scholarly journals Mast Cells in Human Cutaneous Neurofibromas: Density, Subtypes, and Association with Clinical Features in Neurofibromatosis 1

Dermatology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Roope A. Kallionpää ◽  
Kaisa Ahramo ◽  
Eija Martikkala ◽  
Elnaz Fazeli ◽  
Pekka Haapaniemi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Clinical Features ◽  
Disease Burden ◽  
Neurofibromatosis 1 ◽  
Computer Assisted ◽  
Unaffected Skin ◽  
Comprehensive Characterization ◽  
Cutaneous Neurofibromas

<b><i>Background:</i></b> Cutaneous neurofibromas (cNFs) are hallmarks of neurofibromatosis 1 (NF1) and cause the main disease burden in adults with NF1. Mast cells are a known component of cNFs. However, no comprehensive characterization of mast cells in cNFs is available, and their contributions to cNF growth and symptoms such as itch are not known. <b><i>Methods:</i></b> We collected 60 cNFs from ten individuals with NF1, studied their mast cell proteinase content, and compared the mast cell numbers to selected clinical features of the tumors and patients. The tumors were immunolabeled for the mast cell markers CD117, tryptase, and chymase, and the percentage of immunopositive cells was determined using computer-assisted methods. <b><i>Results:</i></b> The median proportions of positive cells were 5.5% (range 0.1–14.4) for CD117, 4.0% (1.2–7.0) for tryptase, and 5.0% (1.1–15.9) for chymase. The median densities of cells immunopositive for CD117, tryptase, and chymase were 280, 243, and 250 cells/mm<sup>2</sup>, respectively. Small tumors, growing tumors, and tumors from patients below the median age of 33 years displayed a high proportion of mast cells. Cells expressing both tryptase and chymase were the predominant mast cell type in cNFs, followed by cells expressing chymase only. <b><i>Conclusion:</i></b> The results highlight the abundance of mast cells in cNFs and that their number and subtypes clearly differ from those previously reported in unaffected skin.

A Clinicopathologic Study on the Role of Estrogen, Progesterone, and Their Classical and Nonclassical Receptors in Cutaneous Neurofibromas of Individuals With Neurofibromatosis 1

2020 ◽  
Author(s):  
Rafaela E Rozza-de-Menezes ◽  
Lilian M Almeida ◽  
Raquel M Andrade-Losso ◽  
Gustavo de Souza Vieira ◽  
Orlando H K Siqueira ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Laboratory Data ◽  
Serum Levels ◽  
Neurofibromatosis 1 ◽  
Proliferation Index ◽  
Computer Assisted ◽  
Ki 67 ◽  
Clinicopathologic Study ◽  
Cutaneous Neurofibromas

Abstract Objectives To evaluate the expression of progesterone receptor (PR), estrogen receptor (ER), and G protein–coupled estrogen receptor 1 (GPER-1) in cutaneous neurofibromas (cNFs) and their correlation with demographic, clinical, and laboratory data of individuals with neurofibromatosis 1 (NF1). The association of PROGINS polymorphism and PR expression in cNFs, as well as the serum steroidal hormones and the number of cNFs, was investigated. Methods The sample comprised 80 large and 80 small cNFs from 80 individuals with NF1. PR, ER, GPER-1, and Ki-67 expression were investigated by immunohistochemistry in tissue micro- and macroarrays and quantified using a digital computer-assisted method. The number of cNFs, the levels of serum 17β estradiol and progesterone, and the PROGINS polymorphism were identified. Results Twelve (8.5%) small cNFs were weakly positive for ER, 131 (92.3%) cNFs expressed PR, and all (100%) cNFs expressed GPER-1. Large cNFs showed a higher expression of PR (P &lt; .0001) and GPER-1 (P = .019) and had a higher intensity of staining for these receptors (P &lt; .0001). The cell proliferation index was positively correlated with PR (P = .001). Persons with more cNFs had higher serum levels of progesterone (P = .001). Conclusions These findings emphasize the role of estrogen and progesterone in cNF development and suggest that these hormones may act on cNF cells via a noncanonical pathway through GPER-1.

scholarly journals Cutaneous neurofibromas

Neurology ◽  
2018 ◽  
Vol 91 (2 Supplement 1) ◽  
pp. S5-S13 ◽  
Author(s):  
Nicolas Ortonne ◽  
Pierre Wolkenstein ◽  
Jaishri O. Blakeley ◽  
Bruce Korf ◽  
Scott R. Plotkin ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Natural History ◽  
Diagnostic Criteria ◽  
Clinical Features ◽  
Accurate Diagnosis ◽  
Neurofibromatosis 1 ◽  
Radiographic Features ◽  
History Of ◽  
Current Terminology ◽  
Cutaneous Neurofibromas

ObjectiveTo present the current terminology and natural history of neurofibromatosis 1 (NF1) cutaneous neurofibromas (cNF).MethodsNF1 experts from various research and clinical backgrounds reviewed the terms currently in use for cNF as well as the clinical, histologic, and radiographic features of these tumors using published and unpublished data.ResultsNeurofibromas develop within nerves, soft tissue, and skin. The primary distinction between cNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromas may involve the skin, but are not limited to the skin. There are important cellular, molecular, histologic, and clinical features of cNF. Each of these factors is discussed in consideration of a clinicopathologic framework for cNF.ConclusionThe development of effective therapies for cNF requires formulation of diagnostic criteria that encompass the clinical and histologic features of these tumors. However, there are several areas of overlap between cNF and other neurofibromas that make distinctions between cutaneous and other neurofibromas more difficult, requiring careful deliberation with input across the multiple disciplines that encounter these tumors and ultimately, prospective validation. The ultimate goal of this work is to facilitate accurate diagnosis and meaningful therapeutics for cNF.

scholarly journals Establishment and Characterization of a Murine Mucosal Mast Cell Culture Model

2019 ◽  
Author(s):  
Aya Kakinoki ◽  
Tsuyoshi Kameo ◽  
Shoko Yamashita ◽  
Kazuyuki Furuta ◽  
Satoshi Tanaka
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Inflammatory Responses ◽  
Mucosal Mast Cell ◽  
Cell Accumulation ◽  
Culture Model ◽  
Ige Mediated ◽  
Interleukin 9 ◽  
Mast Cell Culture

Accumulating evidence suggests that mast cells should play critical roles in disruption and maintenance of intestinal homeostasis, although it remains unknown how they affect local microenvironment. Interleukin-9 (IL-9) was found to play critical roles in intestinal mast cell accumulation induced in various pathological conditions, such as parasite infection and oral allergen-induced anaphylaxis. Newly recruited intestinal mast cells trigger inflammatory responses and damage epithelial integrity through release of a wide variety of mediators including mast cell proteases. We established a novel culture model (mucosal mast cell-like cultured mast cells, MMC-like MCs), in which murine IL-3-dependent bone marrow-derived cultured mast cells (BMMCs) were further cultured in the presence of stem cell factor and IL-9. In MMC-like MCs, drastic up-regulation of Mcpt1 and Mcpt2 was found. Although histamine storage and tryptase activity were significantly downregulated in the presence of SCF and IL-9, it was entirely reversed when mast cells were co-cultured with a murine fibroblastic cell line, Swiss 3T3. MMC-like MCs underwent degranulation upon IgE-mediated antigen stimulation, which was found to less sensitive to lower concentrations of IgE in comparison with BMMCs. This model might be useful for investigation of the spatiotemporal changes of newly recruited intestinal mast cells.

scholarly journals Flow Cytometry-Based Characterization of Mast Cells in Human Atherosclerosis

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 334 ◽  
Author(s):  
Kritikou ◽  
Depuydt ◽  
de Vries ◽  
Mulder ◽  
Govaert ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mast Cell ◽  
Mast Cells ◽  
Cell Population ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Atherosclerotic Plaques ◽  
Human Atherosclerosis ◽  
Mast Cell Population

The presence of mast cells in human atherosclerotic plaques has been associated with adverse cardiovascular events. Mast cell activation, through the classical antigen sensitized-IgE binding to their characteristic Fcε-receptor, causes the release of their cytoplasmic granules. These granules are filled with neutral proteases such as tryptase, but also with histamine and pro-inflammatory mediators. Mast cells accumulate in high numbers within human atherosclerotic tissue, particularly in the shoulder region of the plaque. These findings are largely based on immunohistochemistry, which does not allow for the extensive characterization of these mast cells and of the local mast cell activation mechanisms. In this study, we thus aimed to develop a new flow-cytometry based methodology in order to analyze mast cells in human atherosclerosis. We enzymatically digested 22 human plaque samples, collected after femoral and carotid endarterectomy surgery, after which we prepared a single cell suspension for flow cytometry. We were able to identify a specific mast cell population expressing both CD117 and the FcεR, and observed that most of the intraplaque mast cells were activated based on their CD63 protein expression. Furthermore, most of the activated mast cells had IgE fragments bound on their surface, while another fraction showed IgE-independent activation. In conclusion, we are able to distinguish a clear mast cell population in human atherosclerotic plaques, and this study establishes a strong relationship between the presence of IgE and the activation of mast cells in advanced atherosclerosis. Our data pave the way for potential therapeutic intervention through targeting IgE-mediated actions in human atherosclerosis.

P159 PHENOTYPIC CHARACTERIZATION OF INFLAMMATORY BOWEL DISEASE BIOPSIES REVEAL THAT MAST CELLS ARE SIGNIFICANTLY ELEVATED AND ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S33-S34
Author(s):  
Bradford Youngblood ◽  
Tina Davis ◽  
Julia Schanin ◽  
Melina Butuci ◽  
Emily Brock ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Mast Cells ◽  
Inhibitory Activity ◽  
Human Colon ◽  
Colonic Tissue ◽  
Colon Tissue ◽  
Inflammatory Bowel

Abstract Rationale Accumulation and activation of mast cells and eosinophils have been implicated in the pathogenesis of several chronic inflammatory gastrointestinal (GI) diseases, including eosinophilic gastrointestinal diseases (EGIDs) and inflammatory bowel disease (IBD). Despite the strong association of mast cell and eosinophil numbers and activation with the pathogenesis of IBD, no further characterization of these cells has been performed. Current treatment options for IBD include aminosalicylates, antibiotics, immunomodulators, biologic agents and small molecules. These therapies are only moderately effective. A significant proportion of patients fail to respond, do not fully respond, or lose response over time. Therefore, there is significant need for more selective and effective therapy options. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils and mast cells and represents a novel target for the treatment of IBD with the anti-Siglec-8 mAb, antolimab (AK002). We aimed to quantify and evaluate the activation state of mast cells and eosinophils in colonic tissue from IBD or non-diseased patients. In addition, we quantified the production of TNFa from human colon tissue mast cells and evaluated the inhibitory activity of antolimab (AK002) on these cells. Methods Single-cell suspensions were prepared by enzymatic digestion of fresh colonic biopsies from patients clinically diagnosed with IBD (n=29) or non-diseased control tissues (n=16). Multi-color flow cytometry was performed to identify major immune cell populations and evaluate the activation state of mast cells and eosinophils. Mast cells were FACS-sorted from human colon tissue to evaluate cytokine production and inhibitory activity of antolimab. Results The percentage of mast cells and the expression of the mast cell degranulation marker CD107a were significantly increased in ulcerative colitis (UC) patient biopsy tissue compared to Crohn’s disease (CD) and non-diseased colonic tissue (Figure 1A and B). Furthermore, FACS-sorted mast cells from human colon tissue produced significant quantities of TNFa that was reduced after ex vivo antolimab treatment. Colonic tissue eosinophils were also elevated in a subset of UC and CD patient biopsies, and all UC and CD tissue eosinophils displayed increased expression of the activation marker CD11b compared to control colonic tissue. Conclusions Mast cells and eosinophils may play a significant role in driving the pathogenesis of ulcerative colitis through the production of inflammatory mediators. The high expression of Siglec-8 and the inhibitory activity against mast cells suggests that antibodies that target this receptor, such as antolimab (AK002) represent a potential novel approach for the treatment of IBD.

scholarly journals Indolent Systemic Mast Cell Disease in Adults: Immunophenotypic Characterization of Bone Marrow Mast Cells and Its Diagnostic Implications

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2731-2736 ◽  
Author(s):  
Luis Escribano ◽  
Alberto Orfao ◽  
Beatriz Dı́az-Agustin ◽  
Jesús Villarrubia ◽  
Carlos Cerveró ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Statistical Significance ◽  
Normal Subjects ◽  
Light Scatter ◽  
Cell Disease ◽  
Mast Cell Disease ◽  
Normal Controls

The aim of the present study was to explore the diagnostic value of the immunophenotypic analysis of bone marrow mast cells (BMMC) in indolent systemic mast cell disease (SMCD) patients. For that purpose, a total of 10 SMCD patients and 19 healthy controls were analyzed. Our results show that BMMC from SMCD are different from normal BMMC with regard to both their light scatter and immunophenotypic characteristics. Accordingly, forward light scatter (FSC), side (90°) light scatter (SSC), and baseline autofluorescence levels were higher in BMMC from indolent SMCD patients than they were in control subjects. From the immunophenotypic point of view, the most striking findings were the constant expression of CD2 (P = .0001), CD25 (P = .0001), and CD35 (P = .06) molecules by BMMC from SMCD patients, markers that were absent from all normal controls. In contrast, CD71, absent in BMMC from indolent SMCD, was positive in BMMC from normal subjects. Although, slight differences between BMMC from SMCD patients and normal controls were found in several other markers, they did not reach statistical significance. In conclusion, our results show that simultaneous assessment of FSC/SSC and reactivity for the CD117, CD2, CD25, CD33, and CD35 forms the basis for the immunophenotypic characterization of BMMC from SMCD in adults and should be integrated with clinical and morphologic studies for the diagnosis of the disease.

scholarly journals Establishment and Characterization of a Murine Mucosal Mast Cell Culture Model

2019 ◽  
Vol 21 (1) ◽  
pp. 236 ◽  
Author(s):  
Aya Kakinoki ◽  
Tsuyoshi Kameo ◽  
Shoko Yamashita ◽  
Kazuyuki Furuta ◽  
Satoshi Tanaka
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Inflammatory Responses ◽  
Mucosal Mast Cell ◽  
Cell Accumulation ◽  
Culture Model ◽  
Ige Mediated ◽  
Interleukin 9 ◽  
Mast Cell Culture

Accumulating evidence suggests that mast cells play critical roles in disruption and maintenance of intestinal homeostasis, although it remains unknown how they affect the local microenvironment. Interleukin-9 (IL-9) was found to play critical roles in intestinal mast cell accumulation induced in various pathological conditions, such as parasite infection and oral allergen-induced anaphylaxis. Newly recruited intestinal mast cells trigger inflammatory responses and damage epithelial integrity through release of a wide variety of mediators including mast cell proteases. We established a novel culture model (IL-9-modified mast cells, MCs/IL-9), in which murine IL-3-dependent bone-marrow-derived cultured mast cells (BMMCs) were further cultured in the presence of stem cell factor and IL-9. In MCs/IL-9, drastic upregulation of Mcpt1 and Mcpt2 was found. Although histamine storage and tryptase activity were significantly downregulated in the presence of SCF and IL-9, this was entirely reversed when mast cells were cocultured with a murine fibroblastic cell line, Swiss 3T3. MCs/IL-9 underwent degranulation upon IgE-mediated antigen stimulation, which was found to less sensitive to lower concentrations of IgE in comparison with BMMCs. This model might be useful for investigation of the spatiotemporal changes of newly recruited intestinal mast cells.

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