Mast cell là gì

Peter Valent1

*
, Cem Akin2, Karin Hartmann3, Gunnar Nilsson4, Andreas Reiter5, Olivier Hermine6, Karl Sotlar7, Wolfgang R. Sperr1, Luis Escribano8, Tracy I. George9, Hanneke C. Kluin-Nelemans10, Celalettin Ustun11, Massimo Triggiani12, Knut Brockow13, Jason Gotlib14, Alberkhổng lồ Orfao8, Petri T. Kovanen15, Emir Hadzijusufovic1,16, Irimãng cầu Sadovnik1, Hans-Peter Horny17, Michel Arock18, Lawrence B. Schwartz19, K. Frank Austentrăng tròn, Dean D. Metcalfe21, Stephen J. Galli22

1. Department of Medicine I, Division of Hematology & Hemostaseology & Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienmãng cầu, Austria.

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2. Division of Allergy và Clinical Immunology, University of Michigan, Ann Arbor, XiaoMI, USA.3. Division of Allergy, Department of Dermatology, University of Basel, Basel, Switzerl&.4. Department of Medicine Solmãng cầu & Mastocytosis Centre, Karolinska Institutet & Karolinska University Hospital, Stockholm, Sweden.5. Department of Hematology and Oncology, University Hospital Mannhelặng, Heidelberg University, Mannhelặng, Germany.6. Imagine Institute Université Paris Descartes, Sorbonne, Paris Cibổ, Centre national de référence des mastocytoses, Paris, France.7. Institute of Pathology, Paracelsus Medical University Salzburg, Austria.8. Servicio Central de Citometria (NUCLEUS), Centro de Investigacion del Cancer (IBMCC; CSIC/USAL & CIBERONC) and Department of Medicine, University of Salamanca, Spain.9. Department of Pathology, University of Utah, Salternative text Lake City, UT, USA.10. Department of Hematology, University Medical Center Groningen, University of Groninren, The Netherlands.11. Division of Hematology-Oncology và Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.12. Division of Allergy and Clinical Immunology, University of Salerno, Italy.13. Department of Dermatology và Allergy Biederstein, Technical University of Munich, Germany.14. Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, USA.15. Wihuri Retìm kiếm Institute, Helsinki, Finland.16. Department of Companion Animals và Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine Vienmãng cầu, Austria.17. Institute of Pathology, Ludwig Maximilian University, Munich, Germany.18. INSERM UMRS1138, Centre de Recherbịt des Cordeliers, Paris, France.19. Department of Internal Medicine, Division of Rheumatology, Allergy và Immunology, Virginia Commonwealth University, Richmond, VA, USA.20. Division of Allergy and Immunology, Department of Medicine, Brigsi and Women"s Hospital, Harvard Medical School, Boston.21. Laboratory of Allergic Diseases, NIAID, NIH, Bethesdomain authority, MD, USA.22. Departments of Pathology and of Microbiology and Immunology, và the Sean N. Parker Center for Allergy và Asthma Research, Stanford University School of Medicine, Stanford, USA.*This paper, reflecting both the more recent developments in the field and the presentations and discussions at a meeting held in 2015 khổng lồ mark the 100th Anniversary of the death of Paul Ehrlich, is dedicated khổng lồ the pioneering work and scientific achievements of this remarkable scientist.


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Citation:
Valent P., Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, Sotlar K, Sperr WR, Escribano L, George TI, Kluin-Nelemans HC, Ustun C, Triggiani M, Brockow K, Gotlib J, Orfao A, Kovanen PT, Hadzijusufovic E, Sadovnik I, Horny HP, Arochồng M, Schwartz LB, Austen KF, Metcalfe DD, Galli SJ. Mast cells as a quality hematopoietic lineage and cell system: From Paul Ehrlich"s visions lớn precision medicine concepts. Theranostics 2020; 10(23):10743-10768. doi:10.7150/dramrajani.com.46719. Available from https://www.dramrajani.com/v10p10743.htm EndNote MEDLINE BibTex ReferenceManager RIS Go Clichồng on Go to lớn download the tệp tin. In Endchú ý Library, go to File – Import. Select the tệp tin that you have just downloaded & select import option Reference Manager (RIS). Click on Import.File import instruction
Abstract

The origin and functions of mast cells (MCs) have been debated since their mô tả tìm kiếm by Paul Ehrlich in 1879. MCs have sầu long been considered "reactive bystanders" & "amplifiers" in inflammatory processes, allergic reactions, & host responses lớn infectious diseases. However, knowledge about the origin, phenotypes và functions of MCs has increased substantially over the past 50 years. MCs are now known lớn be derived from multipotent hematopoietic progenitors, which, through a process of differentiation và maturation, khung a chất lượng hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils & other hematopoietic cells by their unique phenotype, origin(s), và spectrum of functions, both in innate và adaptive sầu immune responses and in other settings. The concept of a chất lượng MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expvà as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis & in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions & physiological processes. In this article, we nhận xét concepts regarding MC development, factors controlling MC expansion and activation, & some of the fundamental roles MCs may play in both health & disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

Keywords: histamine, IgE receptor, KIT, mast cell activation, mastocytosis, tryptase

Introduction

Mast cells (MCs) are tissue-resident, multifunctional effector cells of the innate immune system that can also substantially contribute to adaptive sầu immune responses. Historically, MCs were described & originally named by Paul Ehrlich in 1879 based on their chất lượng dye-staining properties <1>. Ehrlich also described the blood basophil và certain morpholô ghích similarities between both cell types. However, the origin of MCs, và their roles in health and disease, remained mysteries for many decades. Two key clues in defining the functions of MCs were the demonstration that MCs contain histamine & can bind immunoglobulin E (IgE) <2-6>. Based on these observations and subsequent preclinical and clinical studies, MCs are now recognized as key effector cells in IgE-dependent allergic inflammation <3-7>.

Today, the contributions of MCs to lớn allergic & other inflammatory reactions are well established <3-11>. MCs express high-affinity receptors for IgE and produce numerous biologically active substances, some of which are stored in cytoplasmic granules for rapid release <2-4>. It is now known that MCs may be activated by many different agents. These include specific antigens (allergens) through allergen-specific IgE and IgE receptors, by certain cytokines, anaphylatoxins, certain neuropeptides, & exogenous toxins, và also by IgG immune complexes và complement, certain drugs, & products of bacteria or other pathogens <2-9, 11>. MCs activated by such mechanisms can release their granule-stored mediators, including histamine. In addition, activated MCs may syntheform size và secrete many other types of mediators, such as lipid mediators, cytokines & chemokines, và thereby trigger local and systemic reactions <2-7>. Although MC activation is observed in a variety of inflammatory, infectious, & other reactive sầu conditions, it has been best characterized during IgE-dependent allergic reactions.

Human MCs have sầu the ability to re-granulate after degranulation and thereby participate in multiple cycles of activation with mediator secretion <8>. Moreover, certain MCs resident constitutively within tissues have a remarkably long life span, ranging from months to years, contrasting with the much shorter life span of basophils & other type of granulocytes <9-11>. Some MC populations, such as those induced in the gut of mice during infections with certain parasites, can rapidly expvà and then drop bachồng lớn approximately baseline levels upon resolution of the infection <9, 12, 13>. Thus, in addition to lớn the long-term, relatively stable MC populations found in many tissues, shorter-lived populations of MCs also appear khổng lồ exist. These MCs can expand and contract in particular sites in response to lớn local processes, including parasite infections.

However, the rapid expansion of MC populations in multiple organs, including the skin, respiratory system và gastrointestinal tract, is also observed in mice, rats & cynomolgus monkeys injected with the major mast cell growth factor stem cell factor (SCF), also known as KIT ligvà <9, 12-14>. Upon cessation of SCF injections, the numbers of these expanded MC populations can rapidly return toward baseline values <12-14>. These findings, along with the observations that mucosal MCs are absent in T cell-deficient mice, indicate that tissue MC populations may be responsive to changes in ambient levels of soluble SCF, or, perhaps, lớn changes in membrane-bound SCF or other cytokines.

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In this article, we will discuss the progress that has been made over the last decades in addressing the origin & functions of MCs in health và disease, và regarding their neoplastic expansion. We will also discuss current diagnostic & therapeutic approaches lớn diseases involving MCs, particularly neoplastic disorders.

Origin of MCs

After their description và naming by Paul Ehrlich in 1879 <1>, MCs were soon identified as tissue-resident cells in multiple organs, prompting discussions about their origin và functions. It was proposed initially that MCs were derived from blood basophils or from a local histiocytic progenitor. This debate lasted many decades, as no experimental Mã Sản Phẩm was available lớn resolve sầu the issue. However, approximately 100 years after their discovery, the origin of MCs from transplantable hematopoietic stem cells was convincingly demonstrated. This was done in a series of elegant transfer-experiments (và other studies) in mice by Yukihiko Kitamura and his colleagues <15-18>. Later, the origin of MCs from transplantable hematopoietic stem cells was confirmed in humans <10>. In both species, MCs were found to develop from immature (CD34+) hematopoietic precursor cells when these were cultured in the presence of certain cytokines or on stromal cells <19-23>.

Subsequent attempts evaluated whether MCs were directly derived from hematopoietic stem cells, from a later progenitor, or even from a mature leukocyte. However, all attempts to lớn grow human MCs from highly purified blood monocytes or blood basophils failed, regardless of the cytokines or culture conditions employed <24>. Moreover, in colony assay experiments, human MCs were found to lớn grow preferentially in pure MC colonies or in colonies containing MCs và basophil-like cells <24, 25>. Based on these & more recent observations a bi-committed MC/basophil progenitor cell has been postulated, but the existence of such a cell is still under debate. By contrast, some MCs were also detected in mixed colonies derived from pluripotent stem cells <24, 25>. Based on these observations, human MCs were considered lớn derive directly from pluripotent CD34+/KIT+ stem cells in various organ systems. Such multi-lineage và MC-committed CD34+ stem cells are detectable in the bone marrow (BM), peripheral blood (PB) và in the peripheral tissues in most extramedullary organs <9, 22-27>.

Based on such observations, most CD34+/KIT+ MC progenitors are now considered to lớn originate in the BM, to translocate from the BM inkhổng lồ the PB, & to enter peripheral tissue sites after homing to various organs (Figure 1A) <9, 26, 27>. In addition, progenitors with the potential to lớn generate MCs have sầu been identified in the yolk sac <28, 29> and White adipose tissue of mice <30>. These latter observations have supported the assumption that BM-independent pools of self-renewing stem cells giving rise to MC progenitors may also develop in local tissue sites early during prenatal development; these cells then can be maintained (via the self-renewal capacity of local stem cells) throughout the lifetime of the organism (Figure 1B).

The phenotypic properties of MC-committed progenitor cells have been described in mice & humans <22, 26, 27, 31-37>. In humans, these cells express CD34, KIT (CD117), the interleukin-3 receptor (IL-3R) and CD13, but display only low, if any, amounts of FcεRI <31-37>. Later, during MC development, MC precursors stop expressing CD34 và the IL-3R altrộn chain (CD123) và start expressing higher levels of FcεRI and KIT <27, 34-36>. Importantly, MC progenitors display a number of adhesion molecules through which these cells may enter peripheral (extramedullary) organs & tissues. For example, in the mouse, beta7 integrin mediates the adhesion needed for transendothelial movement of BM-derived MC progenitors into lớn peripheral tissues <38>.

Despite the many new insights into lớn the origin and development of MCs, several questions remain. First, it is not clear whether human MCs also can be derived from pre-formed local pools of CD34+ stem cells within extramedullary organs. Such a local pool of CD34+ MC precursors might be established early in life or even during embryogenesis (Figure 1B). Another related question is whether MCs in local tissue sites can sometimes emerge from a bi-committed progenitor cell, giving rise to MCs & macrophages or MCs và other leukocytes. In other words, although the direct origin of MCs from blood-born mature monocytes has been formally excluded <24>, it remains unknown whether some MCs originate from local bi-committed progenitor cells giving rise khổng lồ MCs và macrophages at local tissue sites. In this regard, it is worth noting that MCs và macrophages tóm tắt functional and phenotypic similarities & that advanced systemic mastocytosis (SM) is often accompanied by chronic myelomonocytic leukemia (CMML) <39-42>. On the other hvà, no association between SM & histiocytic tumors has yet been described. Finally, while definitive information about the exact relationship between human mast cells and basophils remains lớn be ascertained, most available evidence is consistent with the conclusion that the mature basophil và mast cell lineages are distinct <24, 43, 44>.

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Regulation of MC Differentiation, Maturation và Survival

In the mouse, a number of interleukins (ILs), including IL-3, IL-4, IL-9 và IL-10, promote the development of MCs from their BM progenitor cells (Table 1) <9, 22, 45-48>. However, apart from the support provided by the IL-network, development of mouse MCs is also regulated by tissue-resident stromal cells <9, 20, 21>. In a series of pivotal studies, SCF was identified as a major player in stem cell- & MC development and survival in the mouse <9, 12, 26, 49, 50>. Deprivation of MC-cultures of SCF (or of SCF-expressing stromal cells) results in MC growth arrest and apoptosis <9, 26>. Correspondingly, Sl/Sld mice (now designated C57BL/6-KitlSl/Sl-d mice) lacking (functional) SCF and W/W-v mice (now designated WBB6F1-KitW/W-v mice) lacking a functional SCF receptor, KIT, exhibit a MC-deficient phenotype <9, 15-18, 26>.


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