Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts

Abstract

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

Keywords: IgE receptor; KIT; histamine; mast cell activation; mastocytosis; tryptase.

Figure 1

Development of human mast cells from stem and progenitor cells. A. Development of mast cells from uncommitted bone marrow-derived stem and progenitor cells. In adult humans, most hematopoietic stem cells (HSC) and mast cell-committed progenitor cells (cells depicted as containing only one cytoplasmic granule in this figure) are considered to originate from the bone marrow (BM) under physiologic (normal) conditions. After leaving the BM, these stem/progenitor cells are detectable in the peripheral blood and after homing to various tissues and exposure to stem cell factor (SCF) these cells undergo maturation and develop into mature mast cells. Note that in the BM, only a few HSC will become mast cell-committed. This is because, apart from SCF, other hematopoietic cytokines are also present and induce differentiation into other (non-mast cell) cell types. B. Stem and progenitor cell evolution and distribution during prenatal development. During embryonal and fetal development, primitive (immature) mesenchymal stem cells develop in the yolk sac and give rise to multipotent HSC. Both types of cells may be distributed through the blood stream and can invade other organ systems, including the liver, BM and skin (green arrows). Some of these cells may form a local pool of self-renewing HSC in extramedullary organs before birth and may be able to maintain local pools of HSC and mast cell progenitors via self-renewal in adulthood. After birth, the largest pool of self-renewing HSC is located in the BM. These HSC can leave the BM and can home to extramedullary organs (red colored arrows) where they can undergo mast cell differentiation (blue arrows). However, pools of self-renewing HSC and HSC-derived mast cell progenitors may also originate from yolk sac-derived stem cells and may later persist in adults. These cells develop into mast cells in local organs independent of the BM. There may be additional trafficking routes followed by certain subsets of HSC and mast cell progenitors homing from one to another organ system (dotted line-arrows); however, robust data supporting such HSC trafficking routes in humans are not available. Abbreviations: GI tract, gastrointestinal tract; LNs, lymph nodes.

Figure 2

Lineage relationships between human mast cells, basophils and monocytes based on CD antigen expression profiles. Human lung mast cells (MC), the human mast cell line HMC-1, normal blood basophils (BA), the human basophil cell line KU812, normal blood monocytes (MO) and the human monoblastic cell line U-937 were analyzed using a panel of 90 different CD antibodies provided by the Leukocyte Typing Workshops. Based on antibody-reactivities, linkage distance analyses were performed (Agis H, et al., Immunology. 1996; 87: 535-43). As expected, the linkage distance within the cell lineages examined (primary cells versus respective cell lines) is low. Primary basophils and monocytes and the respective lines were also found to be related phenotypically. By contrast, however, the phenotype of MC did not reveal a close relationship with BA or MO, neither in the cell line context nor in primary cells (primary MC vs primary BA). These data suggest that MC and BA form two separate (independent) hematopoietic cell lineages within the leukocyte family.