of lymphocytes and a peripheral rim of fibroblasts and connective tissue. Immune System Module Structure of granuloma Immune System Module • Tuberculin test is the prototype of delayed hypersensitivity. Test sensitized T cells • In sensitized individuals,Tuberculin (i.e. who possess DTH due to prior contact with M. tuberculosis); when a preparation of tuberculin antigen (an extract of M. tuberculosis) is injected intradermally. • Local reaction develops after 48-72 hours consisting of induration surrounded by erythema. Immune System Module Contact Dermatitis • Many antigens such as nickel, poison oak, etc act by producing DTH response. • Most of these substances are haptens; they complex with skin proteins, which act as carrier to make the haptens immunogenic. • This hapten-skin protein complex is internalized by skin APCs (e.g., Langerhans cells), then presented to TH cells to induce a TDH reaction. • Activated macrophages release lytic enzymes which result in skin lesions (e.g. redness and pustule seen following contact with poison oak) Immune System Module Examples of DTH Immune System Module Learning Objectives By the end of this session, students should be able to: 1. Summarize the sequence of events in insect allergy. 2. Infer the pathophysiology of contact dermatitis. 3. Interpret the manifestations of drug-induced anaphylaxis. 4. Compare both late phase of dermatologic type I hypersensitivity and type IV hypersensitivity reactions. Case Study 1: A 5-year-old child is brought to the emergency department by his parents for right arm pain. The patient reports that he was playing hide and seek outside and felt a sharp pain on his arm while hiding in some thick bushes. His parents suspect that something had stung him. Physical examination shows an edematous and erythematous plaque with mild central pallor. A residual stinger, located central to the lesion, is readily extracted. The physical examination is otherwise not significant. Which of the following substances is most likely directly responsible for the skin findings observed in this patient? (Explain and discuss your answer) A. C3b B. IL-2 C. Histamine D. Lysozyme E. TNF-α we have atypeofreceptorfor histamine 8 o reaction Answer: C. Histamine beans it is type hypersensitivity This child is experiencing a local allergic reaction (type I hypersensitivity) to an insect sting. The cutaneous findings are consistent with a wheal and flare reaction, an erythematous papule or plaque often with central pallor (wheal) and peripheral erythema (flare). During initial allergen exposure, a patient predisposed to an allergic response will undergo antibody class switching from lgM to lgE antibodies specific for the allergen. lgE produced by B lymphocytes and plasma cells then binds to high-affinity lgE Fc receptors on basophils and mast cells. Reexposure to the allergen results in cross-linking of bound lgE antibodies with subsequent degranulation and release of inflammatory mediators degradation orwecanuseitfor test enzyme (e.g., histamine, proteases [tryptase], leukotrienes, prostaglandins). thnqsedfprot.in Localized vasodilation and increased vascular permeability result in the characteristic wheal-and-flare lesions. In severe cases, widespread release of these agents can also cause systemic vasodilation, bronchoconstriction, and massive fluid shifts, leading to anaphylactic shock and potentially death. I Educational Objective: Wheal-and-flare lesions usually result from allergic (type I hypersensitivity) reactions. On initial exposure, an allergen (e.g., insect venom) promotes antibody class switching to lgE. Subsequent exposure promotes crosslinking of lgE on basophils and mast cells, resulting in degranulation and release of multiple vasoactive mediators, including histamine. iiii Case Study 2: A 34-year-old electric company worker comes to the physician with a skin rash on his right leg. He has not eaten any new foods or changed detergents, soaps, or lotions. On further questioning, the patient recalls that he recently worked on a repair job in an unmaintained, wooded area. He had atopic dermatitis as a child but no other significant illnesses. On physical examination, he appears uncomfortable and is constantly scratching his leg. His lungs are clear bilaterally and his heart sounds are normal. Examination of his right leg shows the findings in the image below. Which of the following cells is most responsible for causing the tissue damage seen in this patient? (Explain and discuss your answer) A. Basophils B. Eosinophils C. Mast cells D. Neutrophils E. Plasma cells F. T lymphocytes Answer: F. T lymphocytes This patient's pruritic skin rash following wilderness exposure is consistent with poison ivy dermatitis, a form of contact dermatitis. Poison ivy, poison oak, and poison sumac all produce urushiol, a small allergenic substance that causes an immune response when attached to proteins (i.e., a hapten). Following contact with these plants, patients develop a highly pruritic, erythematous rash consisting of papules, vesicles, and bullae that may show signs of excoriation. The rash most frequently affects exposed skin (e.g., legs, forearms) and often forms linear streaks as the patient walks past the plant, dragging it along the skin. Contact dermatitis is a type IV (delayed-type) hypersensitivity reaction that occurs in 2 distinct phases: 1. The sensitization phase leads to the creation of hapten-specific T cells and takes 10-14 days. Cutaneous dendritic cells take up the haptens and express them on E MHC-I and MHC-II molecules as hapten-conjugated peptides. These dendritic cells travel to the draining lymph nodes and interact with hapten-sensitive CD4+ and CD8+ T cells, causing activation and clonal expansion. 2. The elicitation phase occurs within 2-3 days following re-exposure to the same antigen (or following sensitization after first exposure to a highly antigenic antigen such as urushiol). In this phase, the hapten is taken up by skin cells and causes activation of hapten-sensitized T cells in the dermis and epidermis. This results in an inflammatory response and the clinical manifestations of contact dermatitis. Depending on the etiologic agent, contact dermatitis can be mediated primarily by cytotoxic CD8+ T cells or CD4+ T H1 cells (that cause indirect damage by activating macrophages). In urushiol-induced contact dermatitis, CD8+ T cells are the primary effector cells and directly destroy keratinocytes expressing haptenated proteins. Educational Objective: Poison ivy dermatitis is a form of allergic contact dermatitis, which is a type and IV hypersensitivity reaction mediated primarily by T lymphocytes. It manifests as intensely pruritic erythematous papules, vesicles, or bullae that often form linear patterns. Case Study 3: An 8-year-old girl is brought to the emergency department due to "not feeling well." The patient was at an outdoor picnic and began experiencing nausea, vomiting, abdominal cramps, and watery diarrhea 30 minutes ago. She also reports feeling dizzy. The patient has no prior medical conditions and takes no medications. Temperature is 37 C, blood pressure is 60/30 mm Hg, pulse is 140/min, and respirations are 28/min. On physical examination, the patient appears pale and listless. There is faint bilateral wheezing. The abdomen is soft and non-tender. Scattered wheals are present. Which of the following is most responsible for this patient's current condition? A. Gram-negative bacterial endotoxin B. Gram-positive bacterial exotoxin C. Kallikrein-generated bradykinin D. Mast cell-derived histamine E. Vasoactive intestinal peptide Answer: D. Mast cell-derived histamine This patient's sudden-onset gastrointestinal symptoms, hypotension and tachycardia, wheezing, and urticaria (eg, wheals) are consistent with anaphylaxis. While at a picnic outdoors, this patient was likely exposed to an allergen (eg, insect sting) that caused cross-linking of basophil-bound and mast cell-bound lgE antibodies, inducing cellular activation, degranulation, and release of histamine and other chemical mediators (eg, prostaglandin, leukotrienes). Although multiple chemical mediators play a role in anaphylaxis, histamine is believed to cause the most significant, broad-ranging effects, including the following: • H1 and H2 receptor stimulation results in vasodilation (causing hypotension) and increased catecholamine secretion (causing tachycardia). E • H1 receptor stimulation causes increased bronchial smooth muscle contraction (resulting in bronchoconstriction and wheezing) and increased vascular permeability (worsening hypotension and contributing to urticaria). • H2 receptor stimulation increases gastric acid secretion, which contributes to gastrointestinal symptoms (eg, nausea, vomiting). In addition, histamine can activate peripheral nociceptive receptors, causing pruritus or pain. To mitigate its widespread effects, an antihistamine is often given as adjunct treatment in anaphylaxis after mainstay treatment with intramuscular epinephrine. (Choice A) Gram-negative bacterial endotoxins are the most potent mediators of gram-negative sepsis. Although sepsis can present with hypotension, tachycardia, and respiratory symptoms, children with sepsis typically have fever, and the onset of symptoms occurs over hours to days (vs minutes). In addition, wheals are not expected. (Choice B) Gram-positive bacterial enterotoxin is the cause of staphylococcal food poisoning, which can cause vomiting, diarrhea, and abdominal cramps. However, symptoms typically occur 2-8 hours after ingestion (vs immediately) of contaminated food, and wheezing and wheals are not expected. (Choice C) Kallikrein-generated bradykinin plays a role in bradykininmediated angioedema (eg, hereditary, ACE inhibitor-related), which can cause bowel wall edema and result in nausea, vomiting, or diarrhea. In contrast to mast cell-mediated angioedema, bradykinin-mediated angioedema does not typically cause bronchospasm, urticaria, or hypotension. (Choice E) Vasoactive intestinal polypeptide is secreted by VIPomas (Vasoactive intestinal polypeptidomas), rare functioning neuroendocrine tumors most often located in the pancreas. VIPomas can cause watery diarrhea, nausea, and vomiting; however, acute-onset hypotension, wheezing, and wheals are not expected. Educational Objective Anaphylaxis is an lgE-mediated response to an allergen that results in the release of histamine by mast cells and basophils. Histamine causes widespread physiologic effects, including vasodilation and increased vascular permeability (eg, hypotension), increased catecholamine secretion (eg, tachycardia), and bronchoconstriction (eg, wheezing). e E IEEE Case Study 4: A 2-year-old boy is brought to the emergency department due to wheezing and difficulty breathing. The patient had been trick-or-treating with his parents and ate several packs of candy containing peanuts. After he receives an intramuscular epinephrine injection, his symptoms resolve. At a follow up appointment, an allergy specialist places droplets of various allergens on the patient's skin and punctures the epidermis at each site. After 15 minutes, the skin at the site with peanut extract is erythematous with a raised, itchy bump that improves by the time the family leaves the office. Four hours later, the parents notice a hard, red swelling at the puncture site. Which of the following is most likely involved in this secondary reaction? A. Cell lysis following lgG autoantibody binding B. Complement activation by immune complexes C. Epithelial damage by major basic protein D. lgE-mediated histamine release from mast cells E. Interferon gamma release from CD4+ T cells Answer: C. Epithelial damage by major basic protein Following skin prick testing, this patient developed an erythematous, edematous welt that was followed 4 hours later by an indurated skin lesion. These findings are consistent with the early and late phases of a type I hyperse nsitivity reaction. After first exposure to an allergen (e.g., peanuts), antigen specific lgE is produced by B-cells and binds to the surface of mast cells. If repeat exposure occurs, the bound lgE can cross-link and stimulate the release of preformed histamine and leukotrienes that cause vasodilation and increased capillary permeability. The result is a rapid (e.g., minutes after exposure) early-phase type I hypersensitivity response characterized by superficial dermal edema and erythema (e.g., wheal and flare reaction) that can progress to a more systemic response (e.g., anaphylaxis). lgE also initiates the late phase of a type I hypersensitivity reaction by stimulating type 2 helper T cells to release cytokines (e.g., IL-5) that activate eosinophils. Cationic proteins (e.g., major basic protein, eosinophil peroxidase) released from eosinophils cause tissue damage, which usually manifests as a palpable, indurated lesion 2-10 hours following the earlyphase reaction. Educational Objective: The late phase of dermatologic type I hypersensitivity reactions manifests as an indurated skin lesion hours after exposure to the allergen due to local o tissue damage caused by major basic protein released from eosinophils. In contrast, type IV hypersensitivity reactions develop over days because of the time needed to produce a cell-mediated immune response.