PBL 4 Flashcards
Discuss the immunological basis of type 1 hypersensitivity reactions
Type 1 hypersensitivity reactions, also known as immediate hypersensitivity or allergic reactions, are characterized by an exaggerated immune response to normally harmless substances, leading to the release of various mediators that cause allergic symptoms. The immunological basis of type 1 hypersensitivity reactions involves several key steps:
Sensitization Phase:
Antigen Exposure:
Allergens (soluble antigens) are encountered by the immune system.
Antigen-presenting cells (APCs), such as dendritic cells, take up and process these allergens.
Presentation to T Cells:
APCs present allergen fragments to naive T helper (Th0) cells in lymph nodes, particularly near mucosal surfaces.
Th2 Differentiation:
Due to a combination of genetic factors and regulatory T cell (Treg) dysfunction, Th0 cells differentiate into Th2 CD4+ T cells.
Cytokine Release:
Th2 cells produce and release cytokines such as interleukin-4 (IL-4) and interleukin-5 (IL-5).
B Cell Activation:
IL-4 and IL-5 stimulate B cells, leading to their activation and proliferation.
IgE Antibody Production:
Activated B cells differentiate into plasma cells that produce immunoglobulin E (IgE) antibodies specific to the encountered allergen.
Effector Phase:
IgE Binding:
IgE antibodies bind to high-affinity Fc receptors (FcεRI) on the surface of mast cells and basophils.
Cross-linking:
When the allergen is encountered again, it binds to multiple IgE antibodies on the surface of mast cells or basophils, causing cross-linking.
Degranulation:
Cross-linking triggers degranulation, leading to the release of preformed mediators from granules within mast cells and basophils.
Mediator Release:
Histamine: Causes vasodilation, increased vascular permeability, and smooth muscle contraction, resulting in symptoms like itching, redness, and bronchoconstriction.
Inflammatory Cytokines: Contribute to the inflammatory response.
Proteases: Contribute to tissue damage.
Clinical Manifestations:
Immediate Symptoms:
Occur within minutes of allergen exposure.
Include itching, hives, redness, nasal congestion, bronchoconstriction, and, in severe cases, anaphylaxis.
Late-phase Reaction:
Some individuals may experience a delayed-phase reaction with prolonged symptoms due to the recruitment of other immune cells.
Key Points:
Genetic Basis: There is a genetic predisposition to allergic conditions.
Treg Dysfunction: Dysregulation of regulatory T cells may contribute to the Th2-biased immune response.
IL-4 and IL-5: These cytokines play a crucial role in the activation and differentiation of B cells toward IgE production.
Contrast the mechanisms of IgE-mediated and non-IgE-mediated allergic reactions, along with their clinical spectrum
IgE-Mediated Allergic Reactions:
Mechanism:
Sensitization Phase:
Exposure to an allergen induces the production of allergen-specific IgE antibodies by plasma cells.
IgE antibodies bind to high-affinity receptors (FcεRI) on the surface of mast cells and basophils.
Effector Phase:
Upon re-exposure to the allergen, it binds to IgE antibodies on mast cells, triggering cross-linking.
Cross-linking activates mast cells, leading to degranulation and the release of histamine, leukotrienes, and other mediators.
Histamine causes the characteristic symptoms of itching, hives, bronchoconstriction, and vasodilation.
Clinical Spectrum:
Onset: Rapid, occurring within minutes to hours upon allergen exposure.
Characteristics: Often biphasic, with an initial reaction followed by a delayed and sometimes more severe response.
Symptoms: Pruritus, urticaria, angioedema, bronchospasm, gastrointestinal symptoms, and, in severe cases, anaphylaxis.
Non-IgE-Mediated Allergic Reactions:
Mechanism:
Dose-Dependent and Monophasic:
The clinical response is generally dose-dependent, meaning the severity of the reaction is related to the amount of the allergen encountered.
The reaction is typically monophasic, with a single phase of symptoms.
Immunological Triggers (Anaphylatoxins):
Activation of the complement system (C3a, C4a, C5a) by immune complexes or microbial products.
Anaphylatoxins act on mast cells directly, leading to degranulation without the involvement of IgE.
Non-Immunological Triggers (Induced Anaphylactoids):
Allergens such as certain foods, drugs, chemicals, physical factors (temperature, exercise) directly activate mast cells.
Histamine release occurs without the formation of immune complexes or IgE antibodies.
Clinical Spectrum:
Onset: Faster, occurring rapidly upon exposure to the allergen.
Characteristics: Typically monophasic, with symptoms that are dose-dependent.
Symptoms: Can include a wide range of manifestations, such as rash, gastrointestinal symptoms, and respiratory symptoms.
Contrast:
Immunological Basis:
IgE-mediated reactions involve the production of allergen-specific IgE antibodies and the activation of mast cells upon re-exposure.
Non-IgE-mediated reactions can be triggered by immune complexes activating complement or direct activation of mast cells without the involvement of IgE.
Clinical Spectrum:
IgE-mediated reactions often exhibit a biphasic response and can lead to severe systemic symptoms, including anaphylaxis.
Non-IgE-mediated reactions are usually monophasic, and the clinical presentation is diverse, ranging from mild to severe, depending on the dose and nature of the allergen.
Triggers:
IgE-mediated reactions are initiated by allergens that induce the production of specific IgE antibodies.
Non-IgE-mediated reactions can be triggered by immune complexes, anaphylatoxins, or direct activation of mast cells by various substances.
Signs and symptoms of type 1 hypersensitivity reactions and their physiological mechanisms
Signs and Symptoms of Type 1 Hypersensitivity Reactions:
Skin Manifestations:
Itching (Pruritus): Caused by histamine release and increased vascular permeability.
Hives (Urticaria): Raised, red, itchy welts on the skin due to increased permeability and fluid leakage.
Respiratory Symptoms:
Bronchospasm: Constriction of smooth muscles in the bronchioles, leading to difficulty breathing.
Wheezing: Audible high-pitched sound during breathing, resulting from narrowed airways.
Dyspnea: Shortness of breath due to bronchoconstriction.
Cardiovascular Symptoms:
Low Blood Pressure (Hypotension): Histamine binding to H1 receptors on vascular endothelial cells can induce the release of nitric oxide, leading to vasodilation and low blood pressure.
High Pulse Rate (Tachycardia): A compensatory response to maintain cardiac output in the presence of hypotension.
Gastrointestinal Symptoms:
Nausea and Vomiting: Possible symptoms, though less common.
Systemic Effects:
Anaphylaxis: A severe, potentially life-threatening allergic reaction that can involve multiple organ systems. It may include a rapid onset of symptoms such as difficulty breathing, swelling of the face and throat, and a drop in blood pressure.
Physiological Mechanisms:
Bronchoconstriction:
Mechanism: Histamine binding to H1 receptors on bronchial smooth muscle induces contraction, leading to bronchoconstriction.
Physiological Effect: Results in reduced airflow, wheezing, and difficulty breathing.
Increased Vascular Permeability:
Mechanism: Histamine causes phosphorylation of cadherin molecules, leading to increased permeability of blood vessels.
Physiological Effect: Allows fluid and proteins to leak into tissues, causing edema, rash, and angioedema.
Bronchiole Inflammation and Edema:
Mechanism: Histamine, along with other mediators released by activated mast cells, induces inflammation and edema in the bronchioles.
Physiological Effect: Contributes to bronchospasm, hyperventilation, and respiratory distress.
Low Blood Pressure and High Pulse:
Mechanism: Histamine binding to H1 receptors on vascular endothelial cells increases the release of nitric oxide, causing vasodilation.
Physiological Effect: Results in decreased systemic vascular resistance, leading to hypotension. Tachycardia is a compensatory response to maintain cardiac output.
Mast Cell Activation:
Mechanism: IgE binding to mast cells triggers degranulation, releasing inflammatory cytokines, prostaglandins, and leukotrienes.
Physiological Effect: Causes sustained airway inflammation, bronchial constriction, and systemic effects observed in anaphylaxis.
Immunological and clinical basis of the treatment options for anaphylactic shock
Immunological and Clinical Basis of Treatment Options for Anaphylactic Shock:
Adrenaline (Epinephrine):
Reduction of Vascular Permeability:
Mechanism: Adrenaline inhibits the phosphorylation of endothelial cadherins, leading to a reduction in vascular permeability.
Immunological Basis: Helps counteract the increased permeability caused by histamine and other mediators released during anaphylaxis, addressing rash and angioedema.
Vasoconstriction:
Mechanism: Adrenaline binds to alpha-1 adrenergic receptors on blood vessels, leading to increased calcium influx and activation of myosin light chain kinase, resulting in vasoconstriction.
Immunological Basis: Counters the vasodilation and low blood pressure associated with anaphylaxis, improving perfusion to vital organs.
Cardiovascular Effects:
Chronotropic and Inotropic Effects: Adrenaline binding to receptors on the heart increases heart rate (chronotropic effect) and enhances contraction force (inotropic effect).
Immunological Basis: Counteracts the cardiovascular collapse often seen in severe anaphylaxis by improving cardiac output.
Bronchodilation:
Mechanism: Adrenaline binding to its receptors on bronchial smooth muscle activates adenylyl cyclase, leading to the production of cAMP. This activates protein kinases, phosphorylating myosin light chain kinase and causing smooth muscle relaxation.
Immunological Basis: Addresses bronchospasm and hyperventilation, which are common respiratory manifestations of anaphylaxis.
Hydrocortisone:
Enhancement of Adrenaline Effects:
Mechanism: Hydrocortisone increases the responsiveness of beta-1 adrenergic receptors in the heart to adrenaline, leading to faster heart rate and stronger contractions.
Immunological Basis: Augments the cardiovascular effects of adrenaline, helping to maintain blood pressure and improve cardiac output.
Reduction of Biphasic Responses:
Mechanism: Hydrocortisone may help reduce the severity of biphasic responses, which involve a recurrence of symptoms after an initial resolution.
Immunological Basis: Modulation of the immune response and inflammation, potentially preventing the recurrence of symptoms.
Anti-inflammatory Effects:
Mechanism: Corticosteroids like hydrocortisone have broad anti-inflammatory effects, suppressing the release of inflammatory mediators.
Immunological Basis: Helps mitigate the systemic inflammatory response associated with anaphylaxis.
Clinical Considerations:
Prompt Administration:
Early administration of adrenaline is crucial for the management of anaphylaxis. Its rapid onset of action can reverse life-threatening symptoms.
Multiple Effects of Adrenaline:
Adrenaline addresses various aspects of anaphylaxis, including vascular permeability, vasodilation, cardiovascular collapse, and bronchospasm.
Adjunctive Use of Hydrocortisone:
Hydrocortisone is often used as an adjunct to address the delayed and prolonged inflammatory components of anaphylaxis.
Monitoring and Supportive Care:
Continuous monitoring of vital signs is essential, and additional supportive measures may be required, such as intravenous fluids, antihistamines, and bronchodilators.
Preventive Measures:
Identification and avoidance of triggers, patient education, and provision of anaphylaxis action plans are crucial for preventing future episodes.
Understand the common causes of the different types of allergic reactions
Allergic reactions can be triggered by a variety of substances, known as allergens. The type of allergic reaction depends on the specific immune mechanisms involved. Here are common causes for different types of allergic reactions:
- IgE-Mediated Allergic Reactions:
Common Causes:
Inhalants:
Pollens (from trees, grasses, and weeds)
Mold spores
Animal dander (skin flakes, fur)
Dust mites
Foods:
Peanuts
Tree nuts
Shellfish
Milk
Eggs
Wheat
Soy
Insect Venom:
Bee stings
Wasp stings
Ant bites
Environmental Triggers:
Medications:
Antibiotics (e.g., penicillin)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Aspirin
Latex:
Found in gloves, balloons, and medical devices.
2. Non-IgE-Mediated Allergic Reactions:
Common Causes:
Food Allergies:
Milk
Soy
Wheat
Eggs
Drug Reactions:
Non-immune reactions to medications, such as side effects or toxic reactions.
Immune-mediated reactions involving T cells, causing delayed-type hypersensitivity.
Physical Factors:
Cold or heat
Sunlight (photosensitivity)
Exercise-induced reactions
Chemical Exposure:
Contact dermatitis due to exposure to certain chemicals (e.g., nickel, poison ivy).
Infections:
Some allergic-like reactions can occur during or after infections, such as drug-induced rashes during antibiotic treatment.
Note: Non-IgE-mediated reactions often involve different immune mechanisms, such as T cell activation, complement activation, or direct mast cell/basophil activation without IgE involvement.
- Mixed or Combined Reactions:
Common Causes:
Certain Foods:
Some individuals may experience both IgE-mediated and non-IgE-mediated responses to certain foods.
For example, a person with a peanut allergy may experience immediate IgE-mediated symptoms but also delayed gastrointestinal symptoms due to a non-IgE-mediated response.
Environmental and Occupational Exposures:
Allergens in the Workplace:
Occupational exposure to certain allergens can lead to both immediate and delayed hypersensitivity reactions.
4. Anaphylaxis:
Common Causes:
Insect Stings:
Bee stings, wasp stings, ant bites.
Foods:
Peanuts, tree nuts, shellfish.
Medications:
Antibiotics, NSAIDs, certain anesthetics.
Note: Anaphylaxis can result from both IgE-mediated and non-IgE-mediated mechanisms and is a severe, life-threatening allergic reaction that requires immediate medical attention.
Generalised IgE-mediated anaphylactic reactions always present with a biphasic course of response. Explain the immunological basis of this response.
The biphasic nature of IgE-mediated anaphylactic reactions refers to the occurrence of two distinct phases of symptoms: an initial acute reaction followed by a second, delayed-phase reaction. The immunological basis of this biphasic response involves a complex interplay of immune cells, mediators, and the immune system’s memory.
Immunological Basis of Biphasic Anaphylactic Reactions:
Initial Acute Phase:
Sensitization: The patient has been previously sensitized to a specific allergen, resulting in the production of allergen-specific IgE antibodies.
Allergen Exposure: Upon re-exposure to the allergen, the allergen cross-links with IgE antibodies on the surface of mast cells and basophils.
Degranulation: Cross-linking triggers degranulation, leading to the release of various mediators such as histamine, leukotrienes, and prostaglandins.
Acute Symptoms: The immediate symptoms occur, including but not limited to hives, itching, bronchospasm, and vascular changes.
Resolution and Second Exposure:
Resolution of Symptoms: The acute phase symptoms are managed through medical intervention (e.g., administration of epinephrine, antihistamines).
Return to Baseline: The patient appears to recover, and symptoms resolve.
Delayed or Second Phase:
Reactivation of Mast Cells: Despite initial symptom resolution, mast cells may remain activated.
Secondary Release of Mediators: Subsequent exposure to the same or a related allergen can lead to a secondary release of mediators from primed mast cells.
Delayed Symptoms: The delayed-phase reaction presents with symptoms similar to the initial phase but can be more severe and prolonged.
Factors Contributing to Biphasic Reactions:
Persistent Mast Cell Activation:
Mast cells may remain activated even after initial symptoms subside, maintaining a heightened state of responsiveness.
Memory Response:
The immune system has memory cells, particularly memory B cells and memory T cells, that “remember” the allergen upon re-exposure.
Memory B cells can quickly differentiate into plasma cells, leading to the rapid production of more IgE antibodies.
Antigen-Presenting Cells:
Antigen-presenting cells, such as dendritic cells, play a role in presenting allergens to T cells, perpetuating the immune response upon subsequent exposure.
Clinical Implications:
Monitoring Periods:
Patients who experience anaphylaxis are often observed for an extended period, typically 4-6 hours, to monitor for the potential onset of a biphasic reaction.
Delayed Discharge:
As you mentioned, patients with IgE-mediated inflammation should not be discharged too early. The risk of a biphasic reaction emphasizes the importance of extended monitoring, sometimes up to 24 hours.
Management Strategies:
Healthcare providers may consider strategies such as prolonged observation, administering additional doses of epinephrine, and providing clear instructions for patients on recognizing and managing potential delayed symptoms.
