The Normal Mast cell

Mast cells begin life in the bone marrow as stem cells - in a line of cells called  cd34+ and then move, via the blood to become cells in our tissues.

 

 

Normal mast cells settle in mucous membranes or connective tissues. This influences the chemicals stored, released and made. This is most noted by the presence of tryptas, chymase or both. These are discussed on the 'Cell Activation' page.

 

The normal mast cell contains granules - which store chemicals and the other normal cell structures.

animalcell

Nucleus - Contains DNA -which codes all body functions. Signals from inside and outside the cell cause the cell to produce new substances .

 

Mitochondria - where the cell makes energy

 

Rough endoplastic reticulum

 

Smooth endoplastic reticulum

a mastcell

Cell signaling

Cell signaling takes signals from the outside of the cell to the nucleus to stimulate an action. This can be producing substances which are released and affect other cells close by, those which affect them only or those which affect cells far away in the body.

 

The point on the cell where a signal is produced is called a receptor and the substance that fits into it is called a ligand.

 

Mast cells have many receptors -the ligands and what chemicals they stimulate production of, are detailed on the 'About Mast cells' page.

 

The new proteins /other chemicals are released through the rough endoplastic reticulum to the outside of the cell (extracellular space )

Mast cells are all over the body . In the linings of many organs - typically those which have acess to the outside, but not exclusively .

 

Mast cells in skin

 

The Mast cells in skin are in the dermis layer - see image . They are bought into action by various chemicals including histamine substance P - from tissue damage. These chemicals can be released from nerves -substance P or delivered in the blood.

IL2  out of mast cells activate langerhans (dendric) cells. These are important in the actions locally.

Histamine makes the blood vessels leaky, by causing nitrous oxide to shrink the cells, which allows fluid to leave the blood-plasma and white blood cells, causing swelling.

Histamine also activates nerves, as does serotonin.

Substance P and crh is released from nerves . Mast cells gather around the nerve endings - so these activate mast cells.

Typtase and prostoglandins from mast cells further activate the nerves - leading to more CRH and substance P release.

 

The CRH presence -which is the stress hormone - has been noted and is described as a HPA - hypothalmus pituatry adrenal axis in the skin . This is a fairly new observation .

 

bradykinin prostoglandins cell_receptors_anxiety_remedies 1cm recptor types

Mast cells have G coupled membrane receptors.

 

They are intrinsic protein receptors in the cell mebrane.

 

G coupled membrane receptors we discovered in                            

and the individuals working to crytalise it -  Brian Kobilka (Stanford) and Robert Lefkowitz (Duke) have won the 2012 Nobel Prize in Chemistry for their work on one of the most important classes of proteins in living organisms.

 

It was hard to crystalise because it was very delicate and moving it from the membrane led to instability now its has been, research can begin in earnest into its many functions in lab conditions .

 

It is known to have 3 classes of ligand -which activates it.

Agonists activate it - this is vital in mast cell G coupled receptors.

Inverse agonists shut it down completely - which could be a target for drug therapy in idiopathic anaphylaxis and Mast cell diseases where mast cells are activated through this mechinsim, as it would provide protection from the many substances known to activate this receptor.

Antagonists prevent binding but don't shut the protein down - the same way antihistamines work on histamine receptors.

A small molecule like a drug binds to one of the GPCR helices on the outside and this results in a complex series of motions of the helices that results in the dissociation of one of the G protein subunits. After dissociating, the G protein can interact with a variety of other proteins, including proteins called kinases which attach and detach phosphate groups and control cell signalling. The end result of this process is usually the activation of a so-called second messenger, a small molecule like cyclic GMP (cGMP) which goes into the nucleus of the cell and brings about specific gene expression and attendant physiological responses. There’s a variety of ways in which GPCRs are regulated, activated and inactivated and G protein binding is just one of them. A recently highlighted class of proteins called arrestins for instance can deactivate GPCRs when they are overstimulated and internalize them for degradation.

Adapted from  Ashutosh Jogalekar 2012

 

 

Research question - Are arrestin levels low in patients with constant mast cell activation via GPCRs ?

Bradykinin - coverted from heparin - as a GPCR ligand on a mast cell leading to prostoglandin production and release

The second messenger is -  phospholipidase a2  -PLA2 or C - which opens up several different cell signaling pathways

moleclues into cell

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Other cell signaling pathways in mast cells

Ckit and secondery -protien kinases

layers of skin nri1782-f2 skin process references

 

Other Known activators of mast cell GPRS receptors

IGE and other antibodies (immunoglobulins )

IGE

 

IGE is made when the body believes a substance is bad, so makes antibodies -IGE -which is then put on mast cell to wait.

 

Then when the substance comes back in,  it attaches to the top region of 2 IGE antibodies -and crosslinks them: this is called the FCERI area. This causes a cell signaling pathway which leads to several chemicals being released and depending on the level of IGE and other factors leads to anaphylaxis.

 

This is 1 of over 100 ways we know mast cells are activated. But this is the best known to most doctors. It is also one of the few that can be tested and so avoided.

 

Degranulation -is release of all or some of the chemicals stored in the granules: in IGE all the contents are released.

 

Cytokines - see chemicals released -these cause many effects including stimulating anaphylaxis via compliment pathways

 

 Eicosaniods - these are made from plasma membrane lipids when they are freed.

GPCRs are essentially both the gatekeepers and molecular messengers of the cell, transmitting signals from inside to outside.

 

The signal can consist of an astonishing variety of stimuli, from photons (light) to neurotransmitters to hormones. They mediate virtually every important physiological process, from immune system function - which is where our interest lies - to taste and smell (both of which are altered in mast cell)

 

GPCRs are also immensely important in medicine and are the target of about 30% of all drugs. Naturally occurring small molecules which bind to GPCRs include adrenaline and prostaglandins - so no direct protoglandin receptor is necessary and GPCRs, are on many cells so prostoglandins from mast cells can have far reaching effects. Also somatostatin -which should turn of stomach acid production but in fact causes mast cell activation (through GPCRs), dopamine and adenosine (not of direct interest in mast cell).

 

Drug-like small molecules which bind to GPCRs include caffeine, morphine, heroin (diamorphine). It is known opiates activate mast cells via GPCRs including inate opiates .

 

Histamine: by reading other pages you will know histamine is huge issue in mast cell with high circulating levels - so it can cause cell effects not only via its own recpetors but through GPCRs .

 

Could this explain Idiopathic anaphylaxis , alongside prostoglandins?

 

The range of stimuli and molecules that GPCRs respond to is remarkable and their role in the workings of life is unquestioned.

Cell Membrane - is made up of phosphate spheres and 2 lipids - in between cholesterol gathers in 2 layers: various structures and receptors are within this .

 

Some allow cells to join together in tissues and organs, fixing together.

 

Others are right through the membrane and act as a passage of chemicals in and out of cells.

 

Of these, some are specific for particular chemicals, enzymes or hormones - others aren't specific.

 

The particles can move accross the membrane with no receptor - from an area of high concentration to lower concentration: example - ca+ -clacium and k+ -potassium. The balance either side of the membrane dictates function, e.g. if the pressure is higher on one side, the substance will move through to make the pressure equal on both sides. This is known as simple diffusion. For example in muscles, when calcium moves from an area of high pressure to low pressure it causes contraction of the muscle.

Also facilitated diffusion - specific and non specific

 

Active Transport - which is against the concentration gradient and requires an energy expenditure.

 

The receptors are proteins

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Mast cells - location and numbers

Deep skin (Dermal) mast cells are often located in close proximity to blood vessels, nerves, and lymphatics (drainage of fluid system) with an estimated density of 7000 to 20,000 mast cells per cubic millimeter of skin. From this strategic location, they can influence the function of blood vessels (vascular structures), monitor the blood for inflammatory and infectious changes, and distribute their mediators throughout the body. Mast cells are found in the choroid plexus of the brain and in the vascular bed of the meninges. Low numbers of mast cells are found in the kidneys and bone marrow.

 

Mast cells in different locations contain different mediators in volume.

 

The bowel has mast cells in each layer. In the bowel they are measured as number per hpf (higher power field) . In a recent review these were established as normal for each layer .

 

 

 

CKIT

Tyrosine kinase  chemicals .

 

These can be recpetors or internal chemcals within the cell .The role of tyrosine kinases is phosphoryaltion - which is important in gpcrs -as its this process  - which switches off the recpetor once its been activated .

 

Receptors - Approximately 20 different RTK classes have been identified.[3]

 

RTK class I (EGF receptor family)(ErbB family) - epidermal growth factor receptor (EGFR)

 

RTK class II (Insulin receptor family)

 

RTK class III (PDGF receptor family) - Platelet-derived growth factor receptors

 

RTK class IV (FGF receptor family) -fibroblast growth factor

 

RTK class V (VEGF receptors family)

 

RTK class VI (HGF receptor family) -

 

RTK class VII (Trk receptor family)

 

RTK class VIII (Eph receptor family)

 

RTK class IX (AXL receptor family)

 

RTK class X (LTK receptor family)

 

RTK class XI (TIE receptor family)

 

RTK class XII (ROR receptor family)

 

RTK class XIII (DDR receptor family)

 

RTK class XIV (RET receptor family)

 

RTK class XV (KLG receptor family)

 

RTK class XVI (RYK receptor family)

 

RTK class XVII (MuSK receptor family)

 

The role with Ckit - when activated - is to control death of mast cells -This uses the jak stat pathway .

 

Cytokines -

 

Other receptor tyrosine kinases - are -

Epidermal growth factor receptor family -

Vascular endothelial growth factor receptor (VEGFR) family -

RET receptor family -

For a full description of CRH - go to - .

 

We know stress = more crh = mast cell activation all over the body.  It's has been long noted skin conditions such as dermatitis, forms of eczema , psriosis all worsten with stress - and this is the connection .

 

In mast cell conditions the skin presenations - hives, dermatographia , urticria pigementosa - angiodeama all are "triggered" by stress .

 

Dr Theoharidies et al, have done extensive work on stress and mast cells.

 

Triggers known as secretogouges -without thier own triggers - use GCRs - to activate mast cells. This is the way that non IGE allergies without their own recepetors cause reactions in various organs including the skin .

So this diagaram shows blood being delivered into the dermis -the skin layer containing mast cells. This allows chemicals which activate mast cells to be delivered to the skin (in the arteries / arteroles) which patients see as flushing as a primary or secondary symptom - where chemicals from remote cells are delivered. Some of the mast cell chemicals either from skin cells or cause:

Prostoglandins -flushing

Histamine -flushing, swelling

 

Skin is often affected first, then chemicals travel to many other areas of the body, through veins. So for example you may have a flush, followed by bowel cramps or brain fog.

 

The local action is as follows: Il2 activates dendric cells, which release TLSP, which activates further mast cells.

 

The fluid from the area in between cells, the intracellular space, is drained away by the lymphatic system, returning fluid and white blood cells to the blood circulation over a period of 3-4 days. It is filtered though the lymphnodes to check for bugs /viruses and damaged cells . So the immune system begins a response very quickly.

 

So in the normal run of things the fluid leaving the blood into the tissues taking white blood cells with it is a normal healthy part of the immune system. In "mast cell" this is happening constantly and or faster than normal, causing sysmptoms which we associate with having an infection.

 

This also leads to mast cell chemicals affecting the lymph nodes - causing symptoms like hot and cold and flu-like symptoms.

 

The mast cell activation is a normal part of our ever-present in-born immunity: it's because it's activated all the time that we have constant symptoms.

 

This fluid drainage from part of the lymphatics, see 'About Symptoms' page.

 

For how the fluid shifts when it happens fast or slowly, but reaches a threshold - leads to serious symptoms go to about symptoms lower down the page 3rd spacing .

http://www.docstoc.com/docs/20282368/Lymphatic-Flow-for-Manual-Lymphatic-Drainage

lymph skin

Blood flow to mast cells in skin

Ckit receptor is on mast cells . Its ligand is GSM-CF .The stem cell factor which dictates how long mast cells live and how they are matured from immature cells into functioning mature cells.

 

This is tyrosine kinase receptor - activating a known pathway of cell signaling called jakstat.

http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Cell-Analysis/Signaling-Pathways/Jak-STAT.html

jaksat simple ckit jakstat infnyjakstat

Lymphopoiesis

 

Mast cells in the digestive tract - Mouth to bottom

In the mouth there are a large number of mast cells. In the gums, tongues and walls of the mouth.

 

The tonsils are min-lymphnodes, picking up on incoming bacteria and launching an immediate immune response. The nose and addrenoids also contain mast cells. Along with the mouth, larynx and pharanx from the upper airways (discussed further down.)

 

The oesopegus, stomach and dueodenum are classified as upper Gastric system (GI). The small and large bowel and sigmiod colon and rectum - lower GI - all contain mast cells naturally .

 

Digestive_Picture_1 images (15) 1mm

The structures of the oesphegus - are smooth muscle

 

Stomach, large and small bowel - are mucous membranes -with smooth muscle underneath

 

There are mast cells in several layers and receptors for chemicals out of mast cells .