Hypersensitivity: Allergies

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T or F: Mast Cells Defend the Tissues in which They Reside

True

Immediate Hypersensitivity: Type1 Hypersensitivity Mechanism

1. Activation of Th2 cells by antigen 2. Induced B cell class switching to IgE 3. Production of IgE and binding of secreted IgE to Mast cell FceR 4. Activation, degranulation, and tissue damage by mast cells/eosinophils upon secondary exposure to antigen

Allergic Asthma Pathology

1. Airway constriction, mucous secretion (histamine and heparin which cause smooth muscle contraction) 2. Airway remodeling (tryptase, chymase, cathepsin G, carboxypeptidase, eosinophil collagenase which causes remodeling of CNT matrix) a. Sub epithelial fibrosis b. Increase in smooth muscle mass

Systemic Anaphylaxis Mechanism

1. Allergen is introduced into the blood stream and disseminated throughout the body 2. Common causes: a. IV drug administration (penicillin) b. Insect sting (Bee sting) c. Rapid absorption of food allergen (peanut) 3. Mast cells throughout body tissues degranulate

IgG/IgM Antibody-Mediated Reactions Page 49

1. Autoimmune a. Breakdown of self tolerance i. Molecular mimicry ii. Anatomical alterations iii. Genetic susceptibility 2. Non-autoimmune a. Modification of self i. Chemical reactions of drugs ii. Blood transfusion reactions b. Hemolytic Disease of the Newborn (HDNB) i. Mother's anti-Rh antibodies attack fetal red blood cells

Treatment and Prevention of Hypersensitivity

1. Avoidance - Patient modifies behavior or environment so as to avoid the allergen. When foods are involved, avoid eating those foods. 2. Modify the response - Drugs are used to modify or dampen the immune response to the allergen (e.g. anti-histamines, anti-IgE, anti-IL-4). 3. Desensitization - Patients are given injections of allergen to induce a change in the type of immune response from an IgE to an IgG1 response. 4. Vaccination - Patients are injected with allergen- derived peptides to induce anergy or tolerance.

Delayed Type Hypersensitivity (DTH) Skin Response

1. Delayed inflammation 2. Predominantly involves Th1 cells a. Leading to Macrophage activation. 3. Can also involve Th2 cells along with Th1 cells 4. Secondary mediators a. IFNg, TNFa, (IL-4 with Th2 involvement) 5. Good Example: TB skin test

Common Examples of Arthus Reaction in Type 3 Hypersensitivity

1. Desensitization injections to treat type I hypersensitivity 2. SLE "Butterfly" rash and inflammation on hands

Classic Type II Hypersensitivity Reactions

1. Drug-induced Anemia or Thrombocytopenia a. Most commonly penicillin, quinidine, methyldopa i. Half-life of drugs: drugs can remain in system long enough to induce Ab response on first exposure b. Treated by halting drug and use of an alternative i. Worst case, remove drug by plasmapheresis

Antibody Mediated Hypersensitivity: Type 2 Hypersensitivity

1. IgM or IgG is generated against "self" cell surface or Extra-cellular Matrix (ECM) protein antigens 2. Antibody binding to antigen on cells/tissues a. Complement or FcR mediated uptake and destruction of cells or local inflammation and tissue damage b. Antibody mediated activation of signaling by cell surface receptors

Type 3 Hypersensitivity Clinical Manifestations

1. Insect bites (in sensitive individuals a Type I reaction may occur immediately at the site. 4-8 hours later a typical Arthus reaction also develops. 2. Farmer's Lung: An intrapulmonary Arthus-type reaction which develops after inhalation of thermophilic actinomycetes from moldy hay. 3. Pigeon Fancier's Disease: Results from inhalation of a serum protein from pigeons in dust derived from pigeon feces.

Serum Sickness

1. Intravenous injection of high doses of antigen a. Non-immune individual (i.e. primary exposure) exception to second exposure rule of hypersensitivity. 2. Onset of symptoms coincides with creation of Ab (7-10 days p.i.) 3. Symptoms vary based on site of immune complex deposition.

Type 3 Hypersensitivity Reaction

1. It takes at least two (2) IgG per immune complex to fix complement and clear the antigen. a. Early in infection there may not be sufficient IgG to clear antigen, and small complexes build up. b. After injection of large doses of perceived antigen (e.g. therapeutics or drug modification of self)

Immediate Hypersensitivity: Type1 Hypersensitivity

1. Mast Cell 2. Eosinophil 3. Basophil

Allergic Asthma in Systemic Anaphylaxis

1. Migration of inflammatory cells to airway: a. Prostaglandin D2 (PGD2) b. Leukotriene C4 (LTC4) 2. Page 36 know process, not all details.

Penicillin-Induced Type II Response

1. Starts by penicillin modifies proteins on human red blood cells to create foreign epitopes. 2. Antibody and complement can lead to cell destruction alone or with the aid of phagocytes. 3. Erythrocytes and platelets are the primary targets for incidental drug modification.

Arthus Reaction in Serum Sickness

1. Subcutaneous injection of antigen a. Immune individual (i.e. secondary exposure) 2. Similarity to and difference from Type I reaction (e.g. timing and immune agents)

Allergic Asthma

1. Symptoms a. Difficulty breathing, wheezing b. Episodic

Allergic Rhinitis/Hay Fever

1. Symptoms a. Nasal congestion with watery rhinorrhea b. Conjunctivitis c. Seasonal 2. Pathology a. Histamine release (Binding to H-1 Receptors) b. Nasal congestion with rhinorrhea c. Sneezing and itching d. Conjunctivitis

Systemic Anaphylaxis

1. Symptoms a. Shock, unconsciousness, lack of breathing 2. Pathology a. Wide-spread Mast cell activation and granule release 3. Emergent Treatment a. Epinephrine injection within 20 minutes 4. Delayed treatment a. IV fluids to replace that lost in tissues b. Anti-histamines to block further responses c. Corticosteroids to block late phase responses

Insect Sting Allergies

1. Symptoms a. Wheal and flare b. Systemic anaphylaxis 2. Pathology a. Wheal and Flare

Food Allergies

1. Symptoms: a. Cramps b. Diarrhea c. Vomiting d. Oral rashes and itching sensation 2. Immediate response to eating 3. Systemic Anaphylaxis is life-threatening! 4. Digestion and absorption can occur throughout the digestive system a. Oral allergy syndrome (most common symptom as people tend to spit out offending food prior to swallowing) b. Allergic eosinophilic esophagitis c. Food protein induced proctocolitis d. Food protein induced enteropathy 3. Food protein induced enterocolitis

Diagnosis of Type I Allergies: Skin Testing

A test is considered positive when the mean of the wheal diameter is 3 mm greater than saline (S). Histamine dihydrochloride (H) is used as a positive control. Histamine size is measured at 10 minutes and allergen at 15 minutes.

Hypersensitivity Subdivided: 4 Types

Chart Page 5

Mediators of Damage in Mast Cell Responses

Chart page 13

Contact Dermatitis

Contact dermatitis results from small molecules which are not normally immunogenic complexing with skin proteins forming a hapten-carrier-like complex. These complexes are then presented by professional antigen-presenting cells (Langerhan's cells) to TDTH cells.

Hypersensitivity

Definition: When an adaptive immune response occurs against an antigen ("allergen") in an exaggerated or inappropriate manner, the term "hypersensitivity" is applied. Initiation: Hypersensitivity reactions can be provoked by many antigens, and the cause of a hypersensitivity reaction often varies from one individual to the next. Key Concept: Hypersensitivity does NOT manifest on first contact with an allergen, only on a subsequent contact (there are some exceptions).

T Cell- Mediated Hypersensitivity: Type 4 Hypersensitivity

Diseases in which T cells play a dominant role in causing tissue injury; antibodies and immune complexes may also contribute. Note that multiple sclerosis, rheumatoid arthritis, and type 1 diabetes are autoimmune disorders. Crohn's disease, an inflammatory bowel disease, is likely caused by reactions against microbes in the intestine and may have a component of autoimmunity. The other diseases are caused by reactions against foreign (microbial or environmental) antigens. In most of these diseases, the role of T cells is inferred from the detection and isolation of T cells reactive with various antigens from the blood or lesions, and from the similarity with experimental models in which the involvement of T cells has been established by a variety of approached diseases.

T or F: Type IV Hypersensitivity takes less than 12 hours to develop, and involves cell-mediated immune reactions rather than humoral (antibody-mediated) immune reactions.

False; more

Contact dermatitis-inducing agents:

Formaldehyde, trinitrophenol, nickel, turpentine, cosmetics, hair dye, penicillin, poison oak, and poison ivy

Eosinophils Function

Granulocytes that also Release Toxic Mediators of Damage in IgE-Mediated Responses (lipid mediators) Chronic diseases

Penicillin-Induced Systemic Anaphylaxis

Hapten vs Hapten Carrier 1. Penicillin binds to bacterial transpeptidase and inactivates it. 2. Penicillin modifies proteins on human red blood cells to create foreign epitopes. 3. Complement coated penicillin-modified RBC are phagocytosed by macrophages. 4. Macrophages present peptides from the penicillin-protein conjugate and activate specific CD4 T cells to become Th2 cells. 5. B cells are activated by antigen and by help from activated Th2 cells. 6. Plasma cells secrete penicillin-specific IgE which arms mast cells. 7. Penicillin- modified RBC activate armed mast cells, causing anaphylaxis.

Classic type 2 hypersensitivity disease

Hemolytic disease of the newborn 1. ADCC (antibody-dependent cellular cytotoxicity)

FceRI has a Very________ Affinity for IgE

High; 1. Resting mast cells have preformed exocytic vesicles waiting to release their cargo outside the cell 2. Crosslinking/antigen binding of FceRI/IgE leads to release of granules

Repeated Subcutaneous Injection of Low Dose Allergen

Hyposensitization: Repeated injections of increasing doses of allergen. Mechanism: There is a gradual switch to higher levels of IgG and lower levels of IgE. The IgG competes with the IgE for allergen forming IgG-allergen complexes which are removed by phagocytes. A switch from Th2 to Th1 cells may also be involved.

Mediators Released During Immediate and Late Phase

Immediate: Initial release from vesicles (histamine which causes smooth muscle contraction) Late Phase (6-24 hours later): Synthesized after initial activation and vesicle release (TNF-a, IL-4, IL-3, IL-5, GM-CSF, Leukotrienes C4, D4 and E4) Page 19

In most of the Antibody-mediated diseases what happens?

In most of these diseases, the role of antibodies is inferred from the detection of antibodies in the blood or the lesions, and in some cases by similarities with experimental models in which the involvement of antibodies can be formally established by transfer studies.

Immune Complex- Mediated Hypersensitivity: Type 3 Hypersensitivity

In these diseases, immune complexes are detected in the blood or in the tissues that are the sites of injury. In all the disorders, injury is caused by complement-mediated and Fc receptor-mediated inflammation. Antibodies (other than IgE) may cause tissue injury and disease by forming immune complexes that deposit mainly in blood vessels (type III hypersensitivity).

Multiple Specificities of Bound IgE on a Single Mast Cell

Page 11

Features of Inhaled Allergens that Promote Priming of the Th2 Cells Driving the IgE Response

Page 18

Clinical Manifestations of Hypersensitivity Type 1

Page 22

Classic Type 1 Reactions

Page 23

Symptoms and Pathology of Hypersensitivity Type 1

Page 24

Treatment of Hypersensitivity Type 1

Page 40

Type 1 Summary

Page 44

Antibody-Mediated Disease Mechanisms

Page 47

Immune Complex Formation

Page 56

Mechanisms of T Cell- Mediated Tissue Injury

Page 64 T cells may cause tissue injury and disease by two mechanisms. 1.Inflammation may be triggered by cytokines produced mainly by CD4+ T cells in which tissue injury is caused by activated macrophages and inflammatory cells; APC, Antigen-presenting cell. 2. Direct killing of target cells is mediated by CD8+ cytotoxic T lymphocytes (CTLs).

Delayed-Type Hypersensitivity Mechanism

Page 68

Intracellular Pathogens & Contact Antigens that Induce DTH Hypersensitivity

Page 69; Note: The Type IV response is designed to eliminate parasites and intracellular pathogens. Problems arise when the response is prolonged as a result of failure to eliminate the pathogen.

Penicillin- Induced Hypersensitive Reactions Comparison

Page 72

Hypersensitivity Types Summarized

Page 73

First Exposure Antigen

Page 8

Subsequent Exposure to Antigen

Page 9

IgE is normally produced in response to:

Parasites

What is the causative agent of poison ivy?

Pentadecacatechol; Will modify self proteins leading to them being seen by the immune system as foreign.

Vaccination - "Allergy Shots" Pros and Cons

Pros - Can be very effective for reduction of symptoms Cons - Can be very difficult or prohibitively costly to identify the specific proteins that are allergens, and then identify specific peptides within the proteins that are being reacted to. Safety is also a concern.

Allergens are _______ Antigens which may Resemble _________Antigens

Protein; Parasite

Basophils Function

Rare Granulocytes that Initiate Th2 Responses and IgE Production (rare)

T or F: In Type 3 Hypersensitivity, immune complexes not cleared eventually deposit somewhere.

True; 1. Vessel Wall 2. Kidney Tubules 3. Enough deposition of complexes in the same location will activate an immune response. a. Phagocytes b. Complement

T or F: IgE-Mediated Allergic Reactions Consist of an Immediate Response followed by a Late-Phase Response

True; Late phase agents (e.g. leukotrienes) tend to have the same effect but LARGER magnitude than immediate released agents (e.g. histamine).

T cell mediated hypersensitive response requires 100-1000 times more antigen than those required to elicit antibody-mediated hypersensitivity.

True; Subdivided into: Contact hypersensitivity (1 - below) Delayed type hypersensitivity (2 - below)


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