April 2015: Post summaries and take home points

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 in nerve pain

  • 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.