Cutting Edge: Genetic Variation Influences FcεRI-Induced Mast Cell Activation and Allergic Responses

Abstract

Mast cell responses are influenced by a diverse array of environmental factors, but little is known about the effect of genetic background. In this study, we report that 129/Sv mice had high levels of circulating IgE, increased expression of the high-affinity receptor for IgE (FcεRI), and greater sensitivity to anaphylaxis when compared with C57BL/6 mice. Bone marrow-derived mast cells (BMMCs) from 129/Sv mice showed more robust degranulation upon the engagement of FcεRI. Deficiency of the Src family kinase Lyn enhanced degranulation in 129/Sv BMMCs but inhibited this response in C57BL/6 cells. C57BL/6 lyn−/− BMMCs had reduced expression of the Src family kinase Fyn, and increasing its expression markedly enhanced degranulation. In human mast cells the silencing of Lyn or Fyn expression resulted in hyperdegranulation or hypodegranulation, respectively. The findings demonstrate a genetic influence on the extent of a mast cell’s response and identify Fyn kinase as a contributory determinant.

Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgE

“…Thus, for example, 129/SvJ mice have considerably higher levels of circulating IgE than that found in C57BL/6 mice. Relative to the C57BL/6 mouse, increased levels of IgE in the 129/SvJ mouse enhances the onset and extent of allergic responses because high IgE levels cause increased expression of FcεRI and also cause full occupancy of this receptor, increasing the sensitivity to an allergenic stimulus (Yamashita et al, 2007). More recently, we've found that the 129/SvJ mice also have higher levels of circulating S1P relative to the C57BL/6 mouse (AO and JR, unpublished observation).…”

“…Interestingly, the role of Fyn and Lyn in human mast cells was also investigated in this study. The silencing of Fyn or Lyn expression in human mast cells caused the inhibition or augmentation of degranulation, respectively (Yamashita et al, 2007). Thus, it appears that human mast cells show a phenotype that is most similar to that of the 129/SvJ mouse rather than the C57BL/6 mouse.…”

“…Analysis of mast cells derived from C57BL/6 mice carrying a null mutation for Lyn showed a dramatic inhibition of FcεRI-mediated degranulation relative to their wild-type counterparts (Yamashita et al, 2007). In contrast, mast cells from 129/SvJ mice carrying the same mutation showed an enhanced degranulation response when compared to their wild-type counterparts and to all C57BL/6-derived mast cells.…”

Basophils and IgE: Linking the Allergic Environment to Autoimmunity

“…However, we and others demonstrated that Lyn kinase has dual function as positive and negative regulator of Fc RI signaling [10,62]. Thus, in the context of increased expression of Fyn kinase (such as seen in mast cells from 129Sv or Balb/c mice), the absence of Lyn causes increased mast cell responses and exacerbation of allergic disease [12,63]. Interestingly, Lyn kinase also seems to control mast cell proliferation or survival in vivo, since Lyn -/-mice have an increased number of peritoneal mast cell, which is IgE-dependent and is seen early in life [10,64].…”

“…This effort has led us to explore the role of *Address correspondence to this author at the NIAMS-NIH, Building Lyn kinase, the kinase that phosphorylates Fc RI and initiates signal transduction, in mast cell and basophils [8,9]. Interestingly, our efforts [10][11][12], as well as those of others [13][14][15][16][17] led to the recognition that a deficiency in Lyn kinase does not necessarily abrogate allergic responses and, in fact, these mice are hypersensitive to an allergic challenge [10,[18][19][20]. Lyn kinase is a member of the Src family of protein tyrosine kinases (SFK) and while expressed in most hematopoietic cells it is not expressed in T cells [21].…”