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Blood, 1 January 2006, Vol. 107, No. 1, pp. 1-2.
Next Article 
IMMUNOBIOLOGY
Comment on Qi et al, page 135, and Edelson et al, page 143
Mast cells: must they always be different?
Hovav Nechushtan, and
Ehud Razin
HADASSAH HEBREW UNIVERSITY MEDICAL CENTER and HEBREW UNIVERSITY-HADASSAH MEDICAL SCHOOL
In this issue of Blood, two papers describe the unexpected role played by 2 known proteins—CD9 and the  2 1 integrin—as receptors for the chemoattractant IL-16 and for C1q, respectively, in mast cells.
Mast cells are widely recognized as critical effector cells in allergic disorders and other immunoglobulin E-associated acquired immune responses, yet one should not overlook their role as initiators and effectors of innate immunity. By secretion of their inflammatory mediators during innate immune responses to pathogens, activated mast cells can amplify the magnitude or regulate the kinetics of adaptive immune responses.
It seems that the trigger and the mechanism behind the migration of mast cells towards the inflammatory sites and their secretion of bioactive molecules are not necessarily similar to those underlying the response of other immune cells. A known example of such specificity is that of the mast-cell regulatory element of IL-4 production, which is distinct from that of T cells.1
Two research groups, Qi and colleagues and Edelson and colleagues, describe in this issue of Blood novel interactions between ligands and surface receptors in mast cells that have not been described before in any other cell types. Qi and colleagues observed that IL-16 can induce mast cell migration not only through CD4, the well-characterized receptor of IL-16, but also through the tetraspanin, CD9. IL-16 was first described as a T-cell chemoattractant factor and it has been linked to pathological events such as asthma and inflammatory bowel disease. Indications for the role played by mast cells in these diseases have been described in the literature.2-4 While this group has previously shown a possible significance of the IL-16 binding to CD4 in mast cells,5 they noticed that IL-16 activates mast cells even in cells that lacked the expression of surface CD4. Thus, they postulated that in mast cells IL-16 receptors could belong to the tetraspanin cell-surface family of proteins, a family that forms multimeric complexes with CD4.6 Using antibodies to different tetraspanins and antisense methodology they revealed that one of those proteins, CD9, is important for IL-16 activation of human mast-cell migration.
Hence, it could be hypothesized that IL-16 might activate mast cells in asthma and inflammatory bowel disease by different mechanisms than those which occur upon T-cell activation.
While this research group has focused on a cytokine that has a major role in mast-cell migration, the second research group of Edelson et al tried to reveal the role played by the 21 integrin in mast cells. Previous work from the same group demonstrated that 21 integrin-deficient mice exhibit markedly diminished inflammatory responses to both Listeria monocytogenes, a Gram-positive bacterium, and zymosan, a fungal polysaccharide, thus demonstrating the critical role of 21 integrin in peritonitis.7 They now describe a hitherto unknown interaction between 21 integrin and the collagen-like domain-containing proteins, including, most importantly, C1q. In their work they demonstrated the binding of C1q and other collections to 21 integrin, and use a site-directed mutated 2 integrin to demonstrate increased binding of C1q to the "open," higher-affinity 2 integrin. In their most physiologically relevant experiment they demonstrated that mast-cell secretion of IL-6, after stimulation by Listeria containing immune complex, could not occur if the serum coating the Listeria originated from C1q knockout mice, or if the mast cells were derived from 2 integrin knockout mice. Thus it seems that C1q interactions with 21 integrin are necessary for the induction of IL-6 secretion. This interaction was not sufficient for IL-6 secretion and was dependent on other stimulatory interactions; for example, it may be that a TLR protein is crucial for the full IL-6 secretion to occur.
Both works describe new receptor-ligand interactions with potentially critical roles in mast-cell function. It seems unlikely that all these receptor-ligand interactions will be unique to mast cells. It is more probable that the accumulation of different receptor-ligand interactions in mast cells compared with other cells such as T cells and macrophages is responsible for the creation of the unique network of responses of mast cells under a variety of physiological conditions. 
References
- Weiss DL, Brown MA. Regulation of IL-4 production in mast cells: a paradigm for cell-type-specific gene expression. Immunol Rev. 2001;179: 35-47.[CrossRef][Medline]
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- Maurer M, Theoharides T, Granstein RD, et al. What is the physiological function of mast cells? Exp Dermatol. 2003;12: 886-910.[CrossRef][Medline]
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- He SH. Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol. 2004;10: 309-318.[Medline]
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- Williams CM, Galli SJ. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J Exp Med. 2000;192: 455-462.[Abstract/Free Full Text]
- Qi JC, Stevens RL, Wadley R, et al. IL-16 regulation of human mast cells/basophils and their susceptibility to HIV-1. J Immunol. 2002;168: 4127-4134.[Abstract/Free Full Text]
- Boucheix C, Rubinstein E. Tetraspanins. Cell Mol Life Sci. 2001;58: 1189-1205.[CrossRef][Medline]
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- Edelson BT, Li Z, Pappan LK, Zutter MM. Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin. Blood. 2004;103: 2214-2220.[Abstract/Free Full Text]
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