In this issue, Matsumoto et al.(1) report that histamine exocytosed from brain mast cells (MCs) after activation by antigenic cross-linking of the high affinity IgE receptor (FcεRI) acts via Hl receptors at the hypothalamus to elicit corticotropin-releasing factor (CRF). These findings reveal a homeostatic response to a pathobiologic event in the dog. Conversely, CRF can also be proinflammatory by mediating activation of tissue MCs (2). This action is implicated in the acute immobilization stress response of the rat, in which degranulation of brain MCs is associated with a histamine H2 receptor–mediated increase in permeability of the blood–brain barrier (3). These models remind us that the inflammatory response is homeostatic in principle and pathobiologic only when the same pathways lead to an outcome that is more detrimental than beneficial to the host. Thus, the elegant demonstration that experimental allergic encephalomyelitis in the mouse can be MC dependent (4) invites readers to think of the contribution of the MC to dysfunction of the blood–brain barrier rather than its homeostatic hypothalamic-pituitary-adrenal signal function. As the documented role of the MC expands beyond recognition of its contribution to adverse local and systemic allergic responses, it is pertinent to review its development, remarkable proinflammatory armamentarium, and participation in an evolving number of models of pathobiologic processes.

Although MCs are derived, like other leukocytes, from hematopoietic stem cells (5), they do not mature before exiting the bone marrow and circulate as committed progenitors. These progenitors complete their maturation with concomitant phenotypic diversity after moving into diverse peripheral tissues (Fig. 1). Their presence in these peripheral tissues depends on the action of their cell surface tyrosine kinase, c-kit, and its ligand, stem cell factor (SCF). The circulating progenitors have been isolated from human blood as c-kit+CD34+CD13+FcεRIJ cells. This population contains both committed progenitors and cells that are bipotent, that is, able to differentiate into either MCs or monocytes (6). Progenitors also have been identified in the blood of 15.5-d-old fetal mice, where they represent an usually high proportion (2.5%) of the mononuclear cells