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March 2015: Post summaries and take home points

Allergic effector unit: The interactions between mast cells and eosinophils

  • Eosinophils are white blood cells that have granules like mast cells.
  • Mast cells and eosinophils are often found together in late and chronic stages of allergic inflammation.
  • Mast cells, eosinophils and their effects on the body are collectively called “the allergic effector unit”.
  • Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. The reverse is also true.
  • Mast cells and eosinophils can activate each other and cause mediator release.
  • Eosinophils make mast cells more responsive to IgE.
  • When mast cells and eosinophils are in contact, eosinophils live longer than usual.


Mast cell mediators: Sphingosine-1-phosphate

  • S1P is involved in development of vessels, vascular permeability and immune function.
  • Receptors for S1P are found on many cell types, including mast cells.
  • When the IgE receptor on mast cells is stimulated, S1P is produced and secreted.
  • Histamine can stimulate S1P production.
  • S1P regulates blood pressure and heart rate.
  • S1P is involved in anaphylaxis recovery and probably helps to counteract low blood pressure.


Allergic to infections: Other behaviors of toll like receptors

  • Toll like receptors (TLRs) are receptors that bind products from bacteria, fungi and viruses to fight infection.
  • TLRs are found on mast cells.
  • When TLRs are bound, mast cells secrete inflammatory molecules like TNF, IL-6, IL-13 and IL-1b.
  • TLRs function independently of IgE.


Leptin: the obesity hormone released by mast cells

  • Leptin is a hormone mostly released by adipose tissue, but also by mast cells.
  • Leptin is a “starvation” signal sent to the brain.
  • Patients with obesity have higher circulatory leptin than those without obesity.
  • Patients with obesity are more resistant to the effects of leptin, so they often feel hungry even if they have eaten.
  • Leptin actives inflammatory cells and induces production of TNF, IL-2 and IL-6.
  • Leptin suppresses signals from the IgE receptor to make mediators.
  • High levels of leptin may suppress ghrelin, the “hunger” hormone.


Allergic to infections: How bacteria, viruses and fungi activate mast cells

  • TLRs are found on several cell types, including mast cells.
  • Unlike many receptors that only have one “matching” molecule, TLRs bind lots of molecules.
  • These molecules are usually from infecting organisms.
  • Some molecules induce production of cytokines.
  • Some molecules, like peptidoglycan from bacterial cell walls, may induce degranulation.
  • Viral, fungal and bacterial infections can all cause mast cell activation.


Diabetes, steroids and hypoglycemia

  • High levels of glucocorticoids deplete mast cell populations.
  • Glucocorticoids interfere with production and release of stem cell factor, a mast cell growth factor.
  • Glucocorticoids decrease mast cell growth and activity.
  • The mechanism by which this occurs is thought to involve insulin.
  • Insulin activates mast cell signaling pathways.
  • Activity in the HPA axis, which regulates steroid levels, is increased in type I and II diabetes, causing elevated cortisol.
  • Hypoglycemia can cause mast cell degranulation.
  • Anaphylaxis can cause hypoglycemia.


Diabetes, mast cells and allergic disease

  • Type I and II diabetes can protect against anaphylaxis and allergic reactions.
  • Mast cells are involved in development of glucose intolerance and insulin resistance.
  • In mice with type II diabetes, mast cell stabilizers protects against glucose intolerance and insulin resistance.
  • In a patient with type II diabetes, treatment with cromolyn normalized plasma glucose and A1C.
  • Type I diabetes has a more complicated relationship with mast cells.
  • Diabetes reduces mast cell degranulation.


Questions on bone involvement

  • Osteosclerosis is hardening of the bones.
  • Osteoblast is the cell type that makes new bone.
  • In osteosclerosis, osteoblasts may lay down new bone faster than osteoclasts can eat up old bone.
  • Osteolysis occurs when abnormal cells grow rapidly and inhibit osteoblasts, and osteoclasts do not work fast enough.
  • It is not clear if having osteosclerosis makes progression of SM more likely.
  • People with all forms of SM have been found ot have osteosclerosis.
  • Osteosclerosis with swelling of liver and spleen, presence of CKIT mutation in multiple cell types and high increase of baseline serum tryptase warrants careful monitoring.
  • For mast cell disease, large osteolytic lesions are the “worst” bone involvement because it immediately classifies you as ASM.
  • Multiple bone breaks due to severe osteoporosis also classifies you as ASM.


Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

  • Osteoporosis is the most common form of bone involvement in SM.
  • Osteoporosis is more common in mast cell patients than in the general population.
  • Patients with rapidly increasing serum tryptase and those without have similar incidence of osteoporosis.
  • Patients with rapidly increasing serum tryptase were more likely to develop osteosclerosis during the period of the study.


Bone involvement in ISM, SSM, SM-AHNMD and ASM: Literature review (part 2)

  • Overall, about half of SM patients have bone involvement.
  • Markers associated with both bone resorption and bone formation were higher in mastocytosis patients.
  • Osteoprotegerin is higher in mastocytosis patients. This protein regulates the activity of osteoclasts.
  • Levels of c-telopeptide were significantly higher in patients with SM-AHNMD and ASM than in ISM or CM.
  • Presence of skin lesions does not change risk for osteoporosis.
  • Bone mineral density and serum tryptase do not correlate with serum markers of bone turnover.


Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

  • In osteosclerosis, your body makes new bone faster than it resorbs it.
  • In osteoporosis, your body resorbs bone faster than new bone is made.
  • In osteolysis, your body resorbs bone faster than new bone is made, but much worse than in osteoporosis.
  • Both osteoporosis and osteolysis can cause pathological fractures.
  • Osteoporosis does not classify you as having ASM.
  • Osteoporosis that caused multiple fractures classifies you as having ASM.