Protease profile of normal and neoplastic mast cells in the human bone marrow with special emphasis on systemic mastocytosis

Abstract

Mast cells (MC) are immune cells that produce a variety of mediators, such as proteases, that are important in the body’s immune responses. MC proteases have pronounced multifunctionality and in many respects determine the biological characteristics of the organ-specific MC population. Although, increased numbers of MC are one of the objective mastocytosis signs, a detailed assessment of the proteases biogenesis and excretion mechanisms in the bone marrow (BM) has not yet been carried out. Here, we performed an analysis of the expression of proteases in patients with various forms of systemic mastocytosis. We presented data on intracellular protease co-localization in human BM MCs and discussed their implication in secretory pathways of MCs in the development of the disease. Systemic mastocytosis, depending on the course, is featured by the formation of definite profiles of specific proteases in various forms of atypical mast cells. Intragranular accumulation of tryptase, chymase and carboxypeptidases in the hypochromic phenotype of atypical mast cells is characterized. Characterization of MC proteases expression during mastocytosis can be used to refine the MC classification, help in a prognosis, and increase the effectiveness of targeted therapy.

Carboxypeptidase A3—A Key Component of the Protease Phenotype of Mast Cells

“…The content of CPA3 in granules and the number of CPA3 + granules in the cytoplasm of MC show a wide variability, from absence or low content to full filling of the cell volume (Figures 2-5). Localization of carboxypeptidases in MC granules is convincingly demonstrated by immunohistochemical protocols and can be used to characterize the structure of the MC population (Figures 2-5) [84]. The technological features of immunomorphological staining make it possible to assess the cellular and intragranular localization of CPA3 in MCs by other specific proteases (Figure 2), as well as co-localization of CPA3-positive MCs with components of a specific tissue microenvironment.…”

“…In particular, this judgment was made in the analysis of secretory granules after degranulation of MC, in which chymase with CPA3, or only tryptase was detected [38,39,43]. At the same time, we have shown that tryptase is also detected in CPA3 + granules after degranulation [84] (Figure 3b,c). Thus, the phenotype of specific proteases of secreted granules can be significantly variable depending on the state of the specific microenvironment.…”

Mast Cell Proteases Tryptase and Chymase Induce Migratory and Morphological Alterations in Bronchial Epithelial Cells

“…It is, however, difficult to determine how much tryptase is released in vivo, as well as the local concentration around each epithelial cell when MCs degranulate. MCs can secrete mediators in various ways, for example, through piecemeal or anaphylactic degranulation [ 63 ], and the effects on the airway epithelial cells are likely to vary with protease concentration. Due to that MC proteases are secreted in large aggregates, complexed with serglycin proteoglycans, and these complexes tend to accumulate locally [ 26 ], the local concentration of MC mediators is likely to be quite high.…”

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

“…Under the influence of local tissue-derived maturation factors, mast cell differentiation results in the development of well-recognized phenotypes: mucosal mast cells (mainly tryptase-expressing or MCT cells, located predominantly in the mucosa) and alveoli and connective tissue mast cells (expressing tryptase, chymase, and carboxypeptidase A3 or MC-TC, located in submucosal and connective tissue sites such as skin) [ 2 , 3 , 4 , 5 ]. Atiakshin and co-workers have demonstrated the colocalization of tryptase and chymase in the same mast cell granules using sophisticated immunohistochemical techniques [ 41 ]. In Th2-mediated diseases, such as atopic asthma and nasal polyposis, intraepithelial MC-T cells may undergo structural changes.…”