Histamine is a bioactive amine .
It is a potent mediator of inflammation causing
-attraction of other immune cells
- Inc white blood cells which - eat dead bacteria cells -split open by inate immunity compliment
- causes nerves to fire
-makes blood vessels pourus allowing white blood cells to the tissues to find and remove bacteria , non self or broken self( cancer) cells .
For full effects see symptoms
It is made from its precursor
and then stored in granules inside mast cells, baspohils, in enterochromaffin cells in the gut and lungs and in nerves.
On stimulation, it is released from mast cells and another white blood cell called a basophil (more commonly in autoimmune conditions), enterochromaffin cells and nerves. It also stimulates nerves.
Histidine is present in all dietry protien and in the presence of Histidine decarbolase converts any dietry protien - L-amino acid - into Histamine in mast cells and nerves - and stores it in Mast cells , basophils , nerves . (as shown above )
Were it is released by several mechnaism
- True IGE allergy
- Inborn immunity compliment (see triggers )
- Direct actions on Mast cells
- Many mechnaisms (see triggers )
There are 4 histamine receptors .
were histamine from mast cells (and basophils ) attaches to apoint on the cell membrane - to cause symptoms by chnaging what the cell does .
Each has many roles and functions .
CNS -Brain ans spinal cord
Smooth muscle from airways,-Lungs
Gastrointestinal tract-mouth to bottom
Genitourinary system-penis vagaina ,bladder, overeis, womb, prostste ,testes.
Cardiovascular system -blood vessels, heart
Adrenal medulla-central aprt of the adrenal glands -producing norepinpeherine and epinpeherine
Endothelial cells -skin ,heart lining
Lymphocytes -white blood cells
Histamine recptor 2
Vascular smooth muscle, -blood vessel walls
Neutrophils -white blood cells
CNS - Central nervous system -brian and spinal nerves
Digestive tract - ilieum
Histamine recptor 3
Inside the brain -
Outside the brain -
Histamine depresses sympathetic neurotransmission in the guinea-pig mesenteric artery by interacting with histamine H3-receptors on the perivascular nerve terminals. The pharmacological properties of these receptors are similar to those reported for the H3-receptors in the brain. Our data provide evidence for the existence of H3-receptors in the autonomic nervous system.
The autonomic nervous system
CNS -centrol nervous system =brain, peripheral nerves, heart, lungs, gastrointestinal tract, endothelial cells
Histamine recptor 4
Bone marrow and leukocytes
It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.
adapted from - harmacologicalBrowser.php?ItemId=5011#.UBRFomHY_Kg
It is thought that histamine not only goes on to affect the body directly, but also prolongs the life of α activity, so a positive feedback cycle occurs
Is stored in and released from human mast cells . It is also reelased from activated platletts
Serotonin has several roles and effects in the body
- Regulation of bowel movements by incresing smooth muscle tone .
- Control of appietite ( higher =hungrier )
- Regulates insulin and growth factor release - so suppresses insulin release from the pancreas
- Breathing rate (more=higher rate )
- heart rate (more = higher rate )
-Constricts blood vessels -vasoconstriction which means the heart has to pump harder (increased cardiac output ) this increases blood pressure
- a neurotransmitter
- activates cells ( with recptors )
- upregulates any mood - anxiety , depression, happy , angry - making it more intense .
- Controls sleep
- has role in building and degerating bone
-In plateletts - heomostatis and clotting
If serotonin release is higher than the platletts can absorb the excess this leads to diarrhoea and the vomiting centre is activated .
Serotonin can not pass the blood brain barrier. Some neurons within the brain make serotonin . brain mast cells make serotonin
The protien Ltyrophan -is made into serotoinin can pass into the brain were it is converted and stored .
Mast cells in mastocytosis pts- release serotonin twice aday . the normal is once
Histamine and Bacteria
Bacteria produce there own histamine . So during a bacterial infection the histamine level is even higher .
Add in Toll like recptors recognising the bacteria -activating mast cells infection can cause very high histamine and symptoms soon after infection
Heparin is stored in mast cells . Its role in the body is not the same as its medical use.
The role of heparin in the body was not clear .It is felt to be released only into the blood vessels ( vasculature ) at sites of tissue injury. In a review of literture and presenting their own work Oschatz et al (2011)show that heparin initiates the production of a hormone -- bradykinin -- that contributes to swelling, anaphylactic and inflammatory symptoms, which are commonly
Notably, mast cell-released heparin , through a pathway generates the chemical which causes inflammation (inflammatory mediator ) bradykinin via activation of factor XII (the so-called Hageman Factor) that belongs to the blood coagulation system. The study thus provides an unexpected link between the clotting cascade and mast cell-driven pro-inflammatory reactions.
This production of bradykinin -causes-
- low blood pressure -from fluid loss (see 3rd spacing)
-and white blood cells sticking together ( which stimulates the immune system )
Drugs that block bradykinin or factor XII activity protect from adverse mast cell (heparin ) -driven effects in patients ( see diagram ) and genetically engineered mouse models and could be a new strategy to treat allergic diseases.
The measure of blood thinness for heparin is human is APTT .
In anaphylaxis APTT is prolonged( longer clotting time ) because of heparin . Mice post anaphylaxis the bblood is unclottable
Prolonged high release of heparin leads to bone denisty loss -leading to osteoprosis /osteopenia in otherwise low risk patients (see osteoprosis in symptoms )
Chymase also causes death of endothlial cells and causes release of IL8 , which is also activates and is released from mast cells .
This highlights one mechanism by which one mast cell being acivated leads to further degranulation ( release of chemical contents from other mast cells )
Which is noted by patents as snowball effect- having one reaction and it makes another more likley-they notice as being more sensitive to triggers.
It is noted medically as second phase reactions , caused by anaphlatoxines from compliment activation ( see triggers ) and also chymase
Chymase is released by mucosal mast cells upon challenge with parasites and parasite antigens promoting an inflammatory response.
Chymases are also known to convert angiotensin I to angiotensin II and thus play a role in hypertension and atherosclerosis.
Renin is also released from mast cells . This also coverts angiotensin 1 to angiotensin 2 .
Angiotensin 2 causes high blood pressure . These 2 chemicals working in this way are sperate from the known renal ( kidney) Renin -angiotensin pathway . Which has angiotensin converting enzyme as the pivital enzyme .
Leucoytes - white blood cells
Adhesion - sticking
Hypotension -Low blood pressure
edeama -odeama -swelling .
Adapted from ;- Chris Oschatzetal (2011)
Mast cell tryptase comes only from mast cells .
It has several functions
- Degrading HDL cholesterol which is good cholertserol which compromises its protective role-in reverse cholesterol transport - leads to clinically high LDL (bad) chlostarol in patients who have good diets
-It can be measured and has been noted to be high in the tissues in several other conditions- Inc Asthma , MS , migraines. irritable bowel syndrome indicatinga role of mast cells in these conditions
These mast cells are activated by substance p - a neurotransmitter- a chemcial which allows nerve electricity to move between nerve endings
Mast cells are also found activated by the presence of tryptase in the tissues in conditions which worsten with stress . research is going on into the connection between the stress hormone -corticosteriod releasing hormone and mast cell activation .
It is a measure of mast cell numbers not disease severity
Documents and references for mast cell tryptase and cholesterol
Leucotrines are poduced from the same free Arachidonic acid , which are relased from the phospholipid membrane of the mast cell when its opened bya trigger.
The Arachidronic acid is processed to HPETE , which becomes leucortrines A-E .
LTA4----------- LTA4H enzyme makes
- A potent lipid chemoattractant - attracts other immune chemicals and immune cells -
( REFS ) 2, 3,
- immune responses 4,
- host defense against infection - 5,
- platelet activating factor (PAF) induced shock ( 2, 6 ) - see mast cells
- lipid homeostasis ( 7)
- Agonist ( causes ) contraction of smooth muscle -
- Induce microvascular permeability ( Makes blood vessels leaky allowing fluid out =swelling )
- mucus secretion in airways.
- Enhance growth of human airway epithelial cells,
- Reduce myocardial contractility and coronary blood flow ( reduced heart contraction strength and blood flow to the heart muscle .
- Induce long lasting hypotension ( low Blood pressure )
- Stimulate angiogenesis.- The physiological process involving the growth of new blood vessels from pre-existing vessels
- Is present at high levels in many inflammatory conditions - collitis, asthma
- LTD4 is associated with the pathogenesis of several inflammatory disorders, such as asthma and inflammatory bowel disease.
- Exposure to LTD4 increases survival and proliferation in intestinal epithelial cells.
- Areas of chronic inflammation have an increased risk for subsequent cancer development;
- CysLT1 regulator is up-regulated in colon cancer tissue and LTD4 signalling facilitates the survival of cancer cells.
- LTD4 could reduce apoptosis( reduce them dying off ) in non-transformed epithelial cells.
- Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2 ( see prostoglandins )
Mast cell membranes- when they are breaking down -following stimaulation froma trigger- compliment+ antibody, compliment alone or direct action of triggers. - Relase arachidonic acid from its outer coating of the cell (membrane ) fats with phosphate (phospholipids ) .
COX1 - Cyclooygenase - is an enzyme- then breaks down this free arachidonic acid . Through the process opposite
to make prostoglandins .
PGD2- has receptors
DP- prostaglandin D2 (PGD2), functions as a mast cell-derived chemical (mediator ) to trigger asthmatic responses. It also causes opening of the blood vessels increasing the inside diameter (vasodilation)
CRT- Receptor is on Th2 cells, eosinophils, and basophils
CRTH2 plays a central role in key aspects of allergic diaease progression ( pathology ) including:
• Making cells go to (recruitment) and activation ( fill a role ) of Th2 cells, eosinophils and other leukocyte
populations to sites of allergic inflammation
• Prevention of apoptosis (death ) of Th2 cells thereby impeding the resolution of allergic inflammation Production of Th2 cytokines (chemicals) leading downstream amplification of allergic disease ( such as interleukin 4, interleukin 5 and interleukin 13 )
• Production of IgE -The true allergy antibody
• Production of mucus
• Airway hyper-responsiveness -Tightening muscles reducing airway inside space for air to move
The role of CRTH2 in the allergic response has been reviewed by Pettipher and hansel(2008) (REF)
-PGD2 -also stimaulated mesingeal cells in the filtrition area of the kidneys to make more urine .This is attanuated (stopped) by cox1 inhibitors .
Main effects of prostaglandin binding to the receptor are:
bronchoconstriction ( contriction of muscles around the airway tubes )
Via activation of this receptor, PGF2-alpha mediates luteolysis- which is affecting the overy - the follicle from which an egg is relased is clalled corpus leuteum -this produces progesterone . Pgf2a act and makes the corpus leautum shirl intoa corpus albicans -leading to menatutation and in preganacy labour .,
May also be involved in modulating intraocular pressure and smooth muscle contraction in uterus and gastrointestinal tract sphincters.
Knockout studies in mice suggest that the interaction of PGF2-alpha with this receptor in ovarian luteal cells initiates luteolysis and thus induces parturition.
PGF2 a -is used to terminate preganacy and induce labour.
The IFN-β proteins are produced in large quantities by fibroblasts. They have antiviral activity which is mainly involved in innate immune response.
Two types of IFN-β have been described, IFN-β1 (IFNB1) and IFN-β3 (IFNB3) (a gene designated IFN-β2 is actually IL-6). IFN-β1 is used as a treatment for multiple sclerosis as it reduces the relapse rate.
IFN-β are secreted by many cell types including lymphocytes (NK cells, B-cells and T-cells), macrophages, fibroblasts, endothelial cells - mast cells , osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, and are also active against tumors. Recently, plasmacytoid dendritic cells have been identified as being the most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells.
IFN-α and IFN-β are secreted by many cell types including lymphocytes (NK cells, B-cells and T-cells), macrophages, fibroblasts, endothelial cells - mast cells , osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, and are also active against tumors. Recently, plasmacytoid dendritic cells have been identified as being the most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells.
IFN-α acts as a pyrogenic factor -makes you have temperture - by altering the activity of thermosensitive neurons in the hypothalamus thus causing fever. It does this by binding to opioid receptors and eliciting the release of prostaglandin-E2 (PGE2).
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TNF alpha- Tumor necrosis factor alpha - Comes from mast cells and is also produced from Leucotrine B4 ( LTB4)
Has affects all over the body
In the hypothalamus:
Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)
On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators. It also induces insulin resistance by promoting serine-phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling
It is a potent chemoattractant for neutrophils, and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils migrate.
Tumor necrosis factor also plays a role in autoimmune diseases not associated with inflammation, such as chronic fatigue syndrome (CFS). Autoimmune sufferers, including CFS patients, often have unexplained symptoms such as malaise, night sweats, sore throat, swollen glands, and low-grade fevers, for no apparent reason.
Researchers found that mast cells release tumor necrosis factor. It journeys
to the lymph nodes, where it activates infection fighting cells. This would
explain the swollen glands that often accompany autoimmune disease, even
without an infectious agent present.
Link is to a research paper on TNFalpha in CFS
Studies show that autoimmune patients have elevated levels of tumor necrosis factor.
According to an article in Molecular Psychiatry, “TNF has long been
implicated in the immunopathogenesis of Multiple Sclerosis (MS), which
is an inflammatory and demyelinating disease of the central nervous system. In MS the magnitude of the elevation of TNF in cerebrospinal fluid
mirrors the severity of the disease,” (Finsen, 2002)
Mast cells release tumor necrosis factor (TNF).TNF (due to activation of the kynurenine pathway)- this pathway is implicated in every cancer, every autoimmune disease and in brain disorders such as Alzheimers.
TNF is regulated by protease.- will clarify which one
Sauerkraut contains both protease and DNase1.
Also, tumor necrosis factor upregulates an enzyme that rapidly degrades tryptophan (the kynurenine pathway). This rapid degradation causes the release of toxic metabolites that selectively target TH1 suppressor T-cells. Without TH1 suppressor T-cells, your body would not be able to control the production of the allergen antibody IgE.
Our bodies need tumor necrosis factor, mast cells, and histamine. The problem in these diseases and in allergies lies in the inability to properly regulate TNF and histamine.
Mast cells release cytokines- These are involved in many of the actions we see from mast cell contents
With Histamine we get
PAF - platlett activating factor -
Involved in several functions
- Including platelet aggregation- clumping and - - - degranulation - splitting open spilling contents - leading to serotonin release
- Inflammation, and
- Increased vascular permeability, - makes blood vessel porous leading to fluid leaking from the blood causing swelling and low blood pressure =anaphylaxis
- the oxidative burst,
- chemotaxis of leukocytes, (attracts them )
- as well as augmentation of arachidonic acid metabolism in phagocytes -
- constriction of the airways ( bronocconstriction )
-Toxins - like bacteris fragments - cause rapid effects which lead to anaphylaxis which wont respond to antihistamines
Thymic stromal lympopietin -comes out of mast cells
It matures dendric cells -antigen preseting cells. Particularly langerhans cells in the skin epipermis .
TLSP causes TNF-alpha release by T cells -which also activates mast cells .
Within the thymus TSLP activation of both myeloid and plasmacytoid (CD123+) dendritic cells results in the production of regulatory T cells.
In the lungs tlsp matures tcells into TH2 (t helper 2 cells ) which continue and upregulate the immune response .In response to a specific antigen in the airways . This explains why some inhaled substances cause symptoms without direct IGE activation of mast cells .
TLSP is also found in higher levels in joints of patients with inflammatory arthritis (RA) .This may explain why mast cell pts get joint inflammtion (Koyama etal 2007)
Also triggers mast cells - with ifn gamma and IL1
BFGF - is fibroblast growth factor and it has role in mkaing new fibroblasts . Fibroblasts are responsible for building the collagen frame work of skin and internal organs . Most notably muscles .
-They promote angiogenesis, the growth of new blood vessels from the pre-existing vasculature.( blood vessels ) which is crucial in wound healing
Lymphotactin is also expressed in activated
CD8+ T cells -
CD8- T cell receptor alpha beta + thymocytes.
It has chemotactic activity ( attracts ) for lymphocytes ( white blood cells ) but not for monocytes or neutrophils.
The gene encoding lymphotactin maps to chromosome one. Taken together, these observations suggest that lymphotactin represents a novel addition to the chemokine superfamily
The effects of IL-1 alpha and beta are associated with inflammation but also IL-1 has also been associated with
Bone formation and remodeling - During bone remodeling, IL-1 stimulates bone resorption and osteoclast formation.
An osteoclast (from the Greek words for "bone" (Οστό) and "broken" (κλαστός)) is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption.
Insulin secretion - In conjunction with TNF@ and inteferon y(2) are known as the filthy 3 -involved in the loss of pancreatic insulin producing cells . (Mandrup Poulson 1996)
Appetite regulation,13, 14 - Research has compellingly demonstrated that IL-1β decreases food intake in a dose-dependent manner
(e.g., Kent, Rodriguez, Kelley, & Dantzer, 1994; Swiergiel et al., 1997a; and many
others). This effect is seen when this cytokine is administered both centrally and
peripherally. IL-1β predominantly affects meal size and not meal frequency (PlataSalama´n, 1994)
Ill ness behaviours - reduced movement in open environments has been demonatrtaed with introduction of IL1 . As has social exploration and the exploration of novel environments. With both paradigms, it has been reliably demonstrated that illness-inducing agents and cytokines disrupt exploratory behavior.
So IL1 (alongside the bacteria /virus)indepandantly cause us to stay still when we are ill .
Neuronal phenotype development,18, 19 and
IGF/GH physiology.20, 21- IL-1 is reported to reduce IGF secretion by the liver, and, at high concentrations, suppresses acid labile
subunit (ALS) secretion by the liver.
IGf is involved in promoting bone growth -so it being supressed by IL1 - further impacts bone loss
Cognitive function vis learning -Infection and cytokines independantly impair cognitive
function by disrupting the acquisition of a learned response.
This could further explain brianfog
TNF (Kapas & Krueger, 1992) and
interferons α and β (Kimura et al., 1994) have similar effects on sleep; like IL-1 they increase NREM sleep, often accompanied by decreased REM sleep. These ﬁndings—
increased NREM sleep, increased EEG amplitude, and in some cases suppressed
REM—are similar to what is seen when animals are exposed to many different infections, including LPS, inﬂuenza virus, and Staphylococcus aureus .This again is in sperate studies were both factors are not found together .
So IL1 , independantly affects sleep reducing REM sleep (deep sleep ) and increased non remsleep .This leads to no physical rejuvenation -which occurs in REM sleep which goes ahuge way to epxlain the oppresive fatigue expereinced by pts with mast cell conditions . Also the amount of sleep needed by patients .
Il1 inhibits female sexual behaviour but not male .
Adapted from Larson et al (2001) and
IL-2 was discovered to be a member of a family of cytokines, which also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor complex consisting of IL-2 specific IL-2 receptor alpha (CD25), IL-2 receptor beta (CD122) and a common gamma chain (γc), which is shared by all members of this family of cytokines. Binding of IL-2 activates the Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules.
As such, IL-2 is necessary for the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones.
IL-2 is also necessary during T cell development in the thymus for the maturation of a subset of T cells that are termed regulatory T cells (T-regs). After exiting from the thymus, T-Regs function to prevent other T cells from recognizing and reacting against "self antigens", which could result in "autoimmunity". T-Regs do so by preventing the responding cells from producing IL-2
Thus, IL-2 is required to discriminate between self and non-self. IL-2 has been found to be similar to IL-15 in terms of function.
IL-2 has a well documented role in induction of pruritus. Direct injection of this cytokine into skin of healthy subjects as well as those with atopic dermatitis has resulted in itching. Furthermore, it has been found to be higher in pruritic lesions of psoriasis compared to non-pruritic ones. Serum levels of IL-2 have been demonstrated to be higher in hemodialysis patients with itch (uremic pruritus) compared to those without itch. As a proof, therapeutic measures that inhibit IL-2 such as Ultraviolet therapy, tacrolimus and thalidomide have been demonstrated to be effective in treatment of uremic pruritus.
Soa second reason why we itch .
Also CD25 is one of the minor criteria for systemic mastocytosis if its expessed on mast cells .
Blocking IL-2 receptor
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases such as corticosteroids, and organ transplant rejection (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen-activated T cells. Others (sirolimus) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells.
Activates B cells( which become pasma cells to make an antibody -IGA,IGG,IGD,IGE
Has role in making nerves cells settle into different roles .Through PC12-
Il6 prevents bone re absorbtion .(remodeling) And has a known role in the development of osteoprosis .
Il6 - also makes bone loss associated with no oestrogen ( post I meopause worse oestrogen bone loss more significant
Increases numbers of-proliferation of -
Inhibition of the growth of Breast cancer cells and melenoma cells( skin cancer)
Regrerates-Liver cells and causes expresion of
app= and production of -C-reactive protein,
serum amyloid A, fibrinogen,
Makes stem cells in bone marrow make -,
In cooperation with IL-1 (11), induces T cell differentiation to cytolytic-T cells (12, 13) and activates natural killer cells (14).
IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into lymphoid progenitor cells or, with the addition of IL-7, into myeloid progenitor cells.
Additionally, IL-3 stimulates proliferation of all cells in the myeloid lineage (erythrocytes, megakaryocytes, granulocytes, monocytes, and dendritic cells),( http://hematologyoutlines.com/atlas.html ) in conjunction with other cytokines, e.g., Erythropoietin (EPO), Granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-6.
It is secreted by basophils , activated T cells and Mast cells to support growth and differentiation of T cells from the bone marrow in an immune response.
Activated T cells can either induce their own proliferation and differentiation (autocrine signalling), or that of other T cells (paracrine signalling) - both involve IL-2 binding to the IL-2 receptor on T cells (upregulated upon cell activation, under the induction of macrophage-secreted IL-1).
its function is quite similar to GM-CSF.
Il3 from T helper 2 cells directly activates mast cells
Stimulus - Low cicrulating volume due to fluid leaving the blood
Blood pressure low and low filtering rate in kidneys (GFR)
Cells in the flitering system in kidneys - arent streached
and cells whic detact fluid amount notice its low
Renin -from mast cells converts angisnogen -angiotensin 1
Chymase (+ace) coverts angiotensin 1 to angiotensin 2 .
Less blood to kidneys becuase arterioles constrict .
Adrenals relase aldosterone -which keeps salt in the body
Hypothalamus signal thirsty ?? do other mast cellchemicals mess with this ?
Pituatry releases adh -anti diuretic ( water loss ) hormone -so more fluid kept
It is also in the pathway in cardiac cells during ischemia( short of oxygen to muscle ) and reperfusion after a blocked aretery is opened and blood flows - Mast cell renin -> as per Renin angiotensin system .renin coverts angiotensinsogen -angiotensin 1
Ace/chymase ->angiotensin 2 -> through ang 2 activating cell -> Norpeinepherine to move into the cell and also be released -> causing cardiac dysfunction = arrthymisa( irrgeualr ) and tachycardia( fast ) heart rythymas e.g VT, VF . This adds to the effects of histamine within the heart .
This would explain the presnece of arrythmias in Anapahylaxis
Increased sympathetic activity - Norepinpherine release is an effect of the main renin angiotensin alodosterone system.
For more detail on norepinepeherine
and the effects of histamine in the adrenal medulla - See next subpage - click here --->
Plasmacytoma - refers to a malignant plasma cell tumor growing within soft tissue or within the skeleton. The skeletal forms usually have other occult tumors and frequently progress to multiple myeloma over the course of 5–10 years. The soft tissue forms (also known as extramedullary or extraosseous plasmacytomas) most often occur in the upper respiratory tract, rarely disseminate, and are cured by resection. Most but not all cases produce paraproteinemia. Solitary tumors in bone can be treated by radiotherapy.
IL6 Increases proliferation of - kidney cells in the fliter parts -which contain renin (mast cells)
A decrease in GFR means less solute in the tubular lumen.
As the filtrate reaches the macula densa, less NaCl is re-absorbed. The macula densa cells detect lower concentrations in Na and Cl and upregulate Nitric Oxide Synthetase (NOS).
NOS creates NO which catalyses the formation of prostaglandins. These prostaglandins diffuse to the granular cells and activate a prostaglandin specific Gs receptor.
This receptor activates adenylate cyclase which increases levels of cAMP. cAMP augments renin release. Prostaglandins and NO also vasodilate the afferent arterioles. Efferent arterioles are spared from this effect by renin release.
For secondery chemicals - that mast cell chemicals cause release of see subpage
Bronconstriction-tightening of airways by contracting muscles
smooth muscle spasms - mouth-bottom, bladder-womb, prostate,overies, fallopian tubes , lungs ,lung walls
fluid leaking from blood vessels into tissues =low circulting volume
Increased stomach acid
Increased strength of heart beat
heparin release from mast cells -see osteoprosis
in anaphylaxis Histamine (via H1‒H4 histaminergic
receptors) cause :-
tachycardia,(fast heart )
rhinorrhoea,(runny nose) bronchospasm ( tightening of aitway tubes ) (H1)
Endothelial release of nitric oxide (NO) leading to
vasodilatation and hypotension (H1)(see subpage )
Hypotension, flushing and headache (H1, 2)
Inhibitory presynaptic (H3) release endogenous
epinephrine (see subpage )
Chemotaxis and mast cell cytokine release (H4)
Adapted from -Nasser et al 2012 9see refs page
Tryptase Activates: complement, coagulation and kalikrein‒kinin
system leading to angioedema, hypotension, and
disseminated intravascular coagulation
Respiratory and gastrointestinal tract mast cells
contain less tryptase than connective tissue mast
cells (tryptase may not increase in food anaphylaxis)
Adaapted from nassar 2012
Responsible for systemic mast cell activation;
high concentration of PAF and low concentrations of
PAF-acetylhydrolase may predispose to severe reaction
Adapted from nassar etal 2012
Tryptase is raised in only 30% of anaphylaxis .poshumous samples can still be negaitive-most commonly in food related or it can rise posthumously when normal pre death .
It is processed quickly by the body .In optinum range for 2 hours after the first symptom of anaphylaxis .
If tryptase is raised outside this -a monoclonal mast cellcondition should be considered - mastocytoss .
Serial measurements give optimum information as arise outside of the pts baseline (even if within norma limits would be signifiacnt .
Ref -Schwartz 2006.WAO guidelines 2011 , Anapahylaxis guidelines 2008 9see subpage anaphylaxis ) and Narrar et al 2012
Low serum ACE concentrations may also contribute
to severe anaphylaxis
Eosinophils Pro-inflammatory (release mediators from their granules)
Anti-inflammatory (metabolise vasoactive substances)
The effects of cariac renin would explain the presence of arrythmias in anaphylaxis
It gets broken down by histamine-N-methyltransferase or diamine oxidase, with the resulting derivities excreeted in urine .It has receptors all over the body. there are currently 4 known receptors and medicines are availble for 2 of these . Histamine causes many symptoms .
IL4 is an interlukin .
It has an essensial role in many parts of the immune system and cells being activated .
In summary -
-is needed to make plasma cells switch to ige production
-is needed to make t neutural cells into T helper 2 cells
-In combination with IL33 ,at a set point - causes anaphylaxis -attracts esinophils to the location - so also contributes to esinophil conditions . These are Asthma, (O)espoheogeal esinophillia .bowel esinophillia .
It is released from mast cells and continues inflammation - this then leads to more mast cell activation -
-IL4 does this directly as do other chemicals out of mast cells -
Swelling causes pain -which releases substance p from nerves -which activates more mast cells .
Symptoms associated with this are -
- Airway inflammation ,which is prolonged.
- inflammation anywere else in the body
- cycle of incresing IGE production ,continually upregualted
- inflammation leads
- to substances coming into the blood which wouldnt normally pass through esp in the bowel -leading to reactions and antibody production to normal things .Well publicised right now is gluten - Dr Oz .
- Also substances moving into deeper layers of bowel lining and other organs . So activating mast cells and continuing the cycle .
See prostoglandin connections to TH2 cells
IL4 signaling Link -
IL-5 Signaling Pathway
Interleukin-5 belongs to the family of cytokines, which includes IL-3 and GM-CSF. It signals through a receptor complex comprising of an IL-5 receptor alpha subunit (IL5RA), and a common beta chain which is shared between all members of this cytokine family. Binding of IL-5 to IL5RA recruits the beta chain to the complex, this then activates the JAK/STAT and Raf/MAPK signaling modules. Source: NetPath http://www.netpath.org/pathways?path_id=NetPath_17