SAN DIEGO—Johnson & Johnson Pharmaceutical Research& Development, L.L.C. have announced the discovery of an unknown role for aclass of molecules that has potential for advanced in immunologic medicine, adiscovery recently published in Nature. The discovery shows a link between EBI2, aG-protein-coupled receptor responsible for controlling B-cell migration, andunexpected immunological effects of certain oxysterols. The findings, whichwere co-authored by Johnson & Johnson's neuroscience and immunologydiscovery teams, were published in a Letter in the July 28, 2011 issue of Nature title "Oxysterols direct B-cell migration throughEBI2."
"This finding reveals a new way in which the body may modulatethe immune system in response to pathogenic attack and will help us understandbetter how B cells and other immune cells coordinate the humoral immuneresponse," said Tim Lovenberg, senior research fellow, Neuroscience Discovery,J&JPRD, said in a press release.
EBI2 is highly expressed in the spleen, and is alsoupregulated if infected with the Epstein-Barr virus. Recent studies indicatethat the receptor is responsible for controlling follicular B-cell migration aswell as T-cell-dependent antibody production. As for oxysterols, they areoxygenated derivatives of cholesterol that have significant effects on bothimmune and inflammatory responses, as well as on cholesterol metabolism.Previously, it was thought that the activation of nuclear hormone receptors wasresponsible for the biological effects of oxysterols. Due to the researchers'findings, however, it was discovered that 7,25-dihydroxycholesterol isolatedfrom pig spleen extracts, an oxysterol, is the endogenous ligand for EBI2,making it capable of also potentially activating a G-protein coupled receptor.
Orphan G-protein-coupled receptors are genes without knownfunctions, ones that display the seven helical conformation hallmark ofG-protein-coupled receptors but are not activated by any of the primarymessengers that usually activate them in vivo. G-protein-coupled receptors are the targets of unknown transmitters,but despite that difficulty, their existence as part of the supergene familywith the widest regulatory role in the organism makes orphan G-protein-coupledreceptors points of great interest for researchers.
The research team used tissue extracts to identify supposedEBI2 activity in rat spleen and purified EBI2 ligands from pig spleens throughorganic extraction followed by chromatography. They then isolated and testedover 30 oxysterols for the activation of EBI2. In both in-vitro and in-vivo analyses, the researchers were able to demonstrate in mice thatoxysterols are specific endogenous ligands for EBI2 because they lack ligandactivity for other G-protein-coupled receptors.
SOURCE: Johnson & Johnson press release