Mast Cell Activation Syndrome (MCAS): Difference between revisions

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3 types of mat cell activation: <ref>https://tmsforacure.org/overview/mast-cell-activation-syndrome-variants/</ref>
3 types of mat cell activation: <ref>https://tmsforacure.org/overview/mast-cell-activation-syndrome-variants/</ref>


# Monoclonal (primary)-
# Monoclonal (primary):
#* This is rare
#* This is a rare form of the dysfunction.
#* The result of over-profiletarion of mast cells and usually mutations in the KIT gene or aberrant expression of the CD25 or CD2
#* It is the result of over-profiletarion of mast cells and usually involves mutations in the KIT gene or aberrant expression of the CD25 or CD2.
#* can also be a result of mastocytosis
#* Monoclonal mast cell activation syndrome can also be a result of mastocytosis.
# Secondary (non-clonal)
# Secondary (non-clonal):
#* Normal level of mast cell production
#* There is a normal level of mast cell production in the tissues.
#* Mast cells are inappropriately activated as an allergic reaction to typically harmful triggers createing either an IgE or non-IgE mediated response
#* Mast cells are inappropriately activated as an allergic reaction to typically harmful triggers creating either a heightened IgE or non-IgE mediated response.
# Idiopathic- no defined allergic or autoimmune cause has been identified
# Idiopathic:
#* Non-clonal/secondary idiopathic MCAS
#* No defined allergic or autoimmune cause has been identified for the diagnosis of idiopathic mast cell activation syndrome.
#* this is potentially more prevalent than the other forms 1 and 2 above
#* It is a non-clonal/secondary idiopathic MCAS.
#* This is likely more prevalent than the other forms ( 1 and 2 above) of mast cell activation syndrome.




MCAS also has correlations with other orthopedic diseases.  While MCAS has been recognized for many decades, there is still much research needed in order to understand the causes, triggers, and the many potential systemic connections.
 
MCAS also has correlations with other orthopedic diseases.  While MCAS has been recognized for many decades, there is still much research needed in order to understand the causes, triggers, and the many potential systemic effects.


== Clinically Relevant Anatomy ==
== Clinically Relevant Anatomy ==


A mast cell is a granule dense cell that lives near blood vessels in the mucosa and in the connective tissues. It is produced in the bone marrow, and is found in great numbers in the GI tract, skin, and the lining of the airway. the granules fontina mediators which respond to allergens and are responsible for the reactions and anaphylaxis responses. (TMS) the granules all have membranes surrounding them or sacs where mediators are contained (<nowiki>https://tmsforacure.org/overview/</nowiki>)
Mast cells are granular cells that originate from the bone marrow and are distributed throughout the body living near blood vessels, mucosa, lymph, and connective tissues. <ref>Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.</ref>They reside in a wide variety of tissues including but not limited to skin and connective tissues, the GI system, and the respiratory system. Mediators are found in the membranes surrounding the granules  are released into the environment as a response to allergens causing an inflammatory response as well as recruiting other immune cells to be released in the region. The intensity of the allergic reaction can vary enormously.  It can be as small as the red bump around a mosquito bite or a full anaphylactic reaction.<ref>Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25.</ref><ref>Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013 Apr;68(4):417-24.</ref>
 
Mast cells are granular cells that originate from the bone marrow and are distributed throughout the body. <ref>Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.</ref>They reside in a wide variety of tissues including but not limited to skin and connective tissues, the GI system, and the respiratory system. They can also be found around blood vessels and lymphoid organs. Mediators such are found in the membranes surrounding the mast cell and are released into the environment causing an inflammatory response and recruiting other immune cells to be released in the region. The eventual release of cytokines and chemokines then mediate the inflammatory response.<ref>Cardamone C, Parente R, Feo GD, Triggiani M. Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett. 2016 Oct;178:10-4. doi: 10.1016/j.imlet.2016.07.003. Epub 2016 Jul 5. PMID: 27393494.</ref>  


The survival of the mast cell is dependent initially on the binding of a stem cell factor to KIT (a transmembrane tyrosine kinase receptor) <ref>Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.</ref>  and then on its ability to adapt using signals in its environment to the specific phenotype for the tissue where they reside. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1. <ref>Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011 Oct 19;12(11):1035-44. doi: 10.1038/ni.2109. PMID: 22012443; PMCID: PMC3412172.</ref>  
The survival of the mast cell is dependent initially on the binding of a stem cell factor to KIT (a transmembrane tyrosine kinase receptor) <ref>Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.</ref>  and then on its ability to adapt using signals in its environment to the specific phenotype for the tissue where they reside. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1. <ref>Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011 Oct 19;12(11):1035-44. doi: 10.1038/ni.2109. PMID: 22012443; PMCID: PMC3412172.</ref>  


Mast cells coordinate an immune response to pathogens through surface receptors, receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins.  When the cells are activated they synthesize more mediators and release histamine and proteases which leads to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemo lines.
Mast cells coordinate an immune response to pathogens through surface receptors, receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins.  When the cells are activated they synthesize more mediators and release histamine and proteases which leads to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemo lines.Once the reaction has taken place cytokines and chemokines are released to reverse the inflammatory process and restore homeostasis.<ref>Cardamone C, Parente R, Feo GD, Triggiani M. Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett. 2016 Oct;178:10-4. doi: 10.1016/j.imlet.2016.07.003. Epub 2016 Jul 5. PMID: 27393494.</ref>


2 types of MC:
2 types of MC:

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Introduction/Definition[edit | edit source]

Mast Cell Activation Syndrome (MCAS) is one of several Mast Cell diseases (MCD) . It is particularly hard to identify and is often misdiagnosed or left unreckogonized for many years. It prenests with a wide range of differing symptoms and can be the result of many different triggers that are not always consistent across the population of these infected and can be inconsistent even within the individual who suffers from MCAS.

Mast cell activation is a normal response in our bodies to the introduction of potentially harmful triggers. The activation of the mast cells can be a result of an IgE mediated response or a non- IgE mediated response [1]the reactions of which, in both cases can vary from mild to severe and include a wide range of varied symptoms. [2] Mast cell Activation Syndrome occurs when there is an over-reaction and/or inappropriate reaction of the mast cells to a stimuli, known or unrecognized, that can not be explained by any other disease.

3 types of mat cell activation: [3]

  1. Monoclonal (primary):
    • This is a rare form of the dysfunction.
    • It is the result of over-profiletarion of mast cells and usually involves mutations in the KIT gene or aberrant expression of the CD25 or CD2.
    • Monoclonal mast cell activation syndrome can also be a result of mastocytosis.
  2. Secondary (non-clonal):
    • There is a normal level of mast cell production in the tissues.
    • Mast cells are inappropriately activated as an allergic reaction to typically harmful triggers creating either a heightened IgE or non-IgE mediated response.
  3. Idiopathic:
    • No defined allergic or autoimmune cause has been identified for the diagnosis of idiopathic mast cell activation syndrome.
    • It is a non-clonal/secondary idiopathic MCAS.
    • This is likely more prevalent than the other forms ( 1 and 2 above) of mast cell activation syndrome.


MCAS also has correlations with other orthopedic diseases. While MCAS has been recognized for many decades, there is still much research needed in order to understand the causes, triggers, and the many potential systemic effects.

Clinically Relevant Anatomy[edit | edit source]

Mast cells are granular cells that originate from the bone marrow and are distributed throughout the body living near blood vessels, mucosa, lymph, and connective tissues. [4]They reside in a wide variety of tissues including but not limited to skin and connective tissues, the GI system, and the respiratory system. Mediators are found in the membranes surrounding the granules are released into the environment as a response to allergens causing an inflammatory response as well as recruiting other immune cells to be released in the region. The intensity of the allergic reaction can vary enormously. It can be as small as the red bump around a mosquito bite or a full anaphylactic reaction.[5][6]

The survival of the mast cell is dependent initially on the binding of a stem cell factor to KIT (a transmembrane tyrosine kinase receptor) [7] and then on its ability to adapt using signals in its environment to the specific phenotype for the tissue where they reside. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1. [8]

Mast cells coordinate an immune response to pathogens through surface receptors, receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins. When the cells are activated they synthesize more mediators and release histamine and proteases which leads to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemo lines.Once the reaction has taken place cytokines and chemokines are released to reverse the inflammatory process and restore homeostasis.[9]

2 types of MC:

  1. MCT  - connective tissue, skin, peritoneal cavity (T for tryptase in the granules). They express interleukin-5 and 6
  2. MCTC- gut and respiratory mucosa (TC for tryptase and chymase). They express interleukin-4 **ADD REFERENCE**


Common mediators released in the mast cell response:

  • Histamine
  • Leukotrines
  • Prostaglandins
  • Tryptase
  • Interleukins
  • Heparin
  • Tumor necrosis factor

Mechanism / Pathological Proces[edit | edit source]

Mast cells coordinate an immune response to pathogens through surface receptors, receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins.

When the cells are activated they synthesize more mediators and release histamine and proteases leading to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemokines. Mast cell activity is the result of the defense process of the body and is triggered and commonly seen in food allergies, venom allergies from insect bites, asthma, and at its extreme leads to anaphylaxis.

Mast cells, in addition to the allergic response, have many other functions in the cell. They are responsible for homeostasis, phagocytosis, cytokine and chemokine production, and the immediate release of vasoactive substances.[10] Mast cells are found within tissues as opposed to other immune cells which are located outside of cells. They are surrounded by nerves, blood vessels, and lymphatic vessels.

Clinical Presentation[edit | edit source]

There are a wide variety of clinical symptoms associated with Mast Cell Activation Syndrome. The symptoms can vary over time and can be a large range of variable symptoms. Symptoms may also change within an individual both in intensity with exposure to a specific stimulant and with exposure to new stimuli. Because of the amount of mast cells in the Gastrointestinal tract, there are often a host of GI symptoms also present.

There are also several different mediators that can be released by the mast cell which provide varied symptoms.

Common Complaints[edit | edit source]

Some of the most common complaints and symptoms include:

  • Flushing, itching, and skin rash, skin lesions, and/ or redness
  • fatigue , headaches, body aches
  • osteoporosis, bone pain
  • Gastrointenstinal symptoms:
    • bloating, pain, nausea, diarrhea, GERD, IBS symptoms
  • throat swelling, shortness of breath
  • cramping
  • weight loss and enlarged lymph nodes
  • problems with clotting and bleeding

Correlates[edit | edit source]

There have also been many non-specific correlates to MCAS, and while there is mounting evidence in favor of correlations between these issues and MCAS, more research is necessary to fully understand the processes with these symptoms and conditions.

  • Nasal congestion
  • Neurological symptoms
  • Fatigue and Fibromyalgia like pain
  • Rashes
  • Psychiatric and neurological disorders
  • Elhers-Danlos syndrome
  • Postural Orthostatic tachycardia syndrome (POTS) [11]
  • Celiac disease and gluten intolerances[12]
  • Autoimmune disorders
  • Hypotension[13]


Because MCAS is episodic and unpredictable and the range of severity of triggers can change over time and in the same individual, the identification of these correlates in the diagnosis of MCAS is not recommended.

Diagnostic Procedures[edit | edit source]

add text here relating to diagnostic tests for the condition
Diagnosis

3 criterion for dx: (1, 3, 4)

  1. Systemic symptoms (involving a minimum of 2 organ systems) of mast cell activation that are severe and recurrent (1)
  2. Noted activation or elevated mast cells

Thresholds for diagnosis are a rise in cell mediators to the following values:

-serum Tryptase: 20% above baseline plus 2ng/ml (1)

-or 24 hour urine test:

urinary n-methyl histamine or other histamine metabolites

-    prostaglandin D2  or its metabolite 11 (beta)-prostaglandin F2(alpha)

-     leukotrienes E4 or MIAA

  1. -a response to treatment with mast cell stabilizer or mast cell mediator therapy, mast cell blockers like histamine receptor blockers
  1. -monoclonal (primary)- abnormal mast cells are identified and but systemic mastocytosis criteria have not been met.  The mutation detected is: KIT D816V and mast cells aberrantly display CD25 in most cases. (1,3,4)
    1. Confirmed mastocytosis with the mutation
    2. Or with only 2 minor SM criteria???  (1)
  2. Secondary- MCAS occurs as an indirect response to another disease process as in an infection or autoimmune disease wtih an IgE mediated allergy or other hypersensitivity reaction
    1. There is another immunological disease present
    2. There is no mutation KIT D816V (CD25+)or neoplasticism (1,3) Mast cells
      1. IN this case treatment would need to focus on both the underlying disease and the MCAS
  3. Idiopathic-MCAS reactions are clearly present abut htere ie no known cause and any secondary criteria: (1)
    1. No disease related
    2. No neoplasticism MCs
    3. No IgE allergy
      1. Treatment is aimed at controlling MCA and anaphylaxis

While these categories have been set, many people suffer from mre than one type of mast cell activation which can lead to severe life threatening reactions and anaphalyxis (1)

DX MCAS:

  • challenging to dx:

4 criteria most commonly used:

  1. Clinical symptoms commonly associated with MCAS: (https://tmsforacure.org/wp-content/uploads/MCD-Symptoms-Infographic.pdf)
    1. Ear/nose/ throat
    2. GI
    3. Skeletal: bone/Musica pain, osteoporosis and osteopenia,
    4. cutaneous: hives, flushing of the face/neck/chest, skin rashes, itching without rash
    5. Cardiovascular:
      1. Lightheadedness, syncope, rapid heart rate, chast pain, low BP, HBO at the start of a reaction, blood pressure instability
    6. Gynecological:
      1. Uterine cramps
      2. Bleeding
    7. Urinary
      1. Bladder irrationality
      2. Frequent urination
    8. Anaphylaxis
    9. Angiodema (swelling)

Testing and Measures[edit | edit source]

  1. Testing for mediator release
    1. Tryptase serum testing: only diagnostic mediator tests for MCAS with a specified increase from baseline to dx. Sample Needs to be collected within 4 hours of symptomatic episode, and then compared to baseline 24-48 hours after. A negative result does not rule out MCAS
    2. Urinary tests:
      1. N-methylhsitamine and prostaglandins D2, DM, F2a (5)
  2. Test by treatment
    1. The theory that if someone responds to a treatment for MCAS that the person actually has it

Urine testing for

Testing: timing needs to be during flare, 24 urine histamine prostaglandins with case stories and historical sxs

Endoscopy 

(see Outcome Measures Database)

Management / Interventions[edit | edit source]

Management interventions

Treatments:

Medications:

-H1 antihistamines: (1st generation H1 antihistamines- hydroxyzine hydrochloride, diphenhydramine, chloroheniramine, doxepin hydrochloride, ketotifen, 2nd generation H1 antihistamines (usually cuase less drowsiness-fexofenadine, loratidine, desloratidine, levocetirixine, cetirizine) may stabilize the mat cells and reduce the acute symptoms of allergy: itching, rashes, flushing and headaches, brain fog

-H2 antihistamines (nizatadine, famotidine, cimetidine: also for general mast cell stability but may also help with GI symptoms

-mast cell stabilizers (oral chromodynamics sodium, ketotifen, Quercetin and luteolin) and: GI symptoms and brain fog

-Leukotrienes inhibitors (montelukast, zafirlukast, zileuton)- mast cell stability and respiratory symptoms

-aspirin therapy for elevated prostaglandins and will help with brain fog, bone pain and flushing

-anti IgE therapy (omalizumab and others) for overall stability and asthma, anaphylaxis (TMS chart)

Range of triggers can be reduced when the rage of sxs has been decreased

PPI have been helpful

Treatment for severe presentations of MCAS may need lifelong immunotherapy omalizumab (anti- IgE) therapy or pharmacological therapy (1)

Differential Diagnosis[edit | edit source]

  1. Differential diagnosis: (1,3)
    1. Infectious diseases
    2. IBS
    3. Adrenal insufficiency
    4. Cardiovascular disorders  and myocardial infarction
    5. Phychological factors
    6. Oncologic disorders
    7. Endocrine dysfunctions
    8. Toxicity

For reference the other mast cell diseases: (3)

-Systemic Mastocytosis (SM)

-cutaneous mastocytosis (CM)

-Smoldering mastocytosis (SSM)

-hereditary alpha tryptasemia (HaT)

Confirmed MCAS cases

Celiac disease testing 87% had +

Dietary changes

Adding to GI list for differential dx

WHy the GI system is so affected:

Mast cells are responsible in the GI tract for:

-immune regulation: adaptive, innate

-epithelial Integrity:ion/water secretion, permeabilty

-endothelial function: vascular permeability, coagulation, blood flow

-Microbial defense: bacterial, viruses, parasites

-tissue remodeling: wound healing, fibrosis

-neurological activity: peristalsis and pain persecption

Adults: bloating, pain, diarrhea, nausea present for many years

Mistaken for IBS 40% dx with IBS

Bloating,

Pain, diarrhea

Nausea

Children:

Pain GERD constipation

Reflux

Dyspepsia

Nausea

Diarrhea

Committing

Dysphasia

Bloating

Pain

Leading to inflammation and allergic type responses

HIgh presence of mast cells in the GI tract and some GI symptoms are commonly activated with MCAS.

Most GI MD do not test for MCAS

Activators: food, stress, exercise, environmental allergens, infection, medication

  1. Allergic sxs
  2. 2. GI next main set of sxs for med referral

text here relating to the clinical presentation of the condition

text here relating to the differential diagnosis of this condition

Relevance in Physiotherapy[edit | edit source]

Because there are many possible triggers for MCAS, it is important that the fisioterapist recognize and help those with suspected disease avoid potential triggers both in the clinic and in everyday life.

Some of the most relevant triggers in the rehabilitier facility and scope include: exercise, medication ( opioids, NSAIDS, local anesthetics, changes in body temperature, friction, and vibration.

Other common triggers include: : food, stress, environmental allergens, infection, and venoms (bee/wasp, snake, spider, fire ant, etc).

Elhers-Danlos Syndrome (EDS) and Hypermobility Sprectum disorders (HSD)[edit | edit source]

Because mast cells are so intertwined in the connective tissues where they reside, there is the possibility that they play a distinct role in autoimmune dysfunctions, although the link between the two is still not clear. In hypermobility dysfunctions the chronic release of mast cell factors may be the link between the hypermobility disorder and the autoimmune disorder. There are many shared clinical features between mast cells disease and hEDS/HSD because of the direct relationship of Mast cells to the connective tissues that there may be a relationship worth noting. (6) this would allow the PT to refer and identify patients sooner.

The connection between MCAS and hEDS/HSD may be due to the presence of tryptase anbd histamine (as well as other mast cell mediators) who also play a role in promoting the proliferation of fibroblasts and collagen production. (6)(7)

Urticaria[edit | edit source]

prevelant in EDS and MCAS- basophils and mast cells are mostly responsible for the urticaria/flushing (6,8,9) but there is no direct cause found as of yet, and may be just a result of the mast cell disease alone.

There have been concernsections drown between the pathogenicity of Lupus erythematosus (SLE), chronic spontaneous urticaria as a result of Mast cell dysfunction.

There has also been a connection/involvement of Mast cells in multiple sclerosis and rheumatoid arthritis. 10,11,12

Rheumatoid arthritis[edit | edit source]

   Chronic autoimmune inflammatory arthritis and immune cells contribute to the RA pathogenicity. Inflammatorion ofsynovuim of joints (small more common than large) and synovial hyperplasia with various immune cells in the synovium: T cells, B cells, and innate immune cells including mast cells in RA synovitis. (13)

In a study that showed histologic evidence that increased mast cells were present in the synovium of those who also presented with RA versus a control group. (14) there has also been evidence of different phenotypes of synovitis according to the density of the MC infiltration in the synovium (8) several studies show the increased number of mast cells or IgE mediated  in RA: both in the synoviumleading to degradation of the synovium of the joint as well as cartilage and bone in some cases. All of the studies (16),


Links for PT

  • linked to connective disorders especially hEDS (6)
    • Mast cell activation has been shown to play a role in the disruption of connective tissue integerty through the activity of its mediators including histamine and tryptase affecting multiple organ systems which leads to mast cells activitaion disorders.

Resources
[edit | edit source]

add appropriate resources here

References[edit | edit source]

  1. ↑ Akin C. Mast cell activation syndromes. J Allergy Clin Immunol. 2017 Aug;140(2):349-355. doi: 10.1016/j.jaci.2017.06.007. PMID: 28780942.
  2. ↑ Anvari S, Miller J, Yeh CY, Davis CM. IgE-Mediated Food Allergy. Clin Rev Allergy Immunol. 2019 Oct;57(2):244-260. doi: 10.1007/s12016-018-8710-3. PMID: 30370459.
  3. ↑ https://tmsforacure.org/overview/mast-cell-activation-syndrome-variants/
  4. ↑ Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.
  5. ↑ Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25.
  6. ↑ Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013 Apr;68(4):417-24.
  7. ↑ Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, Befus AD. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010 Mar;3(2):111-28. doi: 10.1038/mi.2009.136. Epub 2009 Dec 30. PMID: 20043008.
  8. ↑ Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011 Oct 19;12(11):1035-44. doi: 10.1038/ni.2109. PMID: 22012443; PMCID: PMC3412172.
  9. ↑ Cardamone C, Parente R, Feo GD, Triggiani M. Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett. 2016 Oct;178:10-4. doi: 10.1016/j.imlet.2016.07.003. Epub 2016 Jul 5. PMID: 27393494.
  10. ↑ 1.Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, Nedoszytko B, Siebenhaar F, Sperr WR, Oude Elberink JNG, Butterfield JH, Alvarez-Twose I, Sotlar K, Reiter A, Kluin-Nelemans HC, Hermine O, Gotlib J, Broesby-Olsen S, Orfao A, Horny HP, Triggiani M, Arock M, Schwartz LB, Metcalfe DD. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. 2019 Apr;7(4):1125-1133.e1. doi: 10.1016/j.jaip.2019.01.006. Epub 2019 Feb
  11. ↑ Matito A, Escribese MM, Longo N, Mayorga C, Luengo-Sánchez O, Pérez-Gordo M, Matheu V, Labrador-Horrillo M, Pascal M, Seoane-Reula ME; Comité de Inmunología de la Sociedad Española de Alergología e Inmunología Clínica (SEAIC). Clinical Approach to Mast Cell Activation Syndrome: A Practical Overview. J Investig Allergol Clin Immunol. 2021 Dec 21;31(6):461-470. doi: 10.18176/jiaci.0675. Epub 2020 Feb 5. PMID: 33541851.
  12. ↑ Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. New England Journal of Medicine. 2015 Jul 9;373(2):163-72.
  13. ↑ Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, Nedoszytko B, Siebenhaar F, Sperr WR, Oude Elberink JNG, Butterfield JH, Alvarez-Twose I, Sotlar K, Reiter A, Kluin-Nelemans HC, Hermine O, Gotlib J, Broesby-Olsen S, Orfao A, Horny HP, Triggiani M, Arock M, Schwartz LB, Metcalfe DD. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. 2019 Apr;7(4):1125-1133.e1. doi:
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