Overview
This lecture covers the biochemistry, mechanisms, physiological functions, and clinical significance of histamine, including its metabolism, receptors, role in disease, and therapeutic implications.
Introduction to Histamine
- Histamine is a mediator of allergy, autoimmune conditions, gastric acid secretion, and blood cell formation.
- Highest concentrations of histamine occur in lungs, basophils, and mast cells.
- Acts as a potent vasoactive agent affecting bronchial smooth muscle and itch nerves.
- Plays key roles in inflammatory responses and immune system function.
Synthesis, Storage, and Metabolism
- Histamine is synthesized from L-histidine by L-histidine decarboxylase with pyridoxal-5-phosphate as a cofactor.
- Basophils and mast cells store large amounts of histamine in granules.
- Other immune and blood cells can synthesize but not store histamine.
- Histamine is mainly metabolized by histamine-N-methyltransferase and diamine oxidase; a small fraction is excreted unchanged.
Histamine Receptors and Signaling
- There are four types of histamine receptors: H1, H2, H3, and H4, all G-protein coupled.
- H1 receptors (Gq): mediate allergic/anaphylactic reactions, sleep cycle, food intake, emotions, and memory.
- H2 receptors (Gs): mainly found in gastric mucosa; mediate gastric acid secretion and vascular effects.
- H3 receptors: located in the brain, modulate neurotransmitter release and inhibit sympathetic vasoconstriction.
- H4 receptors: found in bone marrow and immune cells; regulate cell differentiation and chemotaxis, especially in inflammatory conditions.
Functions and Immunomodulation
- Histamine influences T cells, B cells, monocytes, and dendritic cells during allergic inflammation.
- Th1 cells respond to histamine by increasing interferon-gamma; Th2 function is suppressed by histamine.
Mechanisms of Action
- Histamine produces allergic symptoms by binding to specific cell receptors.
- Affects blood vessels, nerves, glands, and activates different immune cells.
Histamine in Disease (Pathophysiology)
- Urticaria and angioedema: Acute forms caused by IgE-mediated mast cell degranulation; chronic forms linked to IgG autoantibodies.
- Allergic rhinitis symptoms are due to histamine release after allergen exposure, with H1 blockers moderating symptoms.
- Atopic dermatitis involves Th2 cytokines in acute and Th1 cytokines in chronic phase; often precedes asthma or rhinitis.
- Histamine plays roles in tumor immune evasion and promotes hematopoiesis.
Clinical Significance and Therapeutics
- First-generation H1 antihistamines had sedative side effects, leading to safer, non-sedative second-generation drugs.
- H2 antihistamines reduce gastric acid and treat ulcers and reflux.
- H3 antagonists are under study for neurodegenerative diseases.
- H4 antagonists are potential treatments for allergy and inflammation (e.g., rhinitis, pruritus, asthma).
Key Terms & Definitions
- Histamine — A biogenic amine mediator involved in allergy, immunity, and gastric acid secretion.
- Mast cells/Basophils — Immune cells that synthesize and store histamine.
- Histamine receptors (H1–H4) — Cell surface proteins mediating histamine’s effects.
- Anaphylaxis — Severe allergic reaction involving widespread histamine release.
- Pruritus — Itching sensation, commonly mediated by H1 receptor activation.
Action Items / Next Steps
- Review mechanisms of histamine receptor signaling.
- Study clinical applications of H1 and H2 antihistamines.
- Prepare for discussion on the roles of histamine in allergic diseases.