The Master Switch: The Role of Mast Cells in Autoimmunity and Tolerance

Abstract

There are many parallels between allergic and autoimmune responses. Both are considered hypersensitivity responses: pathologies that are elicited by an exuberant reaction to antigens that do not pose any inherent danger to the organism. Although mast cells have long been recognized as central players in allergy, only recently has their role in autoimmunity become apparent. Because of the commonalities of these responses, much of what we have learned about the underlying mast cell-dependent mechanisms of inflammatory damage in allergy and asthma can be used to understand autoimmunity. Here we review mast cell biology in the context of autoimmune disease. We discuss the huge diversity in mast cell responses that can exert either proinflammatory or antiinflammatory activity. We also consider the myriad factors that cause one response to predominate over another in a particular immune setting.

P2 receptor-mediated signaling in mast cell biology

“…Mast cells are recognized as the key components of allergic inflammatory reactions, but they are also implicated in the pathogenesis of a number of chronic inflammatory diseases, in wound healing, in fibrosis, thrombosis/fibrinolysis, and in innate immunity (reviewed in [11][12][13][18][19][20]). They are described as long-living cells keeping relatively constant numbers in tissues under physiologic conditions.…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast cells can function as effector cells during innate [1][2][3] and acquired 1,[4][5][6] immune responses. Such 'effector functions' of mast cells include killing pathogens 2,3,7 , degrading potentially toxic endogenous peptides [8][9][10] or components of venoms 9,11 , and regulating the numbers, viability, distribution, phenotype or 'non-immune' functions of structural cells, such as fibroblasts and vascular endothelial cells.…”

“…Such 'effector functions' of mast cells include killing pathogens 2,3,7 , degrading potentially toxic endogenous peptides [8][9][10] or components of venoms 9,11 , and regulating the numbers, viability, distribution, phenotype or 'non-immune' functions of structural cells, such as fibroblasts and vascular endothelial cells. Mast cells can exert their effector functions through the direct or indirect actions of a wide spectrum of mast-cell-derived products, and such effects can be observed in both innate [1][2][3]12 and acquired 1,5,6,12,13 immune responses (BOX 1).…”

“…Through effector and/or immunomodulatory functions, mast cells can promote the initiation and increase the magnitude of inflammation, tissue remodelling and, in some cases, tissue injury associated with the innate or adaptive immune responses to pathogens, as well as during allergic or autoimmune disorders [1][2][3][5][6][7]13 . Given the many mechanisms by which mast cells can mediate these effects, they are often thought of as cells whose primary role is to 'turn on an immune response'.…”

“…In this Perspective article, we highlight some basic aspects of mast-cell biology and briefly discuss some of the functions, products and surface receptors expressed by mast cells that contribute to the immunomodulatory function of these cells (reviewed in REFS 1,3,5,6,13 ). We describe mouse models used to analyse mast-cell function in vivo and to identify immunomodulatory roles for mast cells during specific immune responses.…”