MD137 Immunology: Allergy & Autoimmunity

MD137 Immunology: Lecture 4 - Allergy & Autoimmunity

• Learning Objectives: Background on allergies and autoimmunity, four to five types of hypersensitivity reactions, disease mechanisms, and examples of each type.

Hypersensitivity

• Definition: An excessive or inappropriate immune response leading to tissue damage.
• Gell & Coombs (1963): Method for defining and describing hypersensitivity reactions.
• Types: Types I - V; I, II, III and V are antibody-mediated; Type IV is T cell-mediated.

Type I Hypersensitivity (IgE-mediated Allergy)

• Mechanism: Immediate hypersensitivity; IgE produced by B cells. Atopy is a tendency to produce IgE in response to allergens. IgE binds to Fce receptors on mast cells, leading to mast cell degranulation and release of allergic mediators (e.g., histamine).
• Atopic Conditions: Eczema, allergic rhinitis (hay fever), asthma, food allergy. Allergic triggers may or may not be identifiable.
• Sensitization: First exposure to allergen causes IgE to bind to FcεRI receptors on mast cells. Subsequent exposure causes cross-linking of IgE, mast cell degranulation, and allergy symptoms.

Mast Cell Mediators

• Pre-formed Mediators: Stored in granules; released within seconds. Include enzymes like tryptase, serotonin, and histamine.
• Actions: Cause vasodilation, increased vascular permeability, and smooth muscle contraction.
• Newly Synthesized Mediators: Cytokines and lipid mediators produced afterward.

Lipid Mediators in Allergy

• Phospholipase A2: Breaks down phospholipids to release arachidonic acid.
• Arachidonic Acid Pathways: Processed by 12-lipoxygenase and 5-lipoxygenase to produce leukotrienes, and by cyclooxygenase to produce prostaglandins and thromboxanes. Lipoxins A and B are also produced. Various pathways lead to the release of inflammatory mediators. Bronchospasm is a common effect.

Early/Immediate and Late Phase Reactions

• Early/Immediate Phase: Mediated by primary mediators released from mast cells; occurring within minutes of allergen exposure.
• Late Phase Reaction: Caused by infiltration of eosinophils, neutrophils, and T cells, with the release of secondary mediators (e.g., cytokines, lipid mediators). Occurs 4-24 hours after. Responsible for long-term tissue damage, e.g., tissue remodeling in asthma.

Allergy Symptoms and Affected Tissues

• Symptoms depend on affected tissue: Gastrointestinal tract (e.g., diarrhea, vomiting), airways (e.g., wheezing, coughing), blood vessels (e.g., increased blood flow, permeability).

Sensitization (Type IV)

• T cell activation: T cells activated by allergen-presenting cells
• Cytokine production: T helper cells produce cytokines directing B cells to produce IgE
• Local & Systemic Symptoms: include swelling, itching, nausea, vomiting, diarrhea; airway obstruction, hives, low blood pressure, etc
• Example: Peanut allergy.

Anaphylaxis

• Mechanism: Allergen enters the circulation, leading to systemic release of vasoactive mediators, general vasodilation, and smooth muscle constriction, which can lead to sudden loss of blood pressure and severe oedema.
• Triggers: Peanuts, shellfish, penicillin, insect stings.

Type II Hypersensitivity (IgM/IgG-mediated)

• Mechanism: IgG or IgM binds to antigens on cells or tissues, activating complement or binding to Fc receptors on phagocytes.

Goodpasture's Syndrome

• Mechanism: Autoantibodies (IgG) bind to a glycoprotein (subunit of type IV collagen) in the basement membrane of lung and glomeruli, activating complement, leading to inflammation and tissue necrosis.
• Symptoms: Pulmonary hemorrhage, glomerulonephritis, genetic predisposition, environmental factors like exposure to solvents, tobacco, cocaine, or infection.
• Treatment: Aggressive immunosuppressive therapy.

Type III Hypersensitivity (Immune Complex-mediated)

• Mechanism: IgG (mainly) binds to soluble antigen, forming immune complexes. Clearance mechanisms may be defective, leading to deposition in basement membranes of small blood vessels, joints, etc. Activation of complement and release of anaphylatoxins.
• Symptoms: Vasculitis. Examples include SLE.

Type IV Hypersensitivity (T Cell-mediated)

• Mechanism: Delayed-type hypersensitivity, T cell-mediated; includes contact dermatitis, multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis (type III/IV).

Contact Hypersensitivity

• Mechanism: Eczematous reaction at the point of contact with allergens like nickel and chromate. Small molecules (haptens) combine with larger tissue proteins. Self-antigens become immunogenic and presented to T cells.
• Symptoms: Reaction develops 24-72 hrs after exposure, symptoms may last 2-3 days; sensitization required.

Poison Ivy Contact Dermatitis

• Mechanism: Urushiol oil (mixture of pentadecacatechols) is a lipid-soluble substance that crosses membranes and modifies intracellular proteins. Presented to cytotoxic T cells.
• Symptoms: Peak at 24-48 hours.

Granulomatous Hypersensitivity

• Mechanism: A granuloma is a collection of macrophages filled with intracellular antigens, forming in response to persistent immune stimuli. Macrophages fail to destroy pathogens, which leads to recruitment of more macrophages.
• Examples: Crohn's disease and sarcoidosis.

Sarcoidosis

• Mechanism: Chronic, idiopathic, systemic disease with granuloma development in various organs; often leading to lung fibrosis.
• Prevalence: Rare; higher prevalence in African Americans. Ireland has a relatively high prevalence.

Multiple Sclerosis (MS)

• Mechanism: Demyelination followed by sclerosis of nerve tissue, usually at multiple sites. T cells are specific for myelin basic protein in the CNS.

Summary of Main Points (Type I - IV):

• Includes brief descriptions of each type (I-IV) of hypersensitivity along with key mechanisms and disease examples.

Explore the concepts of allergy and autoimmunity in this quiz based on MD137 Immunology Lecture 4. Understand the types of hypersensitivity reactions, their mechanisms, and relevant examples of each. Test your knowledge and grasp the intricacies of immune responses involved in atopic conditions.