Expression of both CH H and

Expression of both CH25H and CYP7B1 by lymphoid stromal myd88 inhibitor is required for the synthesis of 7α,25-OHC in lymphoid tissues and the correct positioning of B cells. Production of EBI2 ligand by hematopoietically derived cells appears limited [24] but may occur under some circumstances, given that both Ch25h and Cyp7b1 can be expressed by hematopoietic cells [24]. Degradation of 7α,25-OHC is mediated by the enzyme 3β-hydroxy-Δ5-C27 steroid oxidoreductase (HSD3B7) [25], which is also expressed in lymphoid stromal cells and in T cell zone DCs [24]. Differential expression of CH25H, CYP7B1, and HSD3B7 in stromal cells present in distinct compartments of secondary lymphoid organs appears to establish a gradient of 7α,25-OHC. The biosynthetic enzymes are more highly expressed in stromal cells at the perimeter of the follicle compared to stromal cells and FDCs in the center of the follicles, therefore, EBI2 ligand is higher at the follicle perimeter than in the inner follicle (Figure 1) [24]. By contrast, the degradation of 7α,25-OHC is increased in T cell zones, due to high levels of HSD3B7 expression in stromal cells within these areas, keeping levels of EBI2 ligand low [24]. HSD3B7 expression by splenic DCs, in particular of the CD8+ subset, helps maintain low EBI2 ligand concentrations in the T cell zone. Levels of 7α,25-OHC have been shown to be increased in mouse lymphoid tissues upon LPS injection in a CH25H-dependent manner 15, 16, suggesting that EBI2 ligand production may be regulated during infection, as has been observed for lymphoid chemokines [26].
Guidance of B cell localization by EBI2
EBI2 expression and B cell disease Although chemoattractant receptors of the GPR family play essential roles in coordinating the migration of lymphocytes for efficient responses against pathogens, their dysregulation can result in the initiation or progression of inflammatory and autoimmune disorders. Involvement of EBI2 with inflammation has been suggested by the association of polymorphisms in the gene encoding EBI2 with susceptibility to type 1 diabetes and other inflammatory diseases [39]. In rats, EBI2 has been shown to regulate the inflammatory response of macrophages [39], but its role in regulating autoimmune B cells in diabetes has not yet been investigated. EBI2 has also been found to be among the group of dysregulated genes in systemic lupus erythematosus patients, and is reported to be downregulated in peripheral blood cells from lupus patients compared to healthy controls [40]. Furthermore, EBI2 maps to a chromosomal region that shows linkage in genome-wide scans of lupus patients 41, 42. Several studies have also linked regulation of EBI2 expression to human neoplastic diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, and diffuse large B cell lymphoma 43, 44, 45, 46. Gene expression profiling has indicated that EBI2 expression is downregulated in follicular and GC B-like diffuse large B cell lymphoma 45, 46. It is yet to be determined whether this low expression of EBI2 is somehow involved in cancer progression or simply reflects the expression of EBI2 by the original cell type prior to transformation. As mentioned above, infection of human B cells by Epstein–Barr virus induces high levels of EBI2 [18]. Upregulation of EBI2 on infected B cells is likely to mediate the observed propensity of Epstein–Barr virus-positive B cells to accumulate in interfollicular regions and avoid GCs 47, 48. During infectious mononucleosis this might be a strategy of Epstein–Barr virus to direct infected B cells to microenvironments conducive for their survival and to escape immune surveillance.
Concluding remarks The GPR nature of EBI2 makes this receptor a highly suitable target for pharmaceutical intervention with small molecule drugs. The structural motifs critical for EBI2 function and the location and composition of its ligand-binding domain in EBI2 have started to be elucidated 49, 50. This information will facilitate future efforts to design novel therapeutic agents that may serve as agonists or antagonists for EBI2 to modulate inflammatory and autoimmune diseases or advance vaccine strategies.