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Mast Cells


The action of these cells is very important in relation to the conditions mentioned on this site.  Most commonly these conditions are treated in two major ways using anti-histamines or corticosteroids.  Both of these treat the symptoms not the underlying cause of the condition.  They both have side effects and should not be used over long periods of time, especially corticosteroids because of the effect they have on the bodies tissues and organs.

For along time the mast cells were thought to instigate the immune IgE response.  The pathophysiology is still in the process of being investigated and understood.  They are now known to be present in many pathologies of the bodies systems.
  • Chronic inflammation processes
  • Fibrotic disorders
  • Wound healing
  • Neo-plastic tissue transformation

For more than twenty years we have been able to help treat patients through specialists and doctors in New Zealand and Australia, basing the treatment on controlling the mast cell reaction which is more severe in these conditions mentioned on this sight.

Understanding the Pathophysiology of the Action of Mast Cells and Basophils

They are the most important cells in activating the inflammatory response in the body.  They develop in the long bones red marrow and taken up by the blood stream to lodge in tissues and organs of the body where they mature as mast cells.  There are similar cells that action the same response that stay in the blood stream called basophils and seem only to be differentiated in that mast cells remain in the tissues of the body especially in the loose connective tissue close to blood vessels and the basophils migrate around the body within the circulation system of the  body.

The highest concentrations are found in vascular  connective tissue:-
  1. Beneath the bodies epithelial surfaces
  2. Submucosal tissue of the GI (gastrointestinal tract)
  3. Respiratory tract
  4. Dermal outer layers of the skin
They produce mediators for a vast variety of cells e.g. fibroblasts, glandular cells, vascular endothelial cells, smooth muscle cells and many cells connected with the immune system.

Mast Cells activate the inflammatory response by:
  • Degranulation when they release the preferred granular contents of the cell into the extracellular matrix.
  • Synthesis of mediators in response to a "threat" stimulus.
Degranulation is Stimulated by:-

Physical Injury:-
  • Excessive heat
  • Mechanical Trauma
  • Ultra-violet light
  • X-rays
Chemical Agents:-
  • Toxins
  • Venoms - insects, bees, wasps, snakes
  • Tissue proteases (enzymes)
  • Dextran
  • Cationic protein released from neutrophils
Immunologic:-
  • Triggering immunoglobulin E (IgE) mediated hypersensitivity reactions
  • direct Processes such as the activation of the complement components
  • Preformed biochemical mediators e.g. histamine, neutrophil chemotactic factor, eosinophil chemotactic factor of anaphylaxis (ECF-A)
The granules are released in seconds and their effect is immediate.  Platelets release another potent mediator serotonin.
In conjunction with platelets release of serotonin, histamine is added and they are both vasoactive mines.  This means they cause temporary rapid constriction of vessel walls.  These have venules or opening within the walls that dilate when constricted increasing blood flow into the microcirculation.  The increased vascular permeability that results with the granule chemotactic factors that are being released by mast cells causes the attraction of leucocytes to the inflammation area.

A chemotactic factor attracts specific leucocytes to an inflammation site to do a particular "job" in restoring balance to the area.

Chemotaxis creates the direction of movement of cells in a particular way.  e.g. neutrophil chemotactic factor attracts neutrophils to the site which are the predominant leucocytes in the early stages of inflammation.

There is another leukocyte an eosinophil that is phagocytic (can engulf and destroy large particles, even parasites).  Their most important role is however to control the mediators released from mast cells.

It is important to remember that in any defence mechanism it should be of short duration or at most a limited time that it takes to restore balance to the system.  Therefore biochemical mediators(contact us) need to be controlled to stop them causing more inflammation than is necessary.  Eosinophils contain several enzymes that degrade the vasoactive amines and thus control the vasoactive effects of inflammation.  These also degrade leukotrienes and prostaglandins mediators that have been released by mast cells. Leukotrienes are slow acting substances that cause anaphylaxis.  They are necessary in the latter stages of the inflammatory response as they sustain the condition at a slower rate than histamines.  They also produce a fatty acid arachdonic acid.  These if not degraded can do damage to surrounding cells and cause more inflammation.

Mast cells also produce prostaglandins unsaturated fatty acids that act directly on the permeability of venules in vessels.  They can also suppress the release of histamine from the mast cells initial response and lysomal enzymes from neutrophils and they also cause pain.

Suppressing the amount of prostaglandin by aspirin or a non steroidal anti-inflammatory (NSAIDs e.g. *cyclooxygenase-2 or COX-2 inhibitors does not block prostaglandin production) and there are less gastric side effects or toxic responses therefore they also inhibits the inflammation and pain.
* Data from Bolten WW: Scientific rationale for specific inhibition of COX-2, J Rheumatol 51(suppl):2-, 1998.  Also Am J Med 104(5):413-421, 1998. Also Vane JR Botting Rm: Mechanism of action of anti-inflammatory drugs. AlsoInt J Tissue Reactions 20(1):3-15. 1998.

So this is the prelude to the Complement Cascade of the Immune Response.  This means that once the mast cells have initiated the defence mechanism there are two pathways of action that can be taken to restore balance.

The Classic Pathway activates when IgG or IgM antigen-antibody sequence is required.  This is an immune response

The Alternative Pathway is activated by many biological substances which include bacteria and fungal cell wall polysaccharides (e.g. endotoxins on gram negative bacteria) and the course includes anaphylatoxins.  These induce mast cells to degranulate, but  also disrupt the cell walls or bacterial membranes causing the cells to burst by water and ions entering them.

Both of these pathways have chain reactions of chemical substance for slightly different reasons.

The main point here is that the mast cells and basophils initiate the response required and once initiated it must be brought back into balance to restore the bodies original condition before a defence was needed.

In the conditions listed on this site they are all mast cell responses and at some point it appears that the control mechanism breaks down in restoring balance to the body after inflammation is initiated.

Anti-histamine used, is specific to the release of histamine and has side effect when taken for any time span and does not work directly on the mast cells.  When corticosteroids are used they are again used as a proactive substance on reducing the effectiveness of the inflammatory agents released in the complement cascade because it appears they are not being degraded and the body self restoring it's equilibrium or balance.  For chronic conditions once these drugs are stopped the condition may abate for a while (sometimes not).  For most people the next "attack" initiated, is usually more severe.

We have worked with Dr. N. Siemensma in Australia and doctors here in New Zealand using treatments that control the mast cell activity in the defence response in the body.  We have also found natural remedies that have enhanced day to day life for acute to chronic skin conditions listed on this site.
 
Latest Research Indicators
Source: U.S.A. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Published in: Allergytoday Issue 123.

There have been two new clinical reports on idiopathic anaphylaxis that can be life threatening for some people.  It has been found that in some people that suffer these conditions the mast cells have a mutated cell surface receptor that disrupts the normal activity and response of these cells.  Researchers say the association of this mutation with unprovoked anaphylaxis is striking.  Their hopes are that they will respond to inhibitors that can be targeted to the mutated receptor on the mast cell surface. 

Two out of three people who suffer these attacks do not know the cause, thus classified as idiopathic.  Anaphylaxis occurs when mast cells release release large quantities of chemicals (Histamines, leukotrienes and prostaglandins)that cause blood vessels to leak fluid into the tissues that causes swelling and blood pressure to drop as fluid is redirected from the blood to the tissues.  When the respiratory tract and/or buccal cavity, especially the tongue are involved, people become unable to breathe.  Usually the body goes into shock followed by unconsciousness and patients need to be treated immediately with adrenaline or similar product and need to be hospitalised.

Abnormally low blood pressure and fainting episodes are also associated with mastocytosis, of which there are three main conditions where the patients have excessive numbers of mast cells.

Dr. Dean Metcalfe and Dr. Cem Akin at NIAID began to look at the association between anaphylaxis and mastocytosis being related to a genetic trigger.  Systemic mastocytosis in adults often results from a mutation in the Kit receptor found on the surface of mast cells. (Discovered by Dr. Metcalfe's team in 1995).  This causes abnormal growth of mast cells and is observed in bone marrow biopsies of patients with mastocytosis.  The team wondered if the same mutation could predispose mast cells to release the chemicals responsible for idiopathic anaphylaxis?

A two year study was undertaken at NIH Clinical Centre examining 48 patients with diagnosed mastocytosis with or without associated anaphylaxis, 12 patients with idiopathic anaphylaxis and 12 patients with neither disease.

5 patients with idiopathic anaphylaxis were found to have a mast cell disorder (clonal mast cell disorder).  The researchers looked for evidence of a Kit mutation in 3 patients analysing bone marrow and all three were positive.  Findings demonstrated that some patients with idiopathic anaphylaxis have an aberrant population of mast cells with mutated Kit receptors.

Dr. Metclafe is now suggesting that that not only patients with anaphylaxis but severe allergies should be looked at for genetic mutations of receptors that may change the way a mast cell reacts.

The NIAID finding have been published in two journals.  The study appears in an early online edition of Blood and describes the presence of an abnormal mast cell population in a subset of patients with idiopathic anaphylaxis.  The findings about the mechanism leading to mass cell activation by Kit and the  IgE receptor responsible for allergic reactions appear online in Cellular signalling.

According to the NIAID team both Kit and the IgE receptor use a common molecule, a protein, inside the cell to activate the mast cell.  They also found that the mutated Kit markedly elevates the function of the protein which results in increased cell signalling.  They are now looking for additional evidence to see if artificial mast cells with mutated Kit behave or release chemicals in a different manner than normal mast cells and whether the mast cells will respond to inhibitors especially targeting Kit.
 

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