Difference between revisions of "2016 Group 5 Project"

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==Future Research==
==Future Research==
- (For pathology- eczema): The precise aetiology of eczema is not completely understood, but current research indicates that it is multifactorial, and the diseases arises from intricate interactions between genetic and environmental factors <ref name="PMID 23752044"><pubmed>23752044</pubmed></ref>
- (For pathology- eczema): The precise aetiology of eczema is not completely understood, but current research indicates that it is multifactorial, and the diseases arises from intricate interaction between genetic and environmental factors <ref name="PMID 23752044"><pubmed>23752044</pubmed></ref>

Revision as of 18:21, 27 April 2016

2016 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Mast Cell



(unfinished)- still working on it!

1878- Mast cells are first identified and named ‘Mastzellen’ by Paul Ehrlich in his doctoral thesis at Leipzig University, Germany. Ehrich described these Mastzellen as being often associated with nerves, blood vessels and glandular ducts. Ehrlich, P. (1878) Beitra¨ge zur Theorie und Praxis der Histologischen Fa¨rbung. Thesis, Leipzig University.

1894- German physician Paul Gerson Unna described mast cells in association with pathology. He noted that the cutaneous lesions called urticarial pigmentosa (UP) were accompanied with an increased number of mast cells below the lesions. Unna PG. Die spezifische färbung der mastzellenkörnung. Monatsh Prakt Dermatol. 1894;19:367–368.

1900- Mast cells are thought to originate from myeloid stem cells. Jolly, M.J. (1900) Clasmatocytes et mastzellen. Compte Rendus Socie´te´ de Biologie (Paris), 52, 437–455.

1939- Erik J. Jorpes identified Mast cells as carriers of heparin. Jorpes JE. The site of formation of heparin. In: Jorpes JE, editor. Heparin: Its Chemistry, Physiology, and Application in Medicine. London, United Kingdom: Humphrey Milford (Oxford Univ Press); 1939. pp. 30–39.

1953- JF Riley described Mast cells as containing histamine. Riley JF, West GB. The presence of histamine in tissue mast cells. The Journal of Physiology. 1953;120(4):528-537.

Late 1950s- Mast cells are understood to play an important role in anaphylaxis. Austin KF, Brocklehurst WE. Anaphylaxis in chopped guinea pig lung. II. Enhancement of the anaphylactic release of histamine and slow reacting substance by certain dibasic aliphatic acids and inhibition by monobasic fatty acids. J Exp Med. 1961;113:541–557.



receptors, microscopy


multifunctional purpose

Origin, differentiation

Mast cells have a hematopoietic origin from the bone marrow. This was shown when a patient suffering from acute myeloid leukaemia underwent an allogeneic bone marrow transplant and after 198 days post transplant mast cells were found. The researchers used Polymerase chain reaction to show that the mast cells showed donor’s genotype. [1]

A mast cell committed precursor has been found in mice by using mast cell specific antibodies to separate them out immunomagnetically. These precursors had mRNA present for some subunits of FCeR1, but did not express the receptor on their surface. They also had mRNA for mast cell specific proteases. [2]

As stated above research suggests in adults mast cells are produced from haematopoietic origins by a committed precursor. However in rat embryos, using similar immunological methods, it has been shown that embryos mature in aorta-gonad-meso-nephros region (AGM) which indicates that in human embryos mast cells may develop outside of the bone marrow [3]

Interestingly mast cells do not differentiate in the bone marrow, their precursor cells travel to extramedullary sites with good vasculature such as connective region of the skin or mucosa of the GIT.[4]

 (draw image of this process). 

The migration of mast cell precursors is tissue specific. It depends on the interaction of the MCP's integrins binding to the corresponding adhesion molecules in the mucosa called MAdCAM-1[5]. The precursors also express chemokine receptors that may play a role in migration [6]

There are both intrinsic and extrinsic factors stimulate Mast cell differentiation from haematopoetic stem cells. The following have been discovered as a result of mice carrying genetic mutations:

Extrinsic and Intrinsic factors influencing Mast Cell Development
Intrinsic Extrinsic
Growth factor Stem Cell Factor have been shown to stimulate mast cell differentiation in vitro [7] . There are also growth factors that inhibit mastopoesis such as thrombopoetin, which acts by down-regulating GATA1[8] Transcription factor MitF - Involved in c-kit expression that influences mast cell specific protease expression[9]
IL-3 from T cells - Induced from T cells as a result of external stimuli [10] . For example: parasite infections. It has been shown to be responsible for Mast Cell survival, developement and maturation in vitro [11] Transcription factors: Gata2 and Gata1[12] - Expressed throughout differentiation in vitro. Mutation in GATA1 gene affects all stages of differentiation of mast cells [13]

Activation, Mediators and degranulation

Activation occurs when two mast cell FceR1 receptors crosslink after antigen binding. Receptor coupling factors such as LYN and SYK phosphorylate other proteins[14] and downstream effects include either: 1) Eicosanoid production: if the MAPK pathway is activated[15] 2) Cytokine production: if Transcription factors are activated by MAPK pathway[16] 3) Degranulation: if intracellular Calcium increases as a result of the phosphorylation cascade[17]

[Diagram gilgillan, 2006][18]

Mast cells produce an array of bioactive molecules. These are released either by vesicular exocytosis or de novo synthesised and secreted through membrane channels. Moon et al.(2014)[19] performed a review of the literature and showed the major stored mediators in one table (see figure _) and the de novo synthesised mediators (see figure__). These mediators have the ability to be mixed in vesicles i.e. b-hexoaminidase and heparine can both be secreted together(heterogenic secretion) or not. Morphometric research shows that the granules that contain mediators result from the fusion of smaller granules (called progranules) that fuse together to form mature granules under regulation of RabGTPases ( this has been shown through genetic mutations of RabGTPases significantly affecting granule size ) [20]


Electron microscopy ultrastructural research suggests that these granules may be secreted in 2 ways: piecemeal degranulation (where only fragments vesicle are selectively exocytosed, then retains granule morphology) or anaphylactic degranulation (fully exocytosed, SNARES mediated, stimulation is FceR1) [21] .

Lipid mediators are de novo synthesised (table 2?) from several places in the cell. Research suggests eicosanoid lipid mediators can be produced in the membrane of Endoplasmic reticuli, nuclear membranes or lipid bodies [22]. They are made via oxidation reactions of long chain fatty acids. These eicosanoids can then take one of two pathways depending on which enzyme acts on them next. The lipoxygenase pathway produces mostly leukotrienes from arachidonic acid and the cyclooxygenase pathway produces prostaglandins. These molecules are involved in inflammation and are secreted via transporters due to their negative charge at physiological pH making them poorly diffusible across the cell membrane [23].


Mast cells are sentinel cells that are found distributed within the connective tissue throughout the body and play an important role in both acute and chronic inflammation. Mast cells that are coated with IgE antibodies specific for certain environmental antigens are triggered to release histamine and other cytokines that induce early vascular changes that are hallmarks of acute inflammation. [24] The immediate responsibility of mast cells is to recognise that infection by a pathogen has occurred, which is achieved by direct recognition of the pathogen by pattern recognition receptors that are activated in response to pathogen-associated molecular patterns (PAMPs). [25] A study conducted by Supajatura et al. demonstrated that the activation of different toll-like receptors (TLR2 or TLR4) by varying PAMPs resulted in differential activation of mast cells evident in lypopolysaccharide stimulation of TLR4 resulting in cytokine release compared to peptidoglycan stimulation of TLR2 receptors resulting in both degranulation and cytokine production.[25] However, mast cells can also act directly on pathogens through the production of reactive oxygen species and phagocytosis, as demonstrated by the engulfing of Fim-H expressing enterobacteria. [26]

Mast cells also play a major role in atopic diseases such as asthma, eczema, anaphylaxis and allergic rhinitis. The basis of these allergic diseases is the activation and binding of the high-affinity immunoglobulin E (IgE) receptor FceR1 to initiate receptor clustering and release of mediators, a signalling network dependent on the strength and type of stimulus. [27] These downstream signal transduction events involve tyrosine phosphorylation which induces the degranulation of mast cells and cytokine and lipid mediator secretion. [28] Furthermore, similarly to neutrophils, mast cells have been seen to produce extracellular traps through the utilisation of the cathelicidin LL-37, histones and tryptase. [29] These three products of mast cells form the structural foundation of the extracellular traps, demonstrated to trap the bacteria S. pyogenes when in close proximity in co-culture in vitro. [29]

Parathyroid bone disease


An increased number of mast cells in the bone marrow can be linked with parathyroid bone disease, most common of which being chronic hyperparathyroidism (HPT). Those suffering from HPT have a disturbed immune function, and mast cells play a major role in innate immunity. Parathyroid hormone (PTH) significantly increases the number of mast cells in those with HPT. There is a 5-fold increase in bone marrow mast cells in those with HPT as compared to the controls. [30] Elevated levels of PTH increase migration of preoestoblastic fibroblasts to the bone surface, and while these generally differentiate into osteoblasts, the increased PTH levels cause terminal differentiation to be impaired. The accumulation of mast cells on bone surfaces as a response to elevated PTH levels lead to this PTH-induced peritrabcular fibrosis, and cause the excessive recruitment of fibroblasts on bone surfaces. [30] An increase in kit- ligand expression causes the build up of mast cells, as it is a potent chemotactic factor for these mast cells. Combined with an increased PDFG-A gene expression, these peritrabcular mast cells promote fibrosis, ultimately leading to bone disease. [30]



Atopic dermatitis, or eczema, is a chronic pruritic inflammatory skin disease [31] characterised by high Immunoglobulin E (IgE) responsiveness. [32] While the aetiology of the disease is not fully understood, it is caused due to a interaction between environmental and genetic factors, particularly involving high levels of IgE. [31] IgE is produced in response to common antigens, and is bound to the surface of mast cells, [32] which infiltrate the skin lesions of the disease. [31]. Thus, an accumulation of mast cells is required for maximum skin inflammation during eczema. (x) The IgE proceeds to bind to FceRI, and consequently has a positive effect on mast cell survival and activation.[31]

In eczema, the impaired skin barriers allow allergens easy access into the dermal and epidermal layers. The allergens are taken up by Langerhans cells, and these cells mature in order to present the allergens to helper T cells in the lymph nodes. Activated Th2 cells migrate once again to the skin sites that are re-exposed to the allergens, and subsequently recruit mast cells which cause the characteristic tissue damage and irritation of eczema. [31]

Mast cell chymase (MCC) is also involved in this condition, and is a serine protease which accumulates in the dermis of the skin. An increase in MCC promotes skin inflammation and eczema. The polymorphism of MCC is significantly associated with the occurrence of eczema, and different variations of this MCC is one source of genetic risk for the condition. [32]

Future Research

- (For pathology- eczema): The precise aetiology of eczema is not completely understood, but current research indicates that it is multifactorial, and the diseases arises from intricate interaction between genetic and environmental factors [31]


Atopy: predisposition to developing IgE associated allergic diseases.

Atopic disease: a clinical condition caused by an allergy

Allergic Rhinitis: commonly known as hay fever

Immunoglobulin E (IgE):antibodies produced by the body's immune system

FceR1: high affinity Immunoglobulin E receptor

  1. <pubmed>7949167</pubmed>
  2. <pubmed>15718418</pubmed>
  3. <pubmed>23505443</pubmed>
  4. <pubmed>17468237</pubmed>
  5. <pubmed>11696590</pubmed>
  6. <pubmed>15705791</pubmed>
  7. <pubmed>7524746</pubmed>
  8. <pubmed>17468237</pubmed>
  9. <pubmed>18839840</pubmed>
  10. <pubmed>7524746</pubmed>
  11. <pubmed>3002522</pubmed>
  12. <pubmed>8562971</pubmed>
  13. <pubmed>12566412</pubmed>
  14. <pubmed>16470226</pubmed>
  15. <pubmed>16470226</pubmed>
  16. <pubmed>16470226</pubmed>
  17. <pubmed>16470226</pubmed>
  18. <pubmed>16470226</pubmed>
  19. <pubmed>25452755</pubmed>
  20. <pubmed>24696234</pubmed>
  21. <pubmed>1483068</pubmed>
  22. <pubmed>1219072</pubmed>
  23. <pubmed>9506966</pubmed>
  24. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  25. 25.0 25.1 <pubmed>12021251</pubmed>
  26. <pubmed>8120397</pubmed>
  27. <pubmed>12782712</pubmed>
  28. <pubmed>12089510</pubmed>
  29. 29.0 29.1 <pubmed>18182576</pubmed>
  30. 30.0 30.1 30.2 <pubmed>20200965</pubmed>
  31. 31.0 31.1 31.2 31.3 31.4 31.5 <pubmed>23752044</pubmed>
  32. 32.0 32.1 32.2 <pubmed>8774571</pubmed>