See the
Mast Cell Activation Syndrome thread for a discussion about mast cell disorders. Let me know in the comments below if you see interesting treatment in literature for Mast Cell Activation Disease (MCAD) especially for the MCAD subtype Mast Cell Activation Syndrome (MCAS) and non-IgE mediated mast cell activation.
Articles below that make use of sci-hub links and are not working: Change .tw to .se and vice versa in the URL.
Symptoms and Triggershttps://www.mastzellaktivierung.info/en/symptoms.htmlhttps://www.mastzellaktivierung.info/en/therapy_triggers.htmlParameters for diagnostic testingThese are relatively/somewhat specific, tryptase is the only unique parameter but not useful in
MCAS. They are being tested when symptomatic. Urine samples need to be refrigerated at all times.
Heparin (Plasma)
Chromogranin A (Serum)
Prostaglandin D2 (PGD2) (24h urine, D2 metabolites below are more stable)
11-beta-Prostaglandin F2alpha or 2,3-Dinor-11-beta-Prostaglandin F2alpha or 9alpha, 11beta-Prostaglandin F2 (24h urine, optional plasma)
N-Methylhistamine or
N-Methylimidazoleacetic acid (24h urine) or Histamine (Plasma) (Warning: Histamine itself is stable for less than 1 minute)
LTE4 (24h urine)(LTC4 holds the largest share of LTs in MCs. This will degrade to LTE4 which is stable for a longer time.)
Tryptase (Rarely shows up in MCAS, sometimes being tested in saliva when oral mucosal problems present)
Relative utility of assorted mast cell mediators in diagnosing mast cell activation syndrome (MCAS).First morning urine can be used instead of 24h urine collection:
Dr. Theoharides:
"We collected both 24-hour urine as well as first morning urine. Unless someone has nocturia, the results were about the same. That makes it much easier for a patient. Roughly the first morning urine collection about eight hours worth of urine during the night. We got the same results."
RefMedical terminology: Labs may use terminology like methylhistamine or urine histamine for N-methylhistamine or use PGF2 for PGD2 metabolites (Warning: there are PGF2 molecules that are not PGD2 metabolites). Ask them what kind of metabolite they are offering.
11-beta-Prostaglandin F2alpha seems to pop up in many papers as relatively more reliable compared to the other ones from the above selection. Although there are a few papers that make a case for Heparin.
Proposed diagnostic criteria and algorithms Current provisional criteria to define mast cell activation syndrome (MCAS)Table 2 & Figure 2:
1) Major criteria 1 + Major critera 2
Or
2) Major criteria 2 + at least one minor criterion
Proposed diagnostic rubric for mast cell mediator disordersMast Cell Mediator Release Syndrome Questionnaire:
Mast Cell Activation Syndrome: A Primer for the GastroenterologistSurface-bound expression markersCD117/CD2 and CD117/CD25
CD117: Classical mast cell marker (standard surface-bound molecule for mast cell recognition).
CD117/CD2: Looking for CD2 co-expression on CD117 mast cells. CD2 shouldn't be there.
CD117/CD25: Idem for CD25 which doesn't belong on CD117 mast cells.
Common routine testsCommon abnormalities in routine hematologic and serum chemistry tests found in the study population.Note:"general laboratory abnormalities in these MCAS patients were common but typically modest in degree (i.e., only slightly above or below the upper or lower limit of normal, respectively) and thus less commanding of attention when viewed as isolated results rather than recurrent findings."
Selective vitamin deficiencies like Vitamin D is common among MCAS patients.
Ref 1,
Ref 2Other ways to observe mast cell activity"Single cell laser microcapture and qRT-PCR should be used to identify mast cell phenotype variability and mediator synthesis/release in situ."
Ref"Electron microscopy using time lapse photography on bladder biopsies from IC/BPS patients and controls to see if the mast cells in the biopsies of IC/BPS patients are degranulating at a more frequent rate, or releasing inflammatory mediators without degranulating compared to the control group."
RefGenetic alterations related to mast cell activation diseaseTable 2 & figure 3More papers discussing genetic alterations:
Ref 1,
Ref 2Eosinophil co-activation markersMast cells are known to communicate with eosinophils. Eosinophil activation could be probed by measuring unique eosinophil-derived mediators:
Charcot-Leyden crystals composed of eosinophil protein galectin-10
Eosinophil cationic protein (ECP)Eosinophil-derived neurotoxin (EDN or Eosinophil protein X (EPX)) Eosinophil peroxidase*
Major basic protein (MBP)MBP homolog (MBP2)
*Also found in MCs but highly specific for eosinophils
Endothelial cellsMast cells are sitting next to the endothelium of the inner lining of blood vessels and can interact easily with endothelial cells.
Endothelial degranulation via
Weibel-Pallade bodies:
Major components:
von Willebrand Factor (vWF or Factor VIII related antigen, also found in MCs)
P-selectin Additional Weibel-Pallade components:
Interleukin-8
Eotaxin-3
Endothelin-1
Angiopoietin-2
Osteoprotegerin
P-selectin cofactor CD63/lamp3
?-1,3-fucosyltransferase VI
Other:
Plasminogen activator inhibitor type 1 (PAI-1,
by mast cell-derived exosomes)
Comorbidity related testing"Premature osteopenia/osteoporosis is frequently found in mast cell disease patients and is usually diffuse but may be focal."
RefOsteoporosis/Osteopenia/Osteosclerosis: Bone mineral density measurements (
DXA scan)
Small intestinal bacterial overgrowth (SIBO) (Solution: Lactulose, gases: Hydrogen+Methane)
"Irritable/inflammatory bowel syndrome (IBS) is commonly diagnosed by gastroenterologists consulting on MCAS patients..."
RefIrritable Bowel Syndrome (
Table 2. Biomarker candidates in IBS)
Conditions Often Comorbid With Mast Cell DiseasesSupplementary Table 4. Allergic and non-allergic diseases for which pathogenetic involvement of mast cells has been demonstrated or suspectedHuman mast cell typesHuman MCs are classified by their content of serine proteases.
MCT: Tryptase-only, predominate in the alveolar septa (93%) and in the small intestinal mucosa (98%).
MCC: Chymase-only, present in synovial tissue.
MCTC: Both tryptase- and chymase-positive MCs, predominant subtype in skin (88%), tonsils and small intestinal submucosa (87%).
Mast Cell MediatorsMast cells can release selectively. They could release/secrete one mediator or a small selection, that's why some authors suggest a new subtype of MCAD called Mast Cell Mediator Disease. Testing negative for the parameters used for diagnosis (at the top of this thread) doesn't exclude MCAD but diagnosis is less likely, other mediators below might be elevated but they aren't sufficient specific to aid diagnosis. Mediator profiles may vary among patients resulting in different symptomatology. Patients who have symptom overlap may share a mediator abnormality.
This is an example of how you could approach mediator testing.
MC mediators exclusive for rats or mice could have made it into the list below accidentally, not all papers make a distinction. And some have been detected only at the mRNA level.
5-hydroxyeicosatetraenoicacid (5-HETE) (Ref)?-D-galactosidaseBeta-glucosaminidase
Beta-glucuronidaseBeta-Hexosaminidase ( Carbohydrate processing)
ACTHADAMTSsAdenosine triphosphate (ATP)Annexin A1 (Lipocortin I,
Ref)
Angiogenin (Ribonuclease 5)AngiopoietinArylsulfatase A (Cerebroside sulfatase)
Arylsulfatase BAntizyme inhibitor 2 (AzI2)BradykininBDNF (Premature ejaculation, depression, burnout, sensitivity to stress)
Calcitonin gene-related peptideCarboxypeptidase A3 (CPA3)
Cathelicidin antimicrobial peptide LL-37Cathepsins B, C, D, E, G, L
CCL1CCL16CCL17 (TARC)
CXCL1CXCL4 (Platelet Factor 4)
CXCL10 (IP-10)
Chondroitin sulfateChromogranin AChymaseComplement factor C3Complement factor C5Collagen type VIIICRHCXCL5 (Epithelial-derived neutrophil-activating peptide 78, ENA78)
DopamineEGFEndorphinsEndothelinEotaxin-1 (CCL11)
Factor VIIIFactor VIII related antigen (=von Willebrand Factor)
FGF2 (Basic fibroblast growth factor, bFGF)
Fractalkine (CX3CL1)
G-CSFM-CSFGM-CSFGonadotropin-releasing hormone (GnRH,
Ref)
Granzyme BH3-corticosterone (
Ref)
Heat shock protein 70 (HSP70)
Heat shock protein 90 (HSP90)
Hemokinin-1
HeparanaseHeparan sulfateHeparinHistamineHyaluronic acidIGF-1IFN-alpha (Response to viral infections regulated by IFN-?, flu type symptoms, such as fever, muscle aches and lethargy.)
IFN-beta (Response to viral infections regulated by IFN-?, flu type symptoms, such as fever, muscle aches and lethargy.)
IFN-gammaIL-1alphaIL-1betaIL-1RAIL-2IL-3IL-4IL-5 (major driver of eosinophilia)
IL-6IL-8 (CXCL8,
Seminal plasma IL-8 in male genital tract inflammation,
"the most abundant cytokine of human mast cells"Ref)
IL-9IL-10IL-11IL-12IL-13 (IL-13 can induce IgE release from B cells, IgE-->IgG4 class switching)
IL-14IL-15IL-16 (
Crohn's disease)
IL-17 (IL17A)
IL-17F
IL-18IL-22 (IL-TIF)
IL-25 (IL-17E)
IL-31IL-33Leukemia inhibitory factor (LIF)
LeptinLTB4LTC4Major basic protein (MBP)
Mast cell
kininogenaseMast cell-derived exosomes (crosses BBB,
Nonspecific B and T Cell-Stimulatory Activity)
MelatoninMitochondrial DNA (
Ref) (Possible immune response by release of anti-mitochondrial DNA antibodies)
MCP-1 (CCL2)
MCP-3 (CCL7)
MCP-4 (CCL13)
MCP-5 (CCL12)
MCP-6 (is this a tryptase enzyme?)
MIFMIP-1alpha (CCL3, fever)
MIP-1beta (CCL4)
MIP-2alpha (CXCL2)
MIP-2beta (CXCL3)
MIP-3alpha (CCL20)
MIP-3beta (CCL19)
MMP2 (degrades collagen I)
MMP9 (degrades collagen IV and V)
NGFNeurolysinNeurotensinNeurotrophin 3Neurotrophin-4 (
Ref)
Nitric oxide (NO)
Nitric oxide synthase (NOS)
Norepinephrine
Oncostatin M (T cell-induced mast cell activation)
PAFPeroxidasePLA2Platelet derived growth factor (PDGF, PDGF-AA & PDGF-BB)
Pro-caspase 3, 4
PGD2 (flushing, hair loss)
PGE2 (Fever, pain)
RANKL (Driver of Osteoporosis)
RANTES (CCL5)
Renin (Angiotensinogenase,
Ref)
ROSSecretogranin III
SCFSerglycinSerotoninSomatostatin (Growth hormone inhibiting hormone, GHIH)
SpermidineSpermineSphingosine-1-phosphate (S1P)
Substance PSuperoxide dismutaseSuperoxideTGF-beta1TGF-beta2ThromboxaneTissue plasminogen activator TNF-alphaTNF-related apoptosis-inducing ligand (TRAIL)
Tryptase-alpha
Tryptase-betaI
Tryptase-betaII
Tryptase-betaIII
Tryptase-gamma
Tryptase-delta
TSLPUrocortinVEGF-A (Opens up BBB, Released
6-12 hours after MC stimulation, stress (CRH) and mercury)
VIPNon-IgE mediated mast cell activationNon-IgE mediated mast cell activationhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318920/table/T3/Differential release of mast cell mediators and the pathogenesis of inflammationSourceshttps://www.mastattack.org/mast-cell-mediators/Table 3:
Differential release of mast cell mediators and the pathogenesis of inflammationhttps://www.frontiersin.org/articles/10.3389/fimmu.2014.00569/fullhttps://sci-hub.tw/10.1007/s12016-019-08769-2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003574/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730566/https://sci-hub.tw/10.1007/s00018-010-0587-0https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701915/https://sci-hub.se/10.1134/S000629791612018XMast Cell Function A New Vision of an Old CellMast Cell Cytokine and Chemokine Responses to Bacterial and Viral InfectionTables of MC mediators sorted by CC and CXC structure:
Mast cell: an emerging partner in immune interactionBDNF production in mast cells:
https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.21.4.3670Oxylipin production ratio's vs time, figure 3:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520518/https://sci-hub.se/https://www.nature.com/articles/ni1158https://static-content.springer.com/esm/art%3A10.1038%2Fni1158/MediaObjects/41590_2005_BFni1158_MOESM1_ESM.pdfhttps://www.frontiersin.org/articles/10.3389/fimmu.2011.00037/fullHeat shock proteins:
Ref 1,
Ref 2Factor VIII,
Factor VIII related antigen,
Type VIII collagen,
Oncostatin MEosinophil link 1CC and CXC chemokine overviewOsteoporosis/osteosclerosis:
"On the other hand mast cell products, possibly via tryptase release, were shown to activate osteoblasts and to increase osteoprotegerin production, thereby limiting osteoclast-mediated bone resorption. The authors have no obvious explanation for the findings of both increased and decreased bone formation markers in the same disease." Page 390:
Ref
