*1.2. Di*ff*erent Roles of Mast Cells in Physiology and Pathophysiology*

MCs take part in processes of innate and adaptive immunity, alerting the body to invasion by bacteria and parasites, and regulating lymphocyte reactions [17,18]. Moreover, through the release of different proteases, MCs are able to attenuate snake-venom-induced and honeybee-venom-induced pathology by degrading the proteinaceous venom components [19]. They also promote homeostasis by limiting endothelin-1-induced toxicity in a carboxypeptidase-A3-dependent manner [20,21]. Also, on the beneficial side, MCs have a positive impact on bone repair, most likely by recruiting vascular endothelial cells during the inflammatory phase, and by coordinating anabolic and catabolic activities during tissue remodeling [22]. Moreover, myocardial MCs regulate heart function after a myocardial infarction [23], and mucosal MCs in the intestinal epithelium execute anti-helminth immunity [24].

In addition to these beneficial functions, MCs play detrimental roles as well, e.g., as central effector cells in acute allergic disorders (such as rhinitis, asthma, and anaphylactic reactions) [25]. Moreover, MCs promote T cell-driven collagen-induced arthritis. However, they are dispensable for antibody-induced arthritis in which T cells are bypassed [26]. MCs are also known to modulate the growth/metastasis of certain solid tumors [27] and can contribute to the development of various fibrotic diseases [28]. In septic peritonitis, MCs have been demonstrated to suppress the phagocytosis of bacteria by peritoneal macrophages in an IL-4-dependent manner. Thus, MCs can aggravate the outcome of severe bacterial infections [29]. Neither the number of positive nor the number of negative functions of MCs mentioned above are exhaustive; nevertheless, they provide an idea about the variety of the biological functions of MCs.

In addition, detrimental outcomes are known for patients suffering from mastocytosis, which is a rare and heterogeneous disease characterized by the expansion and accumulation of clonal (neoplastic) tissue MCs in one or more organ systems [30,31]. Mastocytosis can be divided into subvariants of cutaneous mastocytosis, different types of systemic mastocytosis (SM), and localized MC tumors. SM is further divided into several subtypes (i.e., indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia [30,31]). The different subtypes of mastocytosis exert highly variable clinical courses, ranging from asymptomatic with a normal life expectancy to fatal with high mortality within months or weeks [30,31]. Additionally, clinical conditions related to MC activation, where symptoms are recurrent, are accompanied by an increase in MC-derived mediators in biological fluids, and are responsive to treatment with MC-stabilizing or mediator-targeting drugs, can/might be diagnosed as MC activation syndrome (MCAS) [32] (for a proposed diagnostic algorithm for MCAS we refer to Valent et al. [33]). In conclusion, MCs can be regarded as a versatile cell type with differential functions in physiological and pathophysiological settings, and hence, MCs are very attractive drug targets.
