Future studies should focus on culturing naive and memory cells, changing the period of culture time and TDB concentration for determining the role of Mincle on B cells including immunoglobulin and inflammatory cytokine production. Acknowledgments The authors thank Hajime Tanaka, Yoko M. B cells, we studied the expression of Mincle on subsets of B cells and analyzed cytokines and synthesized immunoglobulin upon ligation of Mincle. The expression of Mincle on CD27?CD19+ na?ve B cells is significantly higher than CD27+CD19+ memory B cells. The stimulation of TLR9 ligand induced Mincle expression on B cells. Furthermore, co-stimulation of TLR9 and Mincle ligand reduced IgG and IgA production from B cells without a significant change in the inflammatory cytokines TNF, IL-6, IL-8 and IL-10. Our data identifies Mincle as a potentially critical player in human B cell responses. Keywords: C-type lectin, Mincle, Toll-like receptor Introduction C-type lectin receptors (CLRs) are Rabbit Polyclonal to EDNRA pattern recognition receptors (PRRs) expressed on the cell membrane with C-type lectin-like domains in their extracellular region. CLRs serve multiple functions through recognizing carbohydrate chains on pathogens in innate immune surveillance. Macrophage-inducible C-type lectin (Mincle), also known as Clec4e and Clecsf9, is a novel 219aa type II transmembrane protein with a highly kept C-type lectin domain [1, 2]. Mincle is expressed on myeloid cells, neutrophils, and is particularly abundant on professional antigen presenting cells including macrophages, dendritic cells and B cells [1]. Mincle is selectively associated with the Fc receptor common (FcR ) chain, an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor, and its ligation on activated macrophages has been shown to produce a variety of pro-inflammatory cytokines and chemokines [3]. Mincle expression is upregulated by various stimuli, including TLRs ligands or cytokines. The fact that Mincle-expressing cells are activated in the presence of necrotic cells led to the identification of nuclear protein SAP130 as an endogenous Mincle ligand that is released from necrotic but not from apoptotic cells. Fungal cell walls contain a variety of complex carbohydrates which include mannose, -glucans Etofylline and chitin [4]. Dectin-1 and Dectin-2 are CLRs that are the specific receptors for -glucans and -mannose, respectively [5, 6]. Recently, several studies reported that Mincle has an important role in the response of macrophages to fungal infections [7C9]. Thus, one study reported that Etofylline macrophages in the absence of Mincle produced markedly lower levels of TNF- in response to (infection [8]. Mincle gene expression is strongly induced by LPS and several pro-inflammatory cytokines, including IFN-, IL-6, and TNF-, using peritoneal macrophages from wild type mice [1]. In our hands, Mincle expression on monocytes from PBMC is significantly Etofylline increased after LPS stimulation (data not shown). Mincle is dramatically upregulated in patients with rheumatoid arthritis [12] which suggests that its dysregulated expression might contribute to inflammation during autoimmune diseases [12]. Mincle transcription is also upregulated by various infections including [13] and (31). Recently, Mincle has been implicated in anti-mycobacterial immunity due to its recognition of a cell wall component [7C9]. Several studies have demonstrated the importance of Mincle for cytokine and chemokine production from macrophages and Etofylline their role in antifungal immunity. In the absence of Mincle, production of TNF- by macrophages was reduced in response to infection, both and [8]. Another study demonstrated that Mincle recognized intraperitoneally, a similar infection of Mincle-deficient mice did not induce this cytokine response [9]. These studies are critical not only for understanding the normal immune response but, in particular, for the mechanism involved in B cell activation in autoimmune disease. Indeed, there are myriad of publications that address the role of B cells as not only antibody producing cells, but also as antigen presenting cells and as immune modulators in the pathogenesis of human and murine autoimmune disease [19C36]. SAP130 is a Mincle ligand derived from necrotic cells [3] and part of a principal autoantigen, snRNP; it interacts with SAP145, SAP155 and SAP49 to form the spliceosome complex in the U2 snRNP complex [37]. Whether this complex formation enhances the reactivity to Mincle is unclear, although SAP130.
Future studies should focus on culturing naive and memory cells, changing the period of culture time and TDB concentration for determining the role of Mincle on B cells including immunoglobulin and inflammatory cytokine production