G protein-coupled receptor (GPCR) is the most important family of drug targets. More than 40% of the current therapeutic agents on the market are targeting GPCRs, including more than a quarter of the 100 top-selling drugs with benefits in the range of several billion US dollars each year. Human genome encodes 800-1000 GPCRs. Discovering new physiological or pathological roles of GPCRs will provide new targets or new ways to treat diseases.

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system and is one of the foremost causes of nontraumatic neurological disability in young adults. Researchers discovered that A2B adenosine receptor (A2BAR), a relatively low affinity GPCR for the key endogenous signaling molecule adenosine, was unregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of EAE mice. A2BAR specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the central nervous system from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited TH-17 cell differentiation by blocking IL-6 production from antigen-presenting cells such as dendritic cells (DCs). In DCs, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The PLCb-PKC and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL-6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs. These results were recently published in the Journal of Immunology on Dec 5，2012.

This work was directed by Dr. XIE Xin, a Principle Investigator of SIMM, the deputy director of the National Center for Drug Screening, and an Adjunct Professor of Tongji University. Her research is mainly focused on GPCR-based drug discovery and chemical biology of stem cells. Her group recently reported that anti-asthmatic drugs targeting the CysLT1 receptor might be used to treat MS (Journal of Immunology. 2011;187(5):2336-45). The clinical samples used in this study were provided by Dr. WU Zhiying from Huashan Hospital.

This work was supported by grants from the National Natural Science Foundation of China, Ministry of Science and Technology of China, and Shanghai Commission of Science and Technology.

Original Article：http://www.jimmunol.org/content/early/2012/12/05/jimmunol.1103721.long

A-B, Blocking or genetic deletion of A2BAR alleviates the clinical symptoms of EAE. C, Deletion of A22BAR reduces pathogenic cell infiltration into the CNS and demyelination. D, Blocking A2BAR on the dendritic cells inhibits the differentiation of Th17 cells.