Mediators of Inflammation

Mediators of Inflammation / 2015 / Article

Review Article | Open Access

Volume 2015 |Article ID 246126 | 8 pages |

Mast Cell and Autoimmune Diseases

Academic Editor: Teresa Zelante
Received16 Dec 2014
Revised25 Mar 2015
Accepted25 Mar 2015
Published05 Apr 2015


Mast cells are important in innate immune system. They have been appreciated as potent contributors to allergic reaction. However, increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases.

1. Introduction

If the immune system fails to recognize self- from non-self-molecules, self-reactive lymphocytes can be activated by innate immune cells and lead to an autoimmune response [1]. Genetics, hormonal influences, and environment play important roles in autoimmune diseases. Some of the factors have been identified [24]. However, the specific determinants that initiate an autoimmune response and allow it to be sustained and cause pathology are still unknown. Autoimmune diseases and allergic diseases share important features. Both of them are the result of “hypersensitive” immune responses directed toward inherently harmless antigens [5]. Besides, many diseases models that we now know are regarded as autoimmune diseases, such as “experimental allergic” neuritis, encephalomyelitis, orchitis, uveitis, and glomerulonephritis [6]. It is accepted that the cells of the adaptive immune system are the directors of autoimmune responses [7]. In addition, innate immune cells are critical for sustaining the response that leads to pathology [813].

Mast cells (MCs) are first described by Paul Ehrlich in 1878 [1]. They have been viewed as effectors in IgE-mediated allergic or antiparasitic responses; however, researches in the last two decades have found that MCs are also involved in innate immunity and inflammation by releasing a large array of inflammatory mediators [14, 15]. These mediators include compounds such as histamine and MC specific proteases prestored in cytoplasmic secretory granules (SGs) and newly synthesized lipid mediators such as leukotrienes or prostaglandins or a variety of cytokines, chemokines, and growth factors [16].

The idea that MCs are involved in the initiation and sustaining events of autoimmunity is based on abundant data from studies of both human disease and animal models [1719].

2. Mast Cells

MCs were discovered by Friedrich von Recklinghausen in 1863 and named by Paul Ehrlich in 1878 [20]. Connective tissue is derived from undifferentiated mesenchymal cells. During the first 100 years after the discovery, it was believed that MCs were a component of connective tissue, functioned, and died within connective tissue [21]. Furthermore, MCs complete differentiation in connective tissue [21]. Until the 1980s, in vivo and in vitro evidence showed that MCs originate from hematopoietic stem cells, but the mast cell-committed precursors (MCPs) have not been identified [21, 22]. In the work of Chen et al., MCPs in the bone marrow of adult mice were identified. They are identified by the phenotype Lin c-Kit+ Sca-1 Ly6cFcεRIα CD27β7+ T1/ST2+ [23]. In addition, the experiment strongly suggests that MCPs are the progeny of multipotential progenitors (MPPs) other than common myeloid progenitors or granulocyte/macrophage progenitors [23].

Development of MCs from MPPs does not need cell division [21]. It is known that MCs leave the bone marrow as immature cells and they mature via abundant cytokines in the local tissue microenvironment [20, 24]. For example, nerve growth factor (NGF) is well known as an important MCs growth factor [25]. However, MCs show plasticity [20]. Moreover, mature MCs show extensive proliferation potential [21].

The granules of MCs can be stained metachromatically purple with Toluidine Blue and it is routine staining for the demonstration of MCs [20, 26]. MCs are defined as connective tissue mast cells (CTMCs) and mucosal mast cells (MMCs) by the histamine, cytokines, and proteolytic enzyme which MCs store [20]. In addition to innate and acquired immunity, MCs play important role in bacterial infection and autoimmunity [24, 27, 28]. MCs can secrete the contents of preformed cytoplasmic secretory granules (SGs) while encountering certain stimulants. For MCs, this process is fundamental to their role in innate and acquired immunity [29]. Various molecules are able to activate MCs.

3. Interactions between Mast Cells and Other Cells

MCs can work with other cells like T and B lymphocytes to enhance activation and migration by cell-cell interactions or secreted products [18, 19]. Recently, the role of the interactions between mast cells and other cells in autoimmune diseases is becoming apparent [30].

3.1. Interaction among Mast Cells, T Regulatory Cell (Treg), and Th17 Cells

Treg cells are defined as CD4+CD25+FoxP3+ and are known to suppress T effector cell response. Thus Treg cells can induce tolerance and control autoimmunity. MCs and Treg cells constitutively express OX40L and OX40, respectively. Therefore, mast cell-Treg cell interactions are in an OX40-dependent way. Gri et al. found that Treg cells directly inhibited FcεRI-dependent MC degranulation through cell-cell contact requiring OX40-OX40L interaction [31] (Figure 1). Kashyap’s group showed that coculture with Treg enhanced cytokines production by MCs [32]. In addition, MCs can also suppress Treg activity in an OX40L-independent way [30]. However, the relationship between MCs and Treg cells needs to be further explored in autoimmunity.

Th17 cells are CD4+ T cells. At the meantime, they are defined by the expression of the transcription factor RORγt and cytokines IL-17. As Th1 cells, Th17 cells are involved in the mouse models of MS and RA. The combination of TGFβ, IL-6, IL-21, IL-23, and IL-1β contributes to the differentiation of Th17 from a naïve CD4+ T cell. TGFβ is essential for the development of Treg cells, but it is inhibited by IL-6. MCs can express TGFβ, IL-6, IL-21, and IL-23 under some condition and promote Treg and Th17 cell differentiation and plasticity [30]. It is interesting that MCs counteract Treg cells suppression through IL-6 and OX40-OX40L axis towards Th17 cell differentiation [33] (Figure 1).

3.2. Interaction between Mast Cells and B Cell

MCs express a variety of B cell-modulating molecules and immunoglobulin (Ig) receptors [30]. MC FcRs include IgE and IgG receptors [34]. Depending upon the type of MCs, IgG-antigen complexes may activate MCs [34]. Conversely, the coengagement of IgG and IgE receptors inhibits cells activation [34]. Increasing data has been established indicating that MCs play critical roles in IgG-dependent tissue-specific autoimmune diseases [34]. Low amounts of MCs are effective in influencing B cell survival and proliferation in vitro through cell-cell contact and MC-derived IL-6 expression whatever state the MC activation is in [35]. Furthermore, MCs can promote B cells to differentiate into CD138+ plasma cells secreting IgA and it is dependent on CD40-CD40L expressed on B cells and MCs, respectively [35] (Figure 2).

4. MCs and Autoimmune Diseases

It is well known that T cells are important in directing and initiating the immune response in the target tissues [30]. In addition, other cells also play an important role in aggravating the inflammatory damage [30]. Furthermore, there are several examples of MCs association with autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), insulin-dependent diabetes mellitus (IDDM), bullous pemphigoid, chronic idiopathic urticaria, and experimental vasculitis [3639]. Here we take MS, RA, IDDM, and chronic urticaria (CU) for example and summarize the role of MCs in the autoimmune diseases.

4.1. MCs and MS

Mostly, the interest in the role of MCs in the initiation and propagation of autoimmune disease comes from studies on MS [40].

MS is a progressive demyelinating disease. Widespread inflammatory lesions present in the brain and spinal cord of patients with MS [30]. The symptoms of MS contain visual disturbances, bowel and bladder incontinence, and sensory and motor dysfunction [30]. Furthermore, patients with MS are found to lose memory, impair attention, and slow information processing [41, 42]. Experimental autoimmune encephalomyelitis (EAE) is a murine model of MS. Similar to MS, the symptoms of EAE resulted from breach of the blood-brain barrier (BBB) which allows inflammatory cells to infiltrate into the central nervous system (CNS) and destruct myelin and oligodendrocytes [30]. CD4+ T cells, including IFN-γ-secreting T helper 1 cells (Th1), IL-17-producing T helper 17 cells (Th17), and IL-9-producing T helper 9 cells (Th9), contribute to the pathogenic autoimmune response in EAE [43]. However, the roles of these cells in MS are still unclear [44].

There are MCs in the leptomeninges, the choroid plexus, thalamus, hypothalamus, and median eminence [24]. Similar to CTMCs and MMCs, brain mast cells (BMCs) can be identified morphologically by Toluidine Blue staining mostly. Moreover, histamine fluorescence with ο-phthaldialdehyde is able to show BMCs in the leptomeninges, thalamus, and hypothalamus. And histamine immunohistochemistry can show BMCs in the median eminence [4548]. However, many BMCs are stained with Sudan Black which is distinct from CTMCs or MMCs [20]. Additionally, the ultrastructural appearance of activated BMCs is different from that of CTMCs because it is primarily characterized by intragranular changes without typical compound exocytosis [49, 50]. They may regulate vascular permeability and inflammatory cell entry in the brain parenchyma [51]. Moreover, there is interaction between functional MCs and neuron in the brain and it can mediate neuroinflammation.

Kruger et al. have observed MCs within the demyelinated plaques in the brains of 7 patients with MS [26]. Moreover, MCs were found mostly located in close connection with small vessels [26]. The data suggest that MCs playing a role in MS have continued to accumulate [30]. It is reported that mast cell deficient mice fail to develop EAE [52]. As in MS, an increase of MCs is also found at sites of inflammatory demyelination in the brain and spinal fluid of EAE [53]. MCs are associated with FcεR, the histamine-1 (H1) receptor, and tryptase [24]. Elevated levels of tryptase are present in the cerebrospinal fluid of MS patients and gene array analyses of MS reveal overexpression of genes encoding FcεR, H1 receptor, and tryptase [24, 54]. BMCs do not express their surface growth factor (c-kit) receptor normally but do so during EAE [55]. Several studies reveal that mast cell-derived mediators can increase BBB permeability [56, 57]. Products produced by MCs can enter neurons and this indicates a new brain-immune system [58]. Rat BMCs can produce tumor necrosis factor (TNF) and TNF take part in both brain inflammation and increased vascular permeability [59, 60]. An increased mast cell tryptase in the cerebrospinal fluid (CSF) of MS patients can activate peripheral mononuclear cells to secrete TNF, IL-6, and IL-1 and stimulate protease-activated receptor (PAR) which leads to microvascular leakage and widespread inflammation [54, 61, 62]. Besides, human MCs will secrete matrix metalloproteinase- (MMP-) 9 and IL-6 while contacting activated T cells [63]. So we proposed that MCs may be an underestimated contributor to the demyelinating process of MS.

All in all, MCs participate in the pathogenesis of MS in many different ways [24]. Firstly, they release cytokines/chemokines to recruit and activate T cell/macrophage after stimulation. Secondly, MCs present myelin antigen to T cell. Furthermore, MCs disrupt the BBB to allow activated T cells to infiltrate to brain and target in myelin basic protein (MBP). What is more, MCs damage myelin and then release fragments resulting in stimulating secretion of tryptase. In turn, it enhances demyelination and induces further inflammation through stimulation of PAR possibly. As a result, MCs can be a possible therapeutic target for MS. In vitro, on one hand, mast cell proteases degrade myelin protein, while on the other hand, myelin stimulates mast cell degranulation directly [64, 65]. Therefore, treatment with inhibitors of mast cell degranulation may be a good way to inhibit MS. Dimitriadou et al. found that hydroxyzine was able to inhibit EAE [66].

4.2. MCs and RA

RA is a systemic and chronic inflammatory disease that affects about 1% of the population worldwide [30, 67]. After decades of research, we have found that T and B lymphocytes, neutrophils, monocytes, and vascular endothelium play the roles in RA [67]. However, the pathogenesis and mechanism of RA are still unclear [67]. Rodent models of autoimmune diseases are of great use to study the pathogenic process of diseases. There are a number of models of RA including K/BxN, adjuvant-induced and pristane models, but the streptococcal cell wall (SCW) arthritis in rat and the collagen-induced arthritis (CIA) in mice are the most widely used [67].

Lee et al. found that W/Wv and Sl/Sld, which are deficient in MCs, were resistant to development of joint inflammation. They proposed that MCs may serve as a cellular link among numerous components in inflammatory arthritis [68]. What is interesting is that MCs are normally expressed in the synovial compartments of healthy people but increased in RA patients [69]. The number of MCs increases 5- to 24-fold in affected joints in human RA when compared to the number of those in normal joints [69]. It is also found that MCs number expand more than 3-fold in multiple animal models of RA [7072]. Besides, the cytokines and proteases which are produced by MCs are involved in the pathogenic process of RA, particularly TNF, IL-1β, IL-17, and tryptase [30, 73]. Tryptase is a preformed mast cell-specific protease and is thought to lead to the inflammatory response by working with heparin to induce the neutrophils and synovial fibroblasts to release cytokines [74]. Tryptase can also directly activate synovial fibroblasts by interacting with the protease-activated receptor 2 (PAR2) to express more proteases that degrade cartilage and bone [75, 76].

Matsumoto and Staub’s group found that RA may be associated with the enzyme glucose-6-phosphate isomerase (GPI) [77]. K/BxN mice produce autoantibodies that can recognize GPI. The antibodies aggregate with GPI, and then immune complex is deposed on the surface of the articular cavity to initiate a signaling cascade including MCs. Cytokines such as IL-1 and IL-17A are also involved [73, 78]. The serum from K/BxN mouse causes similar inflammatory arthritis in a wide range of mouse strains, but mouse deficient in MCs resistant to autoimmune inflammatory arthritis was induced by injection of sera from K/BxN mouse. If the MCs are reconstituted, the sensitivity would be restored [68]. mice deficient in MCs are sensitive to autoimmune inflammatory arthritis induced by injection of sera from K/BxN mouse and mast cell-reconstituted mice are still susceptible to arthritis induced by sera from K/BxN mouse [79].

MCs accumulate in the synovial tissues and fluids of patients with rheumatoid arthritis and produce inflammatory mediators [1]. In addition to the degranulation in the articulate cavity after antibody administration, the activation of MCs through the IgG immune complex receptor FcγRIII can precipitate the initiation of inflammation within the joint through the production and release of IL-1 [68, 80]. Stem cell factor (SCF) is essential for mast cell survival and development in vitro [1]. Furthermore, TNF-α derived from MCs can induce fibroblasts to produce SCF, the ligand for the CD117/c-Kit receptor [81, 82]. SCF increases the recruitment of MCs and creates an amplification loop [81, 82].

4.3. MCs and IDDM

Insulin-dependent diabetes mellitus (IDDM) is also called type I diabetes. IDDM is a chronic metabolic disorder that develops in two discrete phases and is mediated in part by CD8+ T cells [19, 83]. In the process of IDDM, various leukocytes invade the pancreatic islets and lead to insulitis. Then the insulin-producing β cells of the pancreas are destructed and lead to hyperglycemia [19]. Furthermore, IDDM is commonly associated with immune-mediated damage [84]. There are several rodent models of IDDM. In susceptible rodents, small dose of streptozotocin induces insulinopenic diabetes in which immune destruction plays the role, as in human type I diabetes [85]. In addition, the nonobese diabetic (NOD) mouse and biobreeding (BB) rat are the two most commonly used animals that spontaneously develop diseases with similarities to human type I diabetes [85].

Normally, MCs locate within the pancreatic ducts and are close to the pancreatic islets [86]. A lot of studies have found a striking increase in the frequency of MCs in the acinar parenchyma in inflammatory disease of pancreas [8688]. Besides, MCs produce various mediators which are able to affect the development of IDDM. For example, leukotriene B4 (LTB4), which is released by MCs and may be important for recruitment or retention of autoreactive T cells in the target organ, is found increased in type I diabetes [89]. What is the most important is that Geoffrey et al. discovered more MCs in the pancreatic lymph nodes of lymphopenic diabetic BB rats before disease onset [36]. As a result, there is suspicion that MCs are involved in IDDM.

4.4. MCs and CU

Chronic urticaria (CU) is a distressing disorder that adversely impacts the quality of life, but its pathogenesis is not delineated well [90]. An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally based on laboratory and clinical evidence that has accrued over the last 20 years [91]. In 1983, Leznoff et al. suggested that urticaria should be considered autoimmune [92]. Gruber et al. detected functional anti-IgE antibodies and proposed that these could be the cause of urticarial wheals [93]. And now it is well recognized that about 30–50% CU patients have circulating functional autoantibodies against the high-affinity IgE receptor or against IgE [94]. Besides, CU is associated with various autoimmune diseases [95].

Urticaria is triggered by inappropriate activation and degranulation of dermal mast cells. And the cellular contents released by MCs prime the immediate phase of inflammation, resulting in a lymphocyte and granulocyte mediated hypersensitivity reaction [96]. In turn, the infiltrating inflammatory cells produce more proinflammatory mediators to recruit and activate other cells and extend the host response [96]. It lowers the reactive threshold of MCs to induce stimuli and promotes the maintenance of susceptibility to urticaria [90]. It provides an explanation for Smith’s discovery that MCs numbers remain unaltered [97]. Bossi et al. evaluated permeabilizing activity of sera from CU patients and healthy people by measuring serum-induced degranulation of two MC lines (LDA2 and HMC-1) [98]. They discovered that almost all the CU patients sera promoted degranulation of MCs and 17/19 mast cell supernatant from HMC-1 and SNs from LAD2 incubated with CU sera increased endothelia permeability [98]. It is said that histamine released from MCs is the major effector on pathogenesis [94]. Bossi et al. also found that endothelial cell leakage was prevented by antihistamine [98].

5. Conclusion

It is clear that MCs play an important role in autoimmune diseases. In conclusion, MCs can worsen disease by a number of mediators and counteracting Treg cells function. In the mouse models of RA and MS, MCs promote inflammation in the same way like TNF.

MCs can be a new treatment target in the autoimmune diseases because of their pivotal position in the inflammation process. The therapeutic strategies focus on three aspects as follows: (1) at the level of the molecules produced by MCs, (2) at the level of MCs activation, and (3) at the level of MC proliferation [99]. The study of Saso demonstrated that MCs can be inhibited through the action of an Fcε–Fcγ fusion protein engineered to engage human FcγRIIb with high affinity. This study suggests that analogous fully human Fcε–Fcγ tandem Fc biologic has potential as a potent and selective inhibitor of cellular activation and degranulation and thus represents a promising approach in treating mast cell and basophil-mediated pathogenesis [100]. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration, and activity of MCs. Vermersch’s group assessed the masitinib treatment in patient with progressive MS and the data suggested that masitinib is of therapeutic benefit to MS patients [101].

mice are a strain deficient in MCs. In spite of a great deal of evidence of the involvement of MCs in the autoimmune disease models, using mice in study did not find an active role of MCs in both the K/BxN serum transfer model of RA and the EAE model of MS [102]. Besides, Gutierrez et al. found that IDDM in NOD mice was unaffected by mast cell deficiency [103]. Therefore, the research about the roles of MCs in autoimmune diseases remains a matter of great debate and ought to be further studied, which is important for creating new MC targeted therapies [5].


BB: Biobreeding rat
BBB:Blood-brain barrier
BMCs: Brain mast cells
CIA:Collagen-induced arthritis
CNS:Central nervous system
CSF:Cerebrospinal fluid
CTMCs:Connective tissue mast cells
CU:Chronic urticaria
EAE:Experimental autoimmune encephalomyelitis
GPI:Glucose-6-phosphate isomerase
IDDM:Insulin-dependent diabetes mellitus
LTB4:Leukotriene B4
MBP:Myelin basic protein
MCPs:Mast cell-committed precursors
MCs:Mast cells
MMCs:Mucosal mast cells
MMP:Matrix metalloproteinase
MPPs:Multipotential progenitors
MS:Multiple sclerosis
NGF:Nerve growth factor
NOD:Nonobese diabetic mouse
PAR:Protease-activated receptor
PAR2:Protease-activated receptor 2
RA:Rheumatoid arthritis
SGs:Secretory granules
SCW:Streptococcal cell wall
Th1:T helper 1 cells
Th17:T helper 17 cells
Th9:T helper 9 cells
TNF:Tumor necrosis factor
Treg:T regulatory cell.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


This work was supported by grants from National Nature Science Foundation of China (81373208), Shanghai Commission of Science and Technology (11JC1411602), Shanghai Municipal Education Commission (12ZZ103), and Shanghai Board of Health Foundation (2011177).


  1. E. Z. da Silva, M. C. Jamur, and C. Oliver, “Mast cell function: a new vision of an old cell,” Journal of Histochemistry — Cytochemistry, vol. 62, no. 10, pp. 698–738, 2014. View at: Publisher Site | Google Scholar
  2. S. Kivity, N. Agmon-Levin, M. Blank, and Y. Shoenfeld, “Infections and autoimmunity—friends or foes?” Trends in Immunology, vol. 30, no. 8, pp. 409–414, 2009. View at: Publisher Site | Google Scholar
  3. L. M. Pennell, C. L. Galligan, and E. N. Fish, “Sex affects immunity,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J282–J291, 2012. View at: Publisher Site | Google Scholar
  4. A. V. Rubtsov, K. Rubtsova, J. W. Kappler, and P. Marrack, “Genetic and hormonal factors in female-biased autoimmunity,” Autoimmunity Reviews, vol. 9, no. 7, pp. 494–498, 2010. View at: Publisher Site | Google Scholar
  5. M. A. Brown and J. K. Hatfield, “Mast cells are important modifiers of autoimmune disease: with so much evidence, why is there still controversy?” Frontiers in Immunology, vol. 3, article 147, 2012. View at: Publisher Site | Google Scholar
  6. I. R. Mackay and W. H. Anderson, “What's in a name? Experimental encephalomyelitis: ‘Allergic’ or ‘autoimmune’,” Journal of Neuroimmunology, vol. 223, no. 1-2, pp. 1–4, 2010. View at: Publisher Site | Google Scholar
  7. J. Lohr, B. Knoechel, V. Nagabhushanam, and A. K. Abbas, “T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens,” Immunological Reviews, vol. 204, pp. 116–127, 2005. View at: Publisher Site | Google Scholar
  8. J.-F. Bach, A. Bendelac, M. B. Brenner et al., “The role of innate immunity in autoimmunity,” The Journal of Experimental Medicine, vol. 200, no. 12, pp. 1527–1531, 2004. View at: Publisher Site | Google Scholar
  9. A. Chervonsky, “Innate receptors and microbes in induction of autoimmunity,” Current Opinion in Immunology, vol. 21, no. 6, pp. 641–647, 2009. View at: Publisher Site | Google Scholar
  10. A. Marshak-Rothstein and P. S. Ohashi, “Intricate connections between innate and adaptive autoimmunity,” Current Opinion in Immunology, vol. 19, no. 6, pp. 603–605, 2007. View at: Publisher Site | Google Scholar
  11. H. Maciejewska Rodrigues, A. Jüngel, R. E. Gay, and S. Gay, “Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis,” Molecular Immunology, vol. 47, no. 1, pp. 12–18, 2009. View at: Publisher Site | Google Scholar
  12. D. S. Pisetsky, “The role of innate immunity in the induction of autoimmunity,” Autoimmunity Reviews, vol. 8, no. 1, pp. 69–72, 2008. View at: Publisher Site | Google Scholar
  13. A. J. Tenner, “Influence of innate immune responses on autoimmunity,” Autoimmunity, vol. 37, no. 2, pp. 83–84, 2004. View at: Publisher Site | Google Scholar
  14. S. J. Galli, M. Grimbaldeston, and M. Tsai, “Immunomodulatory mast cells: negative, as well as positive, regulators of immunity,” Nature Reviews Immunology, vol. 8, no. 6, pp. 478–486, 2008. View at: Publisher Site | Google Scholar
  15. S. N. Abraham and A. L. St. John, “Mast cell-orchestrated immunity to pathogens,” Nature Reviews Immunology, vol. 10, no. 6, pp. 440–452, 2010. View at: Publisher Site | Google Scholar
  16. U. Blank, I. K. Madera-Salcedo, L. Danelli et al., “Vesicular trafficking and signaling for cytokine and chemokine secretion in mast cells,” Frontiers in Immunology, vol. 5, article 453, 2014. View at: Publisher Site | Google Scholar
  17. G. D. Gregory and M. A. Brown, “Mast cells in allergy and autoimmunity: implications for adaptive immunity,” Methods in Molecular Biology, vol. 315, pp. 35–50, 2006. View at: Google Scholar
  18. K. N. Rao and M. A. Brown, “Mast cells: multifaceted immune cells with diverse roles in health and disease,” Annals of the New York Academy of Sciences, vol. 1143, pp. 83–104, 2008. View at: Publisher Site | Google Scholar
  19. B. A. Sayed, A. Christy, M. R. Quirion, and M. A. Brown, “The master switch: the role of mast cells in autoimmunity and tolerance,” Annual Review of Immunology, vol. 26, pp. 705–739, 2008. View at: Publisher Site | Google Scholar
  20. X. Pang, R. Letourneau, J. J. Rozniecki, L. Wang, and T. C. Theoharides, “Definitive characterization of rat hypothalamic mast cells,” Neuroscience, vol. 73, no. 3, pp. 889–902, 1996. View at: Publisher Site | Google Scholar
  21. Y. Kitamura and A. Ito, “Mast cell-committed progenitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11129–11130, 2005. View at: Publisher Site | Google Scholar
  22. H.-R. Rodewald, M. Dessing, A. M. Dvorak, and S. J. Galli, “Identification of a committed precursor for the mast cell lineage,” Science, vol. 271, no. 5250, pp. 818–822, 1996. View at: Publisher Site | Google Scholar
  23. C.-C. Chen, M. A. Grimbaldeston, M. Tsai, I. L. Weissman, and S. J. Galli, “Identification of mast cell progenitors in adult mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11408–11413, 2005. View at: Publisher Site | Google Scholar
  24. T. C. Theoharides, K.-D. Alysandratos, A. Angelidou et al., “Mast cells and inflammation,” Biochimica et Biophysica Acta, vol. 1822, no. 1, pp. 21–33, 2012. View at: Publisher Site | Google Scholar
  25. M. Metz, V. A. Botchkarev, N. V. Botchkareva et al., “Neurotrophin-3 regulates mast cell functions in neonatal mouse skin,” Experimental Dermatology, vol. 13, no. 5, pp. 273–281, 2004. View at: Publisher Site | Google Scholar
  26. P. G. Kruger, L. Bo, K. M. Myhr et al., “Mast cells and multiple sclerosis: a light and electron microscopic study of mast cells in multiple sclerosis emphasizing staining procedures,” Acta Neurologica Scandinavica, vol. 81, no. 1, pp. 31–36, 1990. View at: Google Scholar
  27. M. Rottem and Y. A. Mekori, “Mast cells and autoimmunity,” Autoimmunity Reviews, vol. 4, no. 1, pp. 21–27, 2005. View at: Publisher Site | Google Scholar
  28. S. J. Galli and M. Tsai, “Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity,” European Journal of Immunology, vol. 40, no. 7, pp. 1843–1851, 2010. View at: Publisher Site | Google Scholar
  29. U. Blank and J. Rivera, “The ins and outs of IgE-dependent mast-cell exocytosis,” Trends in Immunology, vol. 25, no. 5, pp. 266–273, 2004. View at: Publisher Site | Google Scholar
  30. M. E. Walker, J. K. Hatfield, and M. A. Brown, “New insights into the role of mast cells in autoimmunity: evidence for a common mechanism of action?” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1822, no. 1, pp. 57–65, 2012. View at: Publisher Site | Google Scholar
  31. G. Gri, S. Piconese, B. Frossi et al., “CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction,” Immunity, vol. 29, no. 5, pp. 771–781, 2008. View at: Publisher Site | Google Scholar
  32. M. Kashyap, A. M. Thornton, S. K. Norton et al., “Cutting edge: CD4 T cell-mast cell interactions alter IgE receptor expression and signaling,” The Journal of Immunology, vol. 180, no. 4, pp. 2039–2043, 2008. View at: Publisher Site | Google Scholar
  33. S. Piconese, G. Gri, C. Tripodo et al., “Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation,” Blood, vol. 114, no. 13, pp. 2639–2648, 2009. View at: Publisher Site | Google Scholar
  34. O. Malbec and M. Daëron, “The mast cell IgG receptors and their roles in tissue inflammation,” Immunological Reviews, vol. 217, no. 1, pp. 206–221, 2007. View at: Publisher Site | Google Scholar
  35. S. Merluzzi, B. Frossi, G. Gri, S. Parusso, C. Tripodo, and C. Pucillo, “Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells,” Blood, vol. 115, no. 14, pp. 2810–2817, 2010. View at: Publisher Site | Google Scholar
  36. R. Geoffrey, S. Jia, A. E. Kwitek et al., “Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the biobreeding rat,” Journal of Immunology, vol. 177, no. 10, pp. 7275–7286, 2006. View at: Publisher Site | Google Scholar
  37. T. Ishii, T. Fujita, T. Matsushita et al., “Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive arthus reaction,” The American Journal of Pathology, vol. 174, no. 6, pp. 2225–2233, 2009. View at: Publisher Site | Google Scholar
  38. S. S. Saini, M. Paterniti, K. Vasagar, S. P. Gibbons Jr., P. M. Sterba, and B. M. Vonakis, “Cultured peripheral blood mast cells from chronic idiopathic urticaria patients spontaneously degranulate upon IgE sensitization: relationship to expression of Syk and SHIP-2,” Clinical Immunology, vol. 132, no. 3, pp. 342–348, 2009. View at: Publisher Site | Google Scholar
  39. B. U. Wintroub, M. C. Mihm Jr., E. J. Goetzl, N. A. Soter, and K. F. Austen, “Morphologic and functional evidence for release of mast-cell products in bullous pemphigoid,” The New England Journal of Medicine, vol. 298, no. 8, pp. 417–421, 1978. View at: Publisher Site | Google Scholar
  40. L. Steinman, “Multiple sclerosis: a two-stage disease,” Nature Immunology, vol. 2, no. 9, pp. 762–764, 2001. View at: Publisher Site | Google Scholar
  41. N. D. Chiaravalloti and J. DeLuca, “Cognitive impairment in multiple sclerosis,” The Lancet Neurology, vol. 7, no. 12, pp. 1139–1151, 2008. View at: Publisher Site | Google Scholar
  42. F. D. Lublin, “Clinical features and diagnosis of multiple sclerosis,” Neurologic Clinics, vol. 23, no. 1, pp. 1–15, 2005. View at: Publisher Site | Google Scholar
  43. A. Jäger and V. K. Kuchroo, “Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation,” Scandinavian Journal of Immunology, vol. 72, no. 3, pp. 173–184, 2010. View at: Publisher Site | Google Scholar
  44. J. M. Fletcher, S. J. Lalor, C. M. Sweeney, N. Tubridy, and K. H. G. Mills, “T cells in multiple sclerosis and experimental autoimmune encephalomyelitis,” Clinical and Experimental Immunology, vol. 162, no. 1, pp. 1–11, 2010. View at: Publisher Site | Google Scholar
  45. J. J. Dropp, “Mast cells in mammalian brain. I. Distribution,” Acta Anatomica, vol. 94, no. 1, pp. 1–21, 1976. View at: Publisher Site | Google Scholar
  46. L. Edvinsson, J. Cervos-Navarro, L. I. Larsson, C. Owman, and A. L. Rönnberg, “Regional distribution of mast cells containing histamine, dopamine, or 5-hydroxytryptamine in the mammalian brain,” Neurology, vol. 27, no. 9, pp. 878–883, 1977. View at: Publisher Site | Google Scholar
  47. R. C. Goldschmidt, L. B. Hough, S. D. Glick, and J. Padawer, “Mast cells in rat thalamus: nuclear localization, sex difference and left-right asymmetry,” Brain Research, vol. 323, no. 2, pp. 209–217, 1984. View at: Publisher Site | Google Scholar
  48. P. Panula, H. Y. T. Yang, and E. Costa, “Histamine-containing neurons in the rat hypothalamus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 8, pp. 2572–2576, 1984. View at: Publisher Site | Google Scholar
  49. V. Dimitriadou, M. Lambracht-Hall, J. Reichler, and T. C. Theoharides, “Histochemical and ultrastructural characteristics of rat brain perivascular mast cells stimulated with compound 48/80 and carbachol,” Neuroscience, vol. 39, no. 1, pp. 209–224, 1990. View at: Publisher Site | Google Scholar
  50. M. Z. M. Ibrahim, M. E. Al-Wirr, and N. Bahuth, “The mast cells of the mammalian central nervous system. III. Ultrastructural characteristics in the adult rat brain,” Acta Anatomica, vol. 104, no. 2, pp. 134–154, 1979. View at: Publisher Site | Google Scholar
  51. T. C. Theoharides, “Mast cells: the immune gate to the brain,” Life Sciences, vol. 46, no. 9, pp. 607–617, 1990. View at: Publisher Site | Google Scholar
  52. M. A. Brown, M. B. Tanzola, and M. Robbie-Ryan, “Mechanisms underlying mast cell influence on EAE disease course,” Molecular Immunology, vol. 38, no. 16-18, pp. 1373–1378, 2002. View at: Publisher Site | Google Scholar
  53. M. Z. M. Ibrahim, A. T. Reder, R. Lawand, W. Takash, and S. Sallouh-Khatib, “The mast cells of the multiple sclerosis brain,” Journal of Neuroimmunology, vol. 70, no. 2, pp. 131–138, 1996. View at: Publisher Site | Google Scholar
  54. J. J. Rozniecki, S. L. Hauser, M. Stein, R. Lincoln, and T. C. Theoharides, “Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients,” Annals of Neurology, vol. 37, no. 1, pp. 63–66, 1995. View at: Publisher Site | Google Scholar
  55. U. Shanas, R. Bhasin, A. K. Sutherland, A.-J. Silverman, and R. Silver, “Brain mast cells lack the c-kit receptor: immunocytochemical evidence,” Journal of Neuroimmunology, vol. 90, no. 2, pp. 207–211, 1998. View at: Publisher Site | Google Scholar
  56. T. C. Theoharides, C. Weinkauf, and P. Conti, “Brain cytokines and neuropsychiatric disorders,” Journal of Clinical Psychopharmacology, vol. 24, no. 6, pp. 577–581, 2004. View at: Publisher Site | Google Scholar
  57. T. C. Theoharides and A. D. Konstantinidou, “Corticotropin-releaslng hormone and the blood-brain-barrier,” Frontiers in Bioscience, vol. 12, no. 5, pp. 1615–1628, 2007. View at: Publisher Site | Google Scholar
  58. M. Wilhelm, R. Silver, and A.-J. Silverman, “Central nervous system neurons acquire mast cell products via transgranulation,” European Journal of Neuroscience, vol. 22, no. 9, pp. 2238–2248, 2005. View at: Publisher Site | Google Scholar
  59. W. E. F. Klinkert, K. Kojima, W. Lesslauer, W. Rinner, H. Lassmann, and H. Wekerle, “TNF-α receptor fusion protein prevents experimental auto-immune encephalomyelitis and demyelination in Lewis rats: an overview,” Journal of Neuroimmunology, vol. 72, no. 2, pp. 163–168, 1997. View at: Publisher Site | Google Scholar
  60. K. S. Kim, C. A. Wass, A. S. Cross, and S. M. Opal, “Modulation of blood-brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat,” Lymphokine and Cytokine Research, vol. 11, no. 6, pp. 293–298, 1992. View at: Google Scholar
  61. V. Malamud, A. Vaaknin, O. Abramsky et al., “Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF-α, IL-6 and IL-1β: possible relevance to multiple sclerosis,” Journal of Neuroimmunology, vol. 138, no. 1-2, pp. 115–122, 2003. View at: Publisher Site | Google Scholar
  62. N. W. Bunnett, “Protease-activated receptors: how proteases signal to cells to cause inflammation and pain,” Seminars in Thrombosis and Hemostasis, vol. 32, no. 1, pp. 39–48, 2006. View at: Publisher Site | Google Scholar
  63. D. Baram, G. G. Vaday, P. Salamon, I. Drucker, R. Hershkoviz, and Y. A. Mekori, “Human mast cells release metalloproteinase-9 on contact with activated T cells: Juxtacrine regulation by TNF-α,” Journal of Immunology, vol. 167, no. 7, pp. 4008–4016, 2001. View at: Publisher Site | Google Scholar
  64. G. N. Dietsch and D. J. Hinrichs, “Mast cell proteases liberate stable encephalitogenic fragments from intact myelin,” Cellular Immunology, vol. 135, no. 2, pp. 541–548, 1991. View at: Publisher Site | Google Scholar
  65. T. Brenner, D. Soffer, M. Shalit, and F. Levi-Schaffer, “Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides,” Journal of the Neurological Sciences, vol. 122, no. 2, pp. 210–213, 1994. View at: Publisher Site | Google Scholar
  66. V. Dimitriadou, X. Pang, and T. C. Theoharides, “Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation,” International Journal of Immunopharmacology, vol. 22, no. 9, pp. 673–684, 2000. View at: Publisher Site | Google Scholar
  67. K. Kannan, R. A. Ortmann, and D. Kimpel, “Animal models of rheumatoid arthritis and their relevance to human disease,” Pathophysiology, vol. 12, no. 3, pp. 167–181, 2005. View at: Publisher Site | Google Scholar
  68. D. M. Lee, D. S. Friend, M. F. Gurish, C. Benoist, D. Mathis, and M. B. Brenner, “Mast cells: a cellular link between autoantibodies and inflammatory arthritis,” Science, vol. 297, no. 5587, pp. 1689–1692, 2002. View at: Publisher Site | Google Scholar
  69. P. A. Nigrovic and D. M. Lee, “Synovial mast cells: role in acute and chronic arthritis,” Immunological Reviews, vol. 217, no. 1, pp. 19–37, 2007. View at: Publisher Site | Google Scholar
  70. L. Aloe, L. Probert, G. Kollias et al., “Level of nerve growth factor and distribution of mast cells in the synovium of tumour necrosis factor transgenic arthritic mice,” International Journal of Tissue Reactions, vol. 15, no. 4, pp. 139–143, 1993. View at: Google Scholar
  71. T. Kambayashi, E. J. Allenspach, J. T. Chang et al., “Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation,” The Journal of Immunology, vol. 182, no. 8, pp. 4686–4695, 2009. View at: Publisher Site | Google Scholar
  72. K. Shin, M. F. Gurish, D. S. Friend et al., “Lymphocyte-independent connective tissue mast cells populate murine synovium,” Arthritis & Rheumatism, vol. 54, no. 9, pp. 2863–2871, 2006. View at: Publisher Site | Google Scholar
  73. A. J. Hueber, D. L. Asquith, A. M. Miller et al., “Cutting edge: mast cells express IL-17A in rheumatoid arthritis synovium,” Journal of Immunology, vol. 184, no. 7, pp. 3336–3340, 2010. View at: Publisher Site | Google Scholar
  74. K. Shin, P. A. Nigrovic, J. Crish et al., “Mast cells contribute to autoimmune inflammatory arthritis via their tryptase/heparin complexes,” Journal of Immunology, vol. 182, no. 1, pp. 647–656, 2009. View at: Publisher Site | Google Scholar
  75. H. S. Palmer, E. B. Kelso, J. C. Lockhart et al., “Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells,” Arthritis and Rheumatism, vol. 56, no. 11, pp. 3532–3540, 2007. View at: Publisher Site | Google Scholar
  76. N. Sawamukai, S. Yukawa, K. Saito, S. Nakayamada, T. Kambayashi, and Y. Tanaka, “Mast cell-derived tryptase inhibits apoptosis of human rheumatoid synovial fibroblasts via rho-mediated signaling,” Arthritis & Rheumatism, vol. 62, no. 4, pp. 952–959, 2010. View at: Publisher Site | Google Scholar
  77. I. Matsumoto and A. Staub, “Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme,” Science, vol. 286, no. 5445, pp. 1732–1735, 1999. View at: Publisher Site | Google Scholar
  78. H. Ji, A. Pettit, K. Ohmura et al., “Critical roles for interleukin 1 and tumor necrosis factor α in antibody-induced arthritis,” Journal of Experimental Medicine, vol. 196, no. 1, pp. 77–85, 2002. View at: Publisher Site | Google Scholar
  79. J. S. Zhou, W. Xing, D. S. Friend, K. F. Austen, and H. R. Katz, “Mast cell deficiency in KitW-sh mice does not impair antibody-mediated arthritis,” Journal of Experimental Medicine, vol. 204, no. 12, pp. 2797–2802, 2007. View at: Publisher Site | Google Scholar
  80. P. A. Nigrovic, B. A. Binstadt, P. A. Monach et al., “Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 7, pp. 2325–2330, 2007. View at: Publisher Site | Google Scholar
  81. C. Benoist and D. Mathis, “Mast cells in autoimmune disease,” Nature, vol. 420, no. 6917, pp. 875–878, 2002. View at: Publisher Site | Google Scholar
  82. D. E. Woolley and L. C. Tetlow, “Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion,” Arthritis Research, vol. 2, no. 1, pp. 65–74, 2000. View at: Publisher Site | Google Scholar
  83. H. McDevitt, “Closing in on type 1 diabetes,” The New England Journal of Medicine, vol. 345, no. 14, pp. 1060–1061, 2001. View at: Publisher Site | Google Scholar
  84. G. Dahlquist, “The aetiology of type 1 diabetes: an epidemiological perspective,” Acta Paediatrica, vol. 87, Supplement 425, pp. 5–10, 1998. View at: Publisher Site | Google Scholar
  85. D. A. Rees and J. C. Alcolado, “Animal models of diabetes mellitus,” Diabetic Medicine, vol. 22, no. 4, pp. 359–370, 2005. View at: Publisher Site | Google Scholar
  86. I. Esposito, H. Friess, A. Kappeler et al., “Mast cell distribution and activation in chronic pancreatitis,” Human Pathology, vol. 32, no. 11, pp. 1174–1183, 2001. View at: Publisher Site | Google Scholar
  87. I. Esposito, J. Kleeff, S. C. Bischoff et al., “The stem cell factor-c-kit system and mast cells in human pancreatic cancer,” Laboratory Investigation, vol. 82, no. 11, pp. 1481–1492, 2002. View at: Publisher Site | Google Scholar
  88. L. Zimnoch, B. Szynaka, and Z. Puchalski, “Mast cells and pancreatic stellate cells in chronic pancreatitis with differently intensified fibrosis,” Hepato-Gastroenterology, vol. 49, no. 46, pp. 1135–1138, 2002. View at: Google Scholar
  89. C. Parlapiano, C. Danese, M. Marangi et al., “The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus,” Diabetes Research and Clinical Practice, vol. 46, no. 1, pp. 43–45, 1999. View at: Publisher Site | Google Scholar
  90. S. Jain, “Pathogenesis of chronic urticaria: an overview,” Dermatology Research and Practice, vol. 2014, Article ID 674709, 10 pages, 2014. View at: Publisher Site | Google Scholar
  91. G. N. Konstantinou, R. Asero, M. Ferrer et al., “EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria,” Allergy, vol. 68, no. 1, pp. 27–36, 2013. View at: Publisher Site | Google Scholar
  92. A. Leznoff, R. G. Josse, J. Denburg, and J. Dolovich, “Association of chronic urticaria and angioedema with thyroid autoimmunity,” Archives of Dermatology, vol. 119, no. 8, pp. 636–640, 1983. View at: Publisher Site | Google Scholar
  93. B. L. Gruber, M. L. Baeza, M. J. Marchese, V. Agnello, and A. P. Kaplan, “Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes,” Journal of Investigative Dermatology, vol. 90, no. 2, pp. 213–217, 1988. View at: Publisher Site | Google Scholar
  94. S. Sachdeva, V. Gupta, S. S. Amin, and M. Tahseen, “Chronic urticaria,” Indian Journal of Dermatology, vol. 56, no. 6, pp. 622–628, 2011. View at: Publisher Site | Google Scholar
  95. Y. C. Wai and G. L. Sussman, “Evaluating chronic urticaria patients for allergies, infections, or autoimmune disorders,” Clinical Reviews in Allergy and Immunology, vol. 23, no. 2, pp. 185–193, 2002. View at: Publisher Site | Google Scholar
  96. M. Caproni, B. Giomi, W. Volpi et al., “Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals,” Clinical Immunology, vol. 114, no. 3, pp. 284–292, 2005. View at: Publisher Site | Google Scholar
  97. C. H. Smith, C. Kepley, L. B. Schwartz, and T. H. Lee, “Mast cell number and phenotype in chronic idiopathic urticaria,” Journal of Allergy and Clinical Immunology, vol. 96, no. 3, pp. 360–364, 1995. View at: Publisher Site | Google Scholar
  98. F. Bossi, B. Frossi, O. Radillo et al., “Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation,” Allergy, vol. 66, no. 12, pp. 1538–1545, 2011. View at: Publisher Site | Google Scholar
  99. L. Frenzel and O. Hermine, “Mast cells and inflammation,” Joint Bone Spine, vol. 80, no. 2, pp. 141–145, 2013. View at: Publisher Site | Google Scholar
  100. S. Cemerski, S. Y. Chu, G. L. Moore, U. S. Muchhal, J. R. Desjarlais, and D. E. Szymkowski, “Suppression of mast cell degranulation through a dual-targeting tandem IgE-IgG Fc domain biologic engineered to bind with high affinity to FcγRIIb,” Immunology Letters, vol. 143, no. 1, pp. 34–43, 2012. View at: Publisher Site | Google Scholar
  101. P. Vermersch, R. Benrabah, N. Schmidt et al., “Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study,” BMC Neurology, vol. 12, article 36, 2012. View at: Publisher Site | Google Scholar
  102. T. B. Feyerabend, A. Weiser, A. Tietz et al., “Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity,” Immunity, vol. 35, no. 5, pp. 832–844, 2011. View at: Publisher Site | Google Scholar
  103. D. A. Gutierrez, W. Fu, S. Schonefeldt et al., “Type 1 diabetes in NOD mice unaffected by mast cell deficiency,” Diabetes, vol. 63, no. 11, pp. 3827–3834, 2014. View at: Publisher Site | Google Scholar

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