Chronic urticaria and angioedema: Part 1
- Urticaria is the medical term for hives.
- Hives are usually called by allergic processes, but can occur for other reasons.
- Angioedema is swelling in the dermis, subcutaneous tissue, mucosa and submucosa. It is sort of “inside hives”.
- Angioedema can be dangerous, especially if it affects the airway.
- Urticaria and angioedema are closely related.
- If acute, they last for less than six weeks. If chronic, they last for more than six weeks.
- Acute urticaria is usually due to activation of mast cells and basophils.
- Antihistamines and brief courses of steroids usually manage acute urticaria.
- Chronic urticaria usually does not have an identifiable cause.
- CU patients can have urticaria and angioedema, either alone or together.
- Cutaneous mast cells drive CU and histamine is the most important mediator.
- CU is rarely IgE mediated.
- CU is associated with several chronic conditions, including autoimmune diseases, neoplastic diseases and thyroid disease.
- 30-50% CU patients make IgG antibodies to the IgE receptor.
- 5-10% CU patients make IgG antibodies to the IgE molecule.
Chronic urticaria and angioedema: Part 2
- CU lesions are swollen pink or red wheals of variable size, sometimes with surrounding redness.
- CU lesions are itchy rather than painful or burning.
- Angioedema is not itchy, is non-pitting and without redness.
- Physical urticarias are triggered by environmental sources. There are many types.
Prostaglandin E2, mast cells and asthma
- Prostaglandin E2 has inflammatory and anti-inflammatory effects in the body.
- PGE2 induces fevers and has many other functions.
- PGE2 can cause mediator release from mast cells.
- PGE2 can enhance IgE production by B cells.
- PGE2 relaxes the smooth muscle and opens the airway.
- When asthmatics take NSAIDs, their asthma often worsens due to interfering with production of PGE2.
Mast cell mediators: PGD2
- Prostaglandin D2 is the dominant prostaglandin made by mast cells.
- It has many functions, including regulation of sleep and perception of pain.
- 9a,11b-PGF2a is a breakdown product of PGD2. Both can be tested for in urine as markers of mast cell disease.
- PGD2 is a strong bronchoconstrictor and is important in asthma.
- PGD2 is involved in nerve pain via the COX-1 pathway.
- Aspirin is commonly used in mast cell patients to inhibit production of PGD2. This protects against PGD2 from both COX-1 and COX-2 pathways.
- PGD2 causes characteristic mast cell flushing.
Prostaglandins and leukotrienes
- Prostaglandins, thromboxanes and leukotrienes are all types of eicosanoids.
- Eicosanoids are made from arachidonic acid.
- COX-1 and COX-2 are enzymes that make prostaglandins.
- 5-LO (lipoxygenase) makes leukotrienes.
- Non steroidal anti-inflammatories interfere with COX-1 and/or COX-2, depending on the medication. This interferes with production of prostaglandins.
- Zileuton is a lipoxygenase inhibitor and interferes with production of leukotrienes.
Mast cell medications: Everything but antihistamines
- Mast cell stabilizers interfere with structures on the cell membrane that prevent with release of mediators.
- Beta-2 adrenergic agonists relax smooth muscles and open airways.
- Leukotriene receptor antiagonists interfere with function of leukotrienes.
- 5-lipoxygenase inhibitors prevent production of leukotrienes.
- Corticosteroids interfere with activity of mast cells and production of mediators.
- Proton pump inhibitors reduce gastric acid.
Mast cell medications: Antihistamines by receptor activity
- H1 antihistamines turn off the H1 receptor. This helps with many symptoms.
- H2 antihistamines interfere with action of the H2 receptor. This helps mostly with GI symptoms, but also skin symptoms.
- H3 antihistamines modulate nerve pain and may normalize levels of neurotransmitters like serotonin.
- While three medications are known to have H3 activity, they are not designed for this purpose and have serious risks.
- Thioperamide is promising as an H3 and H4 blocker, but is not yet available for patient use.
- Mast cells are heavily involved in the generation and sensation of pain.
- Chronic pain has been associated with mast cell degranulation.
- Hyperalgesia, exaggerated pain response, is associated with mast cells.
- Histamine may be important in hyperalgesia.
- Mast cells can transmit nerve pain signals.
- Overly sensitive and painful skin can also be caused by mast cells.
What do all these words mean? (Part 1)
- A neoplasm is an abnormal group of cells.
- SM is a neoplasm.
- Receptors are proteins on the outside of cells that bind specific molecules. This causes a specific action to occur.
What do all these words mean? (Part 2)
- CD117 (CKIT) is a normal marker found on the outside of mast cells.
- CD117 is sometimes not seen on the outside of mast cells in biopsies because the test is not very sensitive.
- Being CD117 positive in a biopsy is not the same as being CKIT positive.
- Being CKIT positive affects options for chemotherapy and disease classification.
- CD25 and CD2 are abnormal markers on the outside of mast cells linked to SM.
- CD30 is sometimes positive on mast cells in SM.
- CD34 is a marker of cells that become mast cells, and on new mast cells.
Mast cells in vascular disease: Part 1
- Mast cells cause formation, progression and destabilization of atherosclerotic lesions.
- Mast cell released histamine can cause coronary spasms.
- Histamine can cause acute coronary vasoplasm that results in heart attack. This is called Kounis Syndrome.
Mast cells in vascular disease: Part 2
- Chymase is a mast cell mediator that participates in blood pressure regulation.
- Chymase release can make atherosclerotic plaques unstable.
- Mast cell activation increases size of atherosclerotic plaques.
- Atherosclerosis is not known to be elevated in mastocytosis.
- Cardiovascular symptoms are common in mastocytosis.
- Some mastocytosis patients have vascular instability.
Effects of Platelet Activating Factor (PAF) in asthma and anaphylaxis
- PAF is released by many cells.
- PAF receptors are on many cells.
- PAF causes airway constriction and is heavily linked to asthma.
- PAF induces leukotriene production.
- PAF is correlated to severity of anaphylaxis.
- PAF causes mast cell degranulation and increased release of PGD2.
Anti-inflammatory properties of H1 antihistamines
- Some H1 antihistamines have anti-inflammatory properties.
- They reduce eosinophil accumulation near allergic sites.
- Some H1 antihistamines inhibit bradykinin induced formation of hives.
- H1 antihistamines have also inhibited allergy processes of methacholine and platelet activating factor.
Pharmacology of H1 antihistamines
- When histamine binds to the H1 receptor, it keeps the receptor “turned on”, causing symptoms.
- H1 antihistamines prevent histamine from “turning on” the H1 receptor.
- First generation H1 antihistamines cross the blood-brain barrier, which can interfere with sleep-wake cycle, memory, cardiovascular regulation and cause other effects.
- First generation H1 antihistamines also bind to other types of receptors.
- Second generation H1 antihistamines only bind to the H1 receptor.
- Second generation H1 antihistamines do not cause sedation or the neurologic issues seen in first generation H1 antihistamines.
Circadian rhythm of mast cells
- The circadian clock is the “body’s clock”. It tells the body what to do on a 24 hour cycle.
- Mast cells and eosinophils have internal clocks.
- Allergic symptoms, including pulmonary ones, are worse between midnight and morning, with onset around 10pm.
- This causes sleep disruption, morning attacks”, poor rest and decreased quality of life.
- Circadian rhythm affects mast cell mediator release.
- Tryptase and histamine are lower in the afternoon and higher at night.
- A signal from adrenal glands “starts the clock”.
Mast cell inhibitory effects of some microorganisms
- Some organisms decrease mast cell mediator release.
- Some of these organisms can cause disease and some are harmless.
- Lactobacillus and Bifidobacteria are healthy bacteria that inhibit mast cell degranulation and activation.