Mast Cells In Mastocytosis Research Articles

Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation.

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo.

Central Role of Mast Cells in Mastocytosis, Hereditary α-Tryptasemia, Mast Cell Activation Syndrome, Urticaria, and Angioedema

Mast cells are the central cells in the pathogenesis of many conditions that are associated with mediator release. New information is emerging about the role of mast cells in a number of conditions. This review summarises current knowledge on the topic. Some conditions such as mastocytosis have a confirmed genetic background; however, the genetic background of hereditary α-tryptasemia has only recently been described, and routine testing is yet to be set up in genetic laboratories. It is still unknown whether there is a genetic predisposition leading to the development of mast cell activation syndrome as well as urticaria and angioedema, and research is under way in this direction. The best known mediator contained in mast cells is histamine 2-(4-imidazolyl)-ethylamine, but it is not the only one. The effects of other mediators are significant in mast cell-mediated conditions, and can be future therapeutic targets. Diamine oxidase deficiency is responsible for digestive issues in some people, and although not directly linked with mast cell pathology, it falls under this umbrella due to symptoms related to the effects of externally consumed histamine. Mast cell-mediated diseases are usually defined through the detection of an elevation of mast cell mediators, response to antihistamines, mast cell stabilisers, and, in some cases, anti-IgE treatment when indicated. They comprise of mastocytosis, hereditary α-tryptasemia, mast cell activation syndrome, urticaria, and angioedema.

A Murine Kitl Allele Regulates Skin Mast Cell Density across 58 Collaborative Mouse Cross Strains

Mast cells contain chemicals needed for the body’s response to extrinsic challenges in various tissues, including the skin. Little is known about the genetic control of mast cell numbers in unchallenged skin. Overabundance of mast cells in mastocytosis, resulting from their excess production in the bone marrow, is characterized by somatic KIT alteration, although such variants are not always found in cutaneous mastocytosis. It appears that many germline variants can predispose to this condition, including those near OTX2, ABCA2, CYP2B5, RPTN (Nedoszytko et al., 2020), CEBPA, LICO1412, and TBLXR1 (Galatà et al., 2021).

Frequency and prognostic impact of blood-circulating tumor mast cells in mastocytosis

AbstractCirculating tumor mast cells (CTMCs) have been identified in the blood of a small number of patients with advanced systemic mastocytosis (SM). However, data are limited about their frequency and prognostic impact in patients with MC activation syndrome (MCAS), cutaneous mastocytosis (CM) and nonadvanced SM. We investigated the presence of CTMCs and MC-committed CD34+ precursors in the blood of 214 patients with MCAS, CM, or SM using highly sensitive next-generation flow cytometry. CTMCs were detected at progressively lower counts in almost all patients with advanced SM (96%) and smoldering SM (SSM; 100%), nearly half of the patients (45%) with indolent SM (ISM), and a few patients (7%) with bone marrow (BM) mastocytosis but were systematically absent in patients with CM and MCAS (P < .0001). In contrast to CTMC counts, the number of MC-committed CD34+ precursors progressively decreased from MCAS, CM, and BM mastocytosis to ISM, SSM, and advanced SM (P < .0001). Clinically, the presence (and number) of CTMCs in blood of patients with SM in general and nonadvanced SM (ISM and BM mastocytosis) in particular was associated with more adverse features of the disease, poorer-risk prognostic subgroups as defined by the International Prognostic Scoring System for advanced SM (P < .0001) and the Global Prognostic Score for mastocytosis (P < .0001), and a significantly shortened progression-free survival (P < .0001) and overall survival (P = .01). On the basis of our results, CTMCs emerge as a novel candidate biomarker of disseminated disease in SM that is strongly associated with advanced SM and poorer prognosis in patients with ISM.

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.

Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis

AbstractMastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins (NTs) have been shown to promote differentiation and survival of MCs, which in turn represent a major source of NTs. Thus, a contribution of NTs to mastocytosis seems highly conceivable but has not yet been investigated. We could demonstrate expression of high-affinity NT receptors tropomyosin-related kinase A (TrkA) for nerve growth factor (NGF)-β, TrkB for brain-derived neurotrophic factor, and NT-4 and TrkC for NT-3 on skin MCs; and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover, increased expression of NGF-β; NT-3; TrkA, TrkB, and TrkC; and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin MCs. Patients with mastocytosis featured elevated serum levels of NGF, NT-3, and NT-4. Levels of NGF-β and NT-4 correlated with tryptase levels, suggesting a link between MC load and blood levels of NGF and NT-4. Migration of CD117+ progenitor cells from the blood was enhanced toward NGF-β gradient in both mastocytosis and controls. Together with enhanced NT levels, the elevated expression of modified Trk receptors on skin and gut MCs might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.

Flow cytometry for systemic mastocytosis

Mastocytosis is a heterogeneous group of disorders characterised by abnormal proliferation of mast cells. In most cases of adult mastocytosis it is possible to demonstrate evidence of clonal proliferation. As is the case with other clonal disorders of haematopoietic lineage, flow cytometry has become a major diagnostic modality. Flow cytometry is particularly useful in the diagnosis of systemic mastocytosis, where the mast cells may still occur at a very low frequency in the bone marrow, despite neoplastic growth. Numerous studies have compared immunophenotype of mast cells in mastocytosis and those in normal and diseased controls. Some aberrantly expressed antigens on mast cells are of such high specificity for systemic mastocytosis that their expression on mast cells has become a minor World Health Organisation (WHO) criterion for diagnosis (CD2, CD25). This presentation will discuss the phenotype of normal mast cell and compare with abnormal immunophenotype – both in the context of the WHO diagnostic criteria as well as other diagnostically useful antigens that are not part of the criteria.

CD4 expression by mast cells in mastocytosis: a case report

A 59-year-old man presented with a five-year history of an asymptomatic widespread truncal rash. Cutaneous biopsies showed mastocytosis, which was shown to be CD4-positive immunohistochemically. This potential diagnostic pitfall in...

Mast cell distribution in normal adult skin

Aims: To investigate mast cell distribution in normal adult skin to provide a reference range for comparison with mastocytosis. Methods: Mast cells (MCs) were counted in uninvolved skin adjacent to...

Immunophenotypic analysis of mast cells in mastocytosis: When and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA).

Mastocytosis is a term used for a heterogeneous group of disorders characterized by an abnormal proliferation and accumulation of mast cells (MCs) in one or multiple tissues including skin, bone marrow, liver, spleen, and lymph nodes, among others. In recent years, multiparameter flow cytometric studies have shown that pathologic MCs from patients with mastocytosis display unique aberrant immunophenotypic characteristics as compared with normal MCs. Among other features, pathologic MCs show aberrant expression of CD25 and CD2 antigens and abnormally high levels of the CD11c and CD35 complement receptors, the CD59 complement regulatory molecule, the CD63 lysosomal membrane antigen, and the CD69 early-activation antigen. In addition, MCs from mastocytosis express abnormally low levels of CD117 and unexpectedly high light scatter and autofluorescence characteristics. These aberrant immunophenotypic features are of great relevance for the assessment of tissue involvement in mastocytosis with consequences in the diagnosis, classification, and follow-up of the disease and in its differential diagnosis with other entities. In this paper we provide the reader with information for the objective and reproducible identification of pathologic MCs by using quantitative multiparametric flow cytometry, information for their phenotypic characterization, and the criteria currently used for a correct interpretation of the immunophenotypic results obtained.

Abstracts

Abstracts

Chymase expressing bone marrow mast cells in mastocytosis and myelodysplastic syndromes: an immunohistochemical and morphometric study

Background: Two cell specific neutral proteases, tryptase and chymase, are produced by human mast cells (MC). Tryptase is constitutively expressed by all MC, whereas chymase is found only in an...

Abnormal Expression of CD Antigens in Mastocytosis

Human mast cells are myeloid cells derived from human pluripotential CD34+ stem cells. Normal mast cells exhibit a myeloid immunophenotype characterized by the expression of CD117, CD33 and FcΕRI in the absence of reactivity for CD14, CD15 and lymphoid-lineage-associated antigens. Multiparametric flow-cytometric studies have shown that mast cells from mastocytosis display unique immunophenotypic characteristics, including coexpression of CD2 and CD25 antigens together with abnormally high levels of the activation-related antigens CD35, CD63 and CD69 among others. Such aberrant immunophenotypic features are of great relevance in the diagnosis and differential diagnosis of the disease, flow-cytometric immunophenotyping of mast cells representing the most sensitive method for the diagnosis of tissue involvement in mastocytosis. From the pathogenetic point of view, the immunophenotypical patterns described suggest the existence of profound changes regarding the adhesion and activation status of mast cells in mastocytosis and may represent a useful tool for a better understanding of some pathophysiological aspects of the disease.

LYMPHOID TISSUES AND THE IMMUNE SYSTEM IN MASTOCYTOSIS

The association of mast cells and lymphoid tissues may reflect either regional overproduction of growth factors for mast cells or a predisposition for mast cells at certain sites within the body, particularly the liver, lymph nodes, and spleen. The significant increase in mast cell number associated with mastocytosis is not sufficient to generate a change in either T-cell or B-cell functions, as evaluated by analyzing cytokine phenotype or immunoglobulin production, respectively, nor to expose these patients to infections or allergic diseases. Mast cells in mastocytosis cannot be said with certainty to be "normal" in all respects, however, and the failure to identify an effect of mast cells on either B-cell Ig production or T-cell cytokine profiles cannot be taken as absolute evidence that mast cell products have no influence on lymphocyte function, particularly at the local tissue level.

Linker for Activation of T Cells (LAT), a Novel Immunohistochemical Marker for T Cells, NK Cells, Mast Cells, and Megakaryocytes: Evaluation in Normal and Pathological Conditions

LAT (linker for activation of T cells) is an integral membrane protein of 36-38 kd that plays an important role in T cell activation. Using a rabbit polyclonal antibody generated against the cytosolic portion of LAT, we investigated the immunohistochemical expression of LAT in normal and pathological hematolymphoid tissues. LAT reacts with human T cells in paraffin sections, including decalcified bone marrow trephines. LAT appears early in T cells at the thymocyte stage and before TdT expression in embryos, and is expressed in peripheral lymphoid tissues, without restriction to any T cell subpopulations. In addition to T cells, natural killer (NK) cells (evaluated with flow cytometry), megakaryocytes and mast cells are also LAT-positive, whereas B cells and other myeloid and monocytic derived cells are negative. Tested on a total of 264 paraffin-embedded tissue biopsies, LAT reacted with the great majority (96.8%) of T/NK-cell neoplasms, covering the full range of T cell maturation. Although antibodies to both LAT and CD3 had a similarly high sensitivity in the staining of T/NK-cell lymphomas, when used in conjunction, they successfully identified a higher number of cases (98.4%). Atypical megakaryocytes from different hematological disorders, as well as mast cells in mastocytosis were also LAT-positive, but all neoplasms of B cell origin, Hodgkin's lymphomas, and several nonlymphoid malignancies were negative. These data indicate that the anti-LAT antibody may be of value to diagnostic histopathologists for the identification of T cell neoplasms.

Heterogeneity of mast cells in mastocytosis and inhibitory effect of ketotifen and ranitidine on indolent systemic mastocytosis

Background: Mastocytosis is a disorder of mast cell proliferation that occurs in both cutaneous and systemic forms. The most frequent site is the skin. Objective: The mast cell subtype of two patients with mastocytosis was investigated. Methods: Immunohistochemical studies were performed on the skin or gastric mucosa or both of the two patients. Blood and urine levels of various mediators were measured for one patient. Results: Mast cells containing tryptase and chymase were the only type seen in the skin lesions of an 11-month-old boy with urticaria pigmentosa. Mast cells containing tryptase were predominant in lesions of the skin and gastric mucosa of a 41-year-old man with indolent systemic mastocytosis. However, mast cells containing tryptase and chymase were predominant in the nonlesional and the normal skin of this patient. Tryptase-positive cells were more numerous in lesional skin than nonlesional skin and normal skin. Elevated blood and urine levels of various mediators were decreased by means of combination therapy with ketotifen and ranitidine. Conclusion: In indolent systemic mastocytosis, mast cell dynamics involve only cells containing tryptase. Release of mediators from mast cells may be inhibited by means of combination therapy with histamine H1 and H2 receptor antagonists. (J Allergy Clin Immunol 1997;100:S25-32.)

Phenotypic characterization of skin lesions in urticaria pigmentosa and mastocytomas.

In order to identify possible cellular abnormalities in human mastocytosis, sections from 13 urticaria pigmentosa lesions and 5 mastocytomas were compared with 5 normal skin specimens using histochemical, enzyme histochemical and immunohistochemical techniques. All toluidine blue-positive mast cells also reacted with Fc epsilon RI and c-kit antibodies, almost all stained for tryptase, many for chymase and the myeloid workshop mast cell antibodies, few for Fc epsilon RII and none for the proliferation marker Ki-67. Urticaria pigmentosa lesions contained fewer epidermal Langerhans cells and a lower percentage of avidin-positive mast cells than mastocytomas and normal skin. Mastocytomas exhibited generally weaker staining for mast cell markers and mostly lacked Fc epsilon RI-bound IgE on mast cells and Langerhans cells, although the receptor was able to bind IgE in tissue sections. Most of the mast cell antibodies also reacted with other cell types. Only toluidine blue, avidin, tryptase and chymase stains were mast cell specific. Mast cells in mastocytosis thus differed only to a minor degree from normal mast cells, although distinct pathomechanisms may play a role in urticaria pigmentosa and mastocytosis.

Dermal mast cells in mastocytosis: fixation, distribution and quantitation

The mast cell distribution and number were studied in skin biopsies of 18 mastocytosis patients and 10 controls. The biopsies were stained for mast cells with toluidine blue at pH 0.5. The number in the upper dermis of lesional abdominal skin was at least twice as high as that of normal adjacent skin. Fixation in iso-osmotic 0.6% formaldehyde and 0.5% acetic acid, revealed more mast cells than conventional 4% formaldehyde fixation. Staining for 5 days, when compared to the normal for 30 min, increased the number of demonstrable mast cells just as did the change in fixation. Conventional formaldehyde fixation thus partially blocks the dye-binding of cutaneous mast cells, about 20% of the cells escaping detection. The degree of aldehyde blocking was similar in lesional and normal skin. A more pronounced blocking of dye-binding has been demonstrated previously in gut mucosal mast cells. Whether the blocking of dye-binding is an expression of heterogeneity in dermal mast cells remains to be determined.