These little proteins (peptides) act as messengers within the nervous system. These are produced and released by nerves (neurons). These act as messengers between one type of neuron and another.
Histamine release from mast cells stimulated with somatostatin resembled that induced by other basic agents.
The process was rapid, independent of added calcium or phospholipids, non-cytotoxic, species and tissue specific, not mediated through cell-fixed antibodies or glucoreceptors, and inhibited by antagonists of the polyamine receptor.
Somatostatin and other polycations may then act through a common receptor or binding site on the mast cell membrane.
TGF beta - Transforming growth factor - is a gateway to many functions involved in bone structure
T cells in the immune system
They develop in the thymus above the thyroid gland . They develop from stem cells . When mature they are T-cytoxic, Th-t helper and T memory .
Your immune system is responsible for helping to eliminate invaders (antigens) such as infectious organisms. The key cells in your immune system are lymphocytes known as B cells and T cells, which originate in your bone marrow. After T cells further develop in your thymus, all of your immune system cells gather in your lymph nodes and spleen.
Antigens-any bacteria /non self (triangular shapes above) are ingested (1), partially digested (2) and then presented to helper T cells by special cells called macrophages- Phagocytes (3). This process activates the helper T cell to release hormones (lymphokines) that help B cells develop (4). These hormones, along with recognition of further antigens (5), change the B cell into an antibody-producing plasma cell (6). The antibodies (Y shapes above) produced can be one of several types (IgG, IgM, IgA, IgE and IgD) (7). The antibody "fits" the antigen much like a lock fits a key. The antigen is thus rendered harmless. The helper T cells also aid in development of cytotoxic T cells (8), which can kill antigens directly; memory T cells are produced (9) so that re-exposure to the same antigen will provide a more rapid and effective response (10).
What makes a mast cell open and spill its contents: Triggers, IGE + antigen
In true allergy, you meet a substance, which is not a problem for most, and the body thinks it's an invader. So it makes an antibody for it, called IGE; this attaches to mast cells. Next time you are exposed to the substance-allergen, it attaches to the IGE, and the cell opens.
Monmeric IGE antibodies can promote the survival of bone marrow-derived cultured mast cells and induce the cells to secrete mediators, in the absence of known specific antigen. This is relevant in mast cell disease.
A) Makes blood vessels porous, which leads to fluid leaving the blood. This causes:
-swelling, but not visible until 2l (2/5 ) of total blood volume is lost
-not enough fluid left in the circulation, causing high pulse and momentarily high blood pressure-then low blood pressure and low pulse
B) Makes smooth muscles spasm- throat, airways, chest wall, oesophegus, stomach, bowels to bottom, bladder, womb -causing vomiting, diarrhoea/cramps, bladder spasm, womb spasm and airway closing and chest wall spasm.
C) makes mast cells open, spilling thier contents - De- granulation.
From 5-9b the parts form a membrane attack complex, which creates a hole in the cell, and the contents are released .
The link shows the complement receptors and how these should control complement process.
This ia an antibody or immunoglobulin .There are several of these -IGE (true allergy ) IGG, IGM, IGA ,IGD . All protecting us every day contunually.
The antigen binding site is specific for one antigen/allergen .
It takes the body approx. 1-2 weeks to make antibodies from b white cells lymphocytes.
Allergen = any substance which the body THINKS is "bad," a foreign invader. When the immune system is working properly, this is a disease causing substance - virus, bacteria or cells with bad DNA -which are called Antigens.
In allergy, this is usually a protein and something that won't harm the person, but the body gets confused.
Allergen presenting cell: these cells take in and partially digest the problematic allergen /antigen, and then present bits of it on its own surface membrane, for T cells to recognise.
T cells - this antigen presenting cell activates T cells, and with the help of cytokines (more on those later).
T cells are Just T- then get activated to become T Helper, type 1 and 2.
- Type 1- makes T killer cells and memory cells
- Type 2 - Make B cells (white blood cells)
These become plasma cells which make a class of antibody -Immunoglobulin -IGE, IGG,IGD, IGA, IGD.
IGE attaches to mast cells all over the body.
When the allergen comes back into the body, it attaches to the IGE; this sends a signal into the cell; this makes the mast cell release contents, which causess symptoms.
Complement is a cascade of chemicals that opens mast cells and kills non self bad cells.
Complement: The diagram to the right demonstrates how the Complement alternative pathway becomes spontaneously activated and leads to anaphlatoxins, which leads mast cells to open and spill contents but also to demonstrate their own symptoms.
Complement is comprised of 3 pathways:
1) Bacteria stimulted pathway "Lectin Pathway," which is
stimulated when bacteria are sensed in the body.
This explains why we are more reactive (symptomatic) when we are ill with a bacterial infection.
2) The Classical Pathway, which is stimulated by antibodies being paired with an antigen (bacteria or non self cell) or allergen (IGE) and leads to the cellwhich the antibody is attached to, and also to mast cells being split open and killed
3) The Alternative Pathway, which can be spontaneously activated - through which the build-up is offshot chemicals - from this and the classical pathway - 3a, 4a and 5a - called anaphylatoxins. These produce symptoms.
Neurotransmitters - Substance P
Substance P is known to be involved in inflammation processes throughout the body.
It is released from nerve endings as a neurotransmitter, some of which, once released, activates the next nerve, (post-synaptic cell); some doesn't attach to the receptors, and diffuses out.
(Mast cells are located very close to these nerve endings.)
Substance P activates mast cells. which causes histamine to activate nerve activity = more substance P = more mast cell activation.
Some consideration is being given to Neurogenic switching, where a signal produced, travels to the brain and is sent out for action to a -wrong nurone (nerve) for actioning. This remains thoretical.
In the case of substance P
A normal signal to the tissue for contraction, say for a bladder, would begin the cycle with production of substance P. Mast cells located close by to nerve endings are then activated by the substance P. (See interstitial cystitis in symptoms.)
Stem cell receptor -ckit -
SCF promotes mast cell adhesion, migration, proliferation, and survival.
The activation of c-Kit leads to the activation of multiple signaling cascades, including the RAS/ERK, PI3-Kinase, Src kinase, and JAK/STAT pathways. The end result being the cell nucleus or other cell structures being told to act differently.
This can be to degranulate -open and release contents
In the case of Jak/stat it is gene expression of interkins.
Each cell is programmed to react individually to the same signal- which can be an interleukin, a drug or cytokine.
It also promotes the release of histamine and tryptase, which are involved in the allergic response.
The kit receptor being activated - causes leucotrine C4 generation (Arm et al 1995)
Stress and mast cells
Eutamene et al 2003 found that in a stressful situation rat gut mast cells accumulated more histamine under the influence of the stress hormone -cortcotrophin releasing hormone and interleukin 1.
Guilarte et al 2007 found proof of mast cells in the jejenum of patients with IBS which has previously been seen as a"stress"only disorder .
Dr Theoharides TC. et al in 1998 , found that urocortin (a neuropeptide) -which becomes CRH - caused potent mast cell activation and release of histamine causing increased vascular permebility in (rat) skin mast cells . Urocortin is released in response to acute stress - so proving that stress can directly cause mast cell degranulation.
In a further study in 2004 Dr Theoharides TC. et al - consolidated research in idenifying that Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcεRI) crosslinking.
Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators.
Dr Theoharides TC. etal 1999 -Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules.
These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines
In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I).
They were stimulated to release histamine by substance P and CRH .This effect was increased when the mast cells were preincubated with esteriodol .This is unsurprising because these mast cells have esterogen receptors .
By placing blockers in the solution neither substance P nor CRH could stimulate mast cell release of contents .
This supports the role of dura-brain lining mast cells and their involvement in migraines which are precipated or worstened by stress
T cells bring antigens- parts of bad or percieved bad cells - to the mast cell to activate it directly
CD28 attaches to CD80 -Causing release of IL2, IL4 .IL13 and [reduction of of IL6 (see below )
4-1BB to 4-BBL - IL2 secretion
CD30 to CD30L
LFA-1 to ICAM -1
Zaitsu et al(2008) Found Oestrogen directly causes mast cell activation - also leucotrine 4 was highest in the perimenstral phase . Mast cells, in various tissues, express estrogens (ERs) (Harnish et al., 2004; Jiang et al., 2002; Nicovani and Rudolph, 2002; Zhao et al., 2001)
Mast cells exposed to physiological concentrations of E2 undergo partial degranulation. Esterogen E2 alone induced the release of a substantial proportion of preformed mediators and was additive with the IGE-dependent release.
In contrast, E2 alone had a statistically significant, but small effect on the synthesis and release of leucotrince c4 (LTC4.) from mast cells . However, E2 strongly potentiated the effects of IGE cross-linking on LTC4 release.
Incubation of mast cells with estrogen leads to higher histamine content of mast cells when crosslink activated to IGE - with allergen. This could explain why patients with IGE levels too low to stimualte anaphylaxis <100, experience worse symptoms around menstruation.
So mast cells produce esterogen, have receptors for esterogen and release mediator when activated by esterogen. With esterogen increasing leuctrine c4 release from mast cells when IGE is stimulated by an allergen. This explains why female patients experience more asthama and mast cell activation/idiopathic anaphylaxis around peaks on oestrogen in the menstrual cycle
This raises the question, does this cross linking stimulate compliment activation?
OX40- keeps the immune response active after day 3.
OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production.
OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response, due to its ability to enhance survival.
OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo.
Here we show that resting tonsillar MCs, when compared with lung MCs, revealed significantly higher expression levels for CC chemokines (CCL3 and 4), which recruit T cells, and for TNFR superfamilies (OX40 ligand and 4-1BB ligand), which induce multilpication (proliferation ) of T cells.
After aggregation of FcεRI (IGE), not only tonsillar MCs but also lung MCs up-regulated the expression of these molecules.
We confirmed that T cell proliferation is induced in direct cross-talk by the MC surface molecule OX40 ligand.
These results suggest that human MCs may play important roles in adaptive immunity through the T cell responses.
Fischer et al (2006) found a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines, so releasing some but not all mast cell contents.
CD30 induced a new synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, a process involving the MAPK/ERK pathway.
Mast cells were found to be the predominant CD30 ligand–positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were (upregulated ) increased in function in skin with symptoms (lesions) in these conditions.
Furthermore, the number of IL-8–positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures.
In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.
Lfa-1 to icam-1
is involved in the migration and aggregation of mast cells at sites of inflammtion.
In the presnce of IL4 -which increses the expression of these molcules - LFA-! and VLA adhesion molecules upregulate degranulation and cytokine release from mast cells ( when activated by another means )
Without il4- few aggregates of mast cells are seen .
Il4 treated mast cells release more histamine than non treated cells
These data strongly support the hypothesis that IL-4 is a potent activator of human mast cells. The signal transduction pathway of the IL-4 on the activation of mast cells, which is likely to be regulated in transcriptional level, should be determined. Because IL-4 is produced in increased amounts by T cells of patients with allergic disorders,23 mast cells of allergic individuals may be in a constant hyper-reactive state and contribute to all processes of allergic inflammation.
T and B cell membrane markers which have recepetors on mast cells
IGE INDEPENDENT MECHANISMS of MAST CELL ACTIVATION
-Complement classical and
- Bacteria, which have antibodies already waiting for them
- Neutrophils, in response to TNF@ -activating complement alternative pathway
- IGA -alternative pathway
-Immunoglbulin light chain
- increasing CRH from hypothalamus
- Mast cell tryptase
- CRH-corticotrophin releasing hormone
- Stress -
CD30-T helper 2
Leucotrines activate mast cells
LT1-links with leucotrine c4 ,d4 and e4 - see leucotrines below for actions -also causes mast cell activation with release of mast cell contents (to be specified )
LT2 - LTD4 results in
- contraction and proliferation of smooth muscle,
- eosinophil migration and
- damage to the mucus layer in the lung.
Is the receptor of prostoglandin d2 -so prostoglandin d2 activates mast cells .
Chemokines -work as ligands (the substance which attaches to / triggers) in receptors on many cells beginning processes within the cells and attracting other immune cells
Tumor necrosis factor, triggered the alternative complement pathway on their surface in normal and C2-depleted, (but not in factor B-depleted serum and on incubation with purified C3, factors B and D.) this was independent of any other mechanisms.
So TNF@out of mast cells - stimulates compliment activation -through the pathway not affected by external triggers - leading to c3a and c5a further degranulating mast cells and causing anaplactiod reactions to life threatening symptoms
Il4 actiavtes mast cells
It has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation B cells into Plasma Cells.
It is a key regulator in humoral and adaptive immunity.
IL-4 induces B-cell class switching to IgE, and up-regulates MHC class II production. It also induces B cell class switching to IgG4.
IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12.
Overproduction of IL-4 is associated with allergies.
New reasearch - being published shows
IL-33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.
So this is an -ige and allergen indepandnat cause of anaphylaxis .
IL5 is produced T helper-2 cells and mast cells. Its functions are to stimulate B cell growth and increase immunoglobulin secretion.
It also activates mast cells -were it activates cellular pathways involved in cell growth and differnataion .
It also has effects on esinophils - IL-5 plays an important role in the proliferation and differentiation of eosinophils.
IL-5 induces terminal maturation of eosinophils, prolongs eosinophils survival by delaying apoptotic death, increases eosinophils adhesion to endothelial cells and enhances eosinophils effector function.
Esinophils -what are they ? -
IL-5 plays important roles in the pathogenesis of asthma, hypereosinophilic syndromes and eosinophil-dependent inflammatory diseases.
IL-5 is produced by eosinophils, mast cells, Th2 cells, Tc2 cells and gamma delta T cells
In a recant study several clinically relevant stimuli leading to TSLP production by primary human airway and skin epithelial cells were identified.
We have further shown that these stimulated epithelial cells release TSLP in sufficient amounts to activate, in synergy with IL-1/TNF, MCs to produce high levels of Th2 cytokines.
IL-5, IL-13, IL-6, GM-CSF, CXCL8,
and CCL1 were released after 24 hours of mast cell stimulation by TSLP in the presence of IL-1/TNF
Stimulation of MCs with IL-1/TNF induced the release of high levels of CCL2 and CCL3, and this was not affected by TSLP
Given the important role of TNF in severe asthma (18), it is of note that this cytokine was released at high levels by MCs stimulated with IL-1 and TSLP (not depicted)
(The suppressive activity on the production of TGF, This is interesting, together with the observation that TGF-β inhibits the response to TSLP)
Il12 and il23
IGG + antigen
IGG is an antibody which circulates around the body -
It is also present on mast cells. It is increased in potency to cause mast cell opening by interon Y (see lower).
It meets an antigen, which it needs far more of to act - but then makes mast cells open.
Immunoglobulin light chain
The light chain is the short piece on each side which is pink (in the diagram )
These light chains can become a full antibody or can operate alone .
Recent studies have shown that these Ig light chains can bind to mast cells and, using their ability to bind antigen, facilitate activation of these mast cells (Redegeld (2002))
Activation of mast cells results in the release of various pro-inflammatory mediators which are believed to contribute to the development of the inflammatory disease.
Very recent studies have shown that Ig light chains not only activate mast cells but also dorsal root ganglia (Rijnierse, 2009)) and neutrophils (Braber and Thio (2012)), expanding their possible role as mediators in inflammatory disease.
Neuropeptide y is released from mast cells
Mast cells express a high density of ST2 -IL33 receptors and produce a variety of pro-inflammatory cytokines in vitro in response to IL-33 (1, 12–14). Here, we explored directly the role of IL-33 and mast cells in inflammatory arthritis.
T Helper 2 cells also express high levels of il33 -st2 receptors
Synovial fibroblasts may be the main source of IL-33 (36). We found that resting synovial fibroblasts expressed little or no IL-33 whereas expression was markedly enhanced by the presence of proinflammatory cytokines, such as TNFα and IL-1β, which are abundantly produced during CIA and RA (15). Thus, IL-33-mast cell interactions that lead to the enhanced production of IL-1β and TNFα may represent a self-amplification circuit in the proinflammatory response during the development and perpetuation of arthritis. Such a model is compatible with the notion that the synovial microenvironment is critical to the maintenance and amplification of local inflammatory responses.
So TNF alpha and IL1 - upregualtes production of il33 in Joints in RA
Both of these also actiavte mast cell indepandantly.
Mast cell contents -
Full degranualtion and production of
Catagory 2 cyctokines are produced - IL-5 and IL-13
IL6 and IL1
Il6 and il1 make t0cells become t 17 cells which are highly pathogenic
A more natural role for Th17 cells is suggested by studies that have demonstrated preferential induction of IL-17 in cases of host infection with various bacterial and fungal species. Th17 cells primarily produce two main members of the IL-17 family, IL-17A and IL-17F, which are involved in the recruitment, activation and migration of neutrophils. These cells also secrete IL-21 and IL-22. --------------------------------------------------------------------------------->
Il17 and family and the effects
The regulation and function of IgE in healthy individuals and in antigen-naïve animals is not well understood. IL-33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL-33 provides an antigen-independent stimulus for IgE production and mast cell degranulation.
IL-33 was administered to naïve wild-type (WT), nude and ST2−/−, IL-4−/−, IL4Rα−/− and T-or B-cell-specific IL-4Rα−/− mice. IgEand cytokines were quantified by ELISA. T- and B-lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release.
IL-33 enhanced IgE production in naïve WT, T-IL-4Rα−/− but not in ST2−/−, IL-4−/−, IL-4Rα−/− or B-cell-specific IL-4Rα−/− mice, demonstrating IL-33 specificity and IL-4 dependency. Moreover, IL-4 was required for IL-33-induced B-cell proliferation and T-cell CD40L expression, which promotes IgE production. IL-33-induced IL-4 production was mainly from innate cells including mast cells and eosinophils. IL-33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen-naïve WT but not in IL-4Rα−/− mice.
IL-33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.
The most exciting thing about this article is -INDEPENDANT of ALLERGEN - so this shows anaphylaxis - true IGE anaphylaxis - is happening due to IL4 - a chemical we know is produced by T cells and is expressed from mast cells explaining how we get anaphylaxis on anaphylaxis .
So no longer idiopathic anaphylaxis -But -maybe - il33/il4 IGE anaphylaxis .
This also explains why many of us get full anaphylaxis when our triggers reach a set point .
Fibrobalst -cell in joints
THp - undifferentiated T helper cell
TH2 - T helper 2 cell
b cell becomes plasm cell = antibodies
TH17 -T cell which can kill other cells -cytotoxic
ST2L -Il33 receptor
IGG -antibody type g
Mast cells are activated by chemicals and allergens (non self harmless) or antigens (non self harmful) or confused immune cells, attached to receptors on the surface, making the mast cell release contents, or to make chemicals make and release them.
T helper 1 cells become cytoxic T cells
Have their main role in utilisinf toll like receptors and responding to virus.
Within this they directly activate mast cells to produce cytokines which are needed for TH2 cell and antibody production
T regualtory cells should switch off the inflammation process when its complete
On reading about IL5 - I put 2 and 2 together - knowing that esniophils play a role in asthma -that mast cells are highly involved in asthma pathology -with Il5 from mast cells - causing further mast cell activation and -increase in eosinpohil pathology.
Eospinophils - cause the airway symptoms noted
Leucocyte recruitment activates - leucocyte's with NK cell like activities - This leads to further release of il13 and il4 -which cause airway symptoms
Dendric cells as atigen presenting cells - cause T helper 2 activation -which also relase IL4 -
IL5 -further recruiting more esinophils and other leucocytes
Prostoglandins also activate TH2 cells - see prostoglandins on mast cell chemicals released
IL33 +Il4 =IGE =Anaphylaxis
Mixes if tlsp ,IL1 ,inteferons ,tnf alpha all bring various mediator release
Histamine -receptor 4
T cells -helper and cytotoxic
Lymphocyte-like nk cells
Direct activation -
-Excercise (even minimal in very ill patients )
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opiate receptors are distributed widely in the brain, and are found in the spinal cord and digestive tract.
Could somastatin activate opioid receptors on mast cells ?
The action of opiates in mast cells is known to be non-immunological in nature. A survey of the histamine-releasing properties of a variety of opiates shows that the pharmacology of opiate-induced histamine release from mast cells is distinct from that of known opiate receptors. Although functional opiate receptors may exist on mast cells and may be capable of modulating IGE-mediated histamine release, there is no evidence that these receptors account for opiate-induced histamine release. Since other basic compounds have been suggested to release histamine from mast cells by directly activating G-proteins, it seems possible that morphine and endogenous opiates may also share this mechanism.
In their study of skin opiate administration and Mast cells, Blunk et al, 2004, found that large concentrations of morphine and other opioids with lower affinity to the μreceptor induce the liberation of the mast cell mediators' histamine and tryptase. In contrast, the potent μagonists did not activate cutaneous mast cells in vivo or induce neurogenic inflammation and the formation of an axon-reflex flare.- seen a typical wheal flare
These effects seen together indicate that the activation of skin mast cells by morphine, codeine, and meperidine does not depend on μ receptors but, more likely, on the direct activation of G-proteins of mast cells. Thus, rather than using μopioid antagonists, the inhibition of stimulated G-protein activity, for example, by cromolyn (20), seems to be the more promising approach. This could be tested by intradermally co-injecting or co-perfusing the skin with, for example, codeine and cromolyn.
This raises the question of whether IV cromlyn would be protective if opiates are used in patients with mast cell conditions.
Acetylcholine activates mast cells directly, receptors and in a more complex manner dependent upon presence of:
Hydrogen ions (PH)
Calcium (the receptor could allow non-homestatic balance of calcium)
Presence of receptors was confirmed by:
Allergen - Any non harmful substance which the body sees as bad
Antigen presenting cell eats "bad" or actually harmful substance (for normal immune response)
T cell - several types, all present in all areas of the body, hanging about to react to threats. One type cause inflammation and healing .The other help make antibodies.
Cytokines- chemicals required to let each cell type do their job. These are known as IL, followed by a number. In this case, it is Il4.
T cells help plasma cells activate and make antibodies