While most of these effects have been attributed to their soluble products, their contribution to the other stages of EAE/MS immunopathogenesis remains a matter to be clarified. mast cells in the various stages of multiple sclerosis and BPN14770 experimental autoimmune encephalomyelitis development. The final part of this evaluate is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis development. differentiation (B). The presence of numerous granules that can be stained by several dyes, including toluidine blue (A) can BPN14770 be noticed. The granular aspect of mast cells can be also seen by using phase-contrast microscopy (B). Images obtained by Pinke, KH by using Axiostar Plus HBO 50/AC Zeiss standard microscope or LEICA/DM IRBE inverted microscope, both located at Bauru School of Dentistry, University or college of S?o Paulo, Brazil. A great deal of information has been obtained from studies employing systems where progenitor cells of diverse BPN14770 origins (e.g., bone marrow, peripheral blood, fetal liver, and cord blood) can generate these cells in the presence of SCF. However, a recent study revealed that MCs progenitors from human peripheral blood can survive, mature, and proliferate independently of SCF and c-kit signaling, thus suggesting that these factors are dispensable for early MC development and that their importance for this process may be overestimated (Dahlin et al., 2017). Upon leaving the bone marrow, MC precursors populate the peripheral vascularized tissues, where they differentiate according to the locally present cytokines and activating factors. Thus, phenotypically unique populations of MCs are found in different body tissues. Human MCs differ in terms of the BPN14770 surface expression of chemokine receptors and the content of their granules, thereby allowing the categorization of these cells into MCT (made up of tryptase only), MCC (chymase only), and MCTC (both tryptase and chymase). In rats and mice, MCs are classified as mucosal and connective tissue MCs based on tissue localization (DeBruin et al., 2015; Cruse and Bradding, 2016). Additionally, MCs display dynamic plasticity according to their microenvironment, resulting in location- and function-dependent alterations that have important implications in disease clinical manifestations. Notably, tissue-specific foreign microorganisms also contribute to the complexity of MC diversity, suggesting a considerable impact of the microbiome on their functions (Cildir et al., 2017). Once established in the tissue and differentiated into mature cells, they can trigger BPN14770 an inflammatory response associated with innate and/or adaptive immunity whose general characteristics will be resolved below. Briefly, by releasing preformed and newly produced mediators, MCs are considered sentinels that warn the immune system of the RFC37 presence of numerous exogenous intruders or endogenous deleterious factors (Agier et al., 2018). Notably, MCs have a broad set of pattern recognition receptors that are able to detect and bind both pathogen- and damage-associated molecular patterns from a variety of infectious or inflammatory conditions (Agier et al., 2018). For this reason, these cells are strategically located at interface areas such as the skin, conjunctiva, genitourinary/gastrointestinal tracts, pulmonary epithelial lining, and especially round the blood/lymph vessels and nerves in a manner similar to other tissue-resident immune cells (Cruse and Bradding, 2016). In the CNS, they are specifically found in the dura mater/meninges of both the spinal cord and brain around the abluminal side of the blood-brain barrier (BBB) and, interestingly, in close proximity to astrocytes and neurons. In addition, disrupted BBB can also lead to MCs crossing into the CNS (Silverman et al., 2000; Khalil et al., 2007). The Main Immunological Properties of Mast Cells The most well-known activation pathway of MCs is the cross-linking of high-affinity receptors for IgE (FcRI), which are expressed on their surface, by specific antigens. This binding triggers the release of pre-stored bioactive mediators such as histamine, serotonin, heparin, proteolytic enzymes (e.g., tryptase and chymase), proteoglycans, arachidonic acid products, growth factors, cytokines/chemokines, and antimicrobial peptides into the extracellular microenvironment. Upon activation, they also release newly synthesized mediators with inflammatory action such as prostaglandin D2, leukotriene C4, cytokines/chemokines, as well as growth factors such as platelet-activating factor, interleukins, granulocyte.