Mast Cell Development and Differentiation

Mast cells develop from progenitor cells that in turn arise from uncommitted hematopoietic stem cells in the bone marrow (5,6). These cells express the receptor for stem cell factor (SCF receptor or c-kit) that binds to SCF, the latter being a major growth factor for mast cells (5-7). Researchers have described a CD34+, c-kit+, and CD13- precursor that develops into mast cells in the presence of specific growth factors (8,9). Mast cell progenitors also have been described in peripheral blood by others, which may suggest the presence of a distinct pool of cells separate from leukocytes or mononuclear cells (10). The interactions between SCF and c-kit and the subsequent signaling that follows are crucial for the growth and development of mast cells (11). In humans, studies have demonstrated that mutations of c-kit and elevated levels of the c-kit proto-oncogene are associated with the development of the syndrome of mas-tocytosis, a condition characterized by mast cell infiltration of skin and other tissues (12,13). SCF has multiple biological effects on mast cells, including modulating differentiation and homing, prolonging viability, inducing mast cell hyperplasia, and enhancing mediator production (7). However, mast cells that have been deprived of SCF undergo programmed cell death (PCD) or apoptosis (14). It is likely that PCD in mast cells is mediated by the modulation of Bcl-2 and Bcl-XL (15). Interleukin 6 (IL-6), eotaxin, and nerve growth factor (NGF) also enhance mast cell development from hematopoietic stem cells, and the development of mast cells from stem cells derived from umbilical cord blood often requires SCF in conjunction with IL-6 (5,16). Adventitial cells, including fibroblasts, contribute to further differentiation and maturation of mast cells in tissue by elaboration of SCF, NGF, or other mechanisms (17,18). After tissue

•FceRI: Antigen/IgE •Neuropeptide receptors: Substance P •Complement receptors: C3a/C5a •Bacterial receptors; Moraxella Catarrhal® •IL-1 receptor: IL-1

•Toll-like receptor; Lipopolysaccharide

Mediators •Histamine •PAF/Lipid •Proteases

•Cytokine-chemokine •Nitric oxide •Endothelin

Fig. 1. Mast cells undergo activation by IgE-dependent and IgE-independent stimuli, leading to release of a cascade of mediators culminating in the inflammatory response. Histamine, platelet-activating factor (PAF), lipid mediators (leukotrienes, prostanoids), proteases, cytokines, chemokines, nitric oxide, and endothelin may be released in the tissue, which can lead to inflammatory cell recruitment, endothelial activation, and cellular adhesion.

localization, mast cells can undergo further differentiation into distinct subsets. Two mast cell subtypes have been described in tissue—the mucosal (MCT) or connective tissue (MCtc) mast cell (Table 1). These subtypes are based on structural, biochemical, and functional differences and have been well characterized by several researchers (3,19-21). Please see Chapter 4 for more information.

Distinctive features help differentiate the two subsets. For example, the McT mast cell predominantly expresses the protease tryptase (Fig. 2A demonstrates tryptase staining of mast cells derived from umbilical cord blood mononuclear cells). This subset usually is localized to mucosal surfaces, often in close prox-

Mediators •Histamine •PAF/Lipid •Proteases

•Cytokine-chemokine •Nitric oxide •Endothelin

Fig. 1. Mast cells undergo activation by IgE-dependent and IgE-independent stimuli, leading to release of a cascade of mediators culminating in the inflammatory response. Histamine, platelet-activating factor (PAF), lipid mediators (leukotrienes, prostanoids), proteases, cytokines, chemokines, nitric oxide, and endothelin may be released in the tissue, which can lead to inflammatory cell recruitment, endothelial activation, and cellular adhesion.

Table 1

Mast Cell Subtypes

Table 1

Mast Cell Subtypes

Feature

MCTC cell

MCT cell

Structural features

Grating/lattice granule

++

-

Scroll granules

Poor

Rich

Tissue distribution

Skin

++

-

Intestinal submucosa

++

+

Intestinal mucosa

+

++

Alveolar wall

-

++

Bronchi

+

++

Nasal mucosa

++

++

Conjunctiva

++

+

Mediator synthesized

Histamine

+++

+++

Chymase

++

-

Tryptase

++

++

Carboxypeptidase

++

-

Cathepsin G

++

-

ltc4

++

++

PGD2

++

++

TNF-a

++

++

IL-4, IL-5, IL-6, IL-13

++

++

imity to T cells. These T lymphocytes are especially of the T-helper 2-type (Th2 secreting IL-4 and IL-5). This subset usually is seen in increased numbers infiltrating the mucosa in patients suffering from allergic and parasitic disease. Because of their unique T cell-dependence, the numbers of MCT cells are diminished in individuals infected with human immunodeficiency virus (HIV) (3). Structurally, granules from MCT are scroll-rich (Fig. 2B demonstrates a typical scroll-like granule in mast cells developed from umbilical cord blood mono-nuclear cells).

The MCtc mast cell, however, expresses tryptase, chymase, carboxypepti-dase, and cathepsin G. It tends to predominate in the gastrointestinal tract as well as in skin, synovium, and subcutaneous tissue (Table 1). Increased numbers of MCTC mast cells are seen in fibrotic diseases whereas its numbers are relatively unchanged in allergic or parasitic diseases and in HIV infection. The presence of these MCtc cells could help explain why patients with HIV infection continue to have allergic reactions (e.g., to medications). MCtc mast cells have lattice and grating structures and are scroll-poor.

Mast Cell Nerve Interaction

Fig. 2. (A) Tryptase immunostaining of human cord blood-derived mast cells (x400). In this specimen, more than 95% of human cord blood-derived mast cells expressed tryptase, with only 20% expressing chymase. (B) Ultrastructurally, mast cells demonstrate microvilli-like projections on the surface and typical granules. This picture demonstrates the presence of scroll-like granules within the mast cell derived from umbilical cord blood mononuclear cells.

Fig. 2. (A) Tryptase immunostaining of human cord blood-derived mast cells (x400). In this specimen, more than 95% of human cord blood-derived mast cells expressed tryptase, with only 20% expressing chymase. (B) Ultrastructurally, mast cells demonstrate microvilli-like projections on the surface and typical granules. This picture demonstrates the presence of scroll-like granules within the mast cell derived from umbilical cord blood mononuclear cells.

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