Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Results br Discussion CYP B and HSD B

    2020-08-07


    Results
    Discussion CYP7B1 and HSD3B7 are best defined for their roles in bile APY29 synthesis in the liver (Russell, 2003). Our studies show that these two enzymes, together with CH25H, are required in lymphoid organs for the generation of EBI2 ligand gradients that guide the movements of naive and activated B cells. We have established that HSD3B7-mediated modification of 7α,25-OHC inactivates EBI2 ligand activity. We demonstrated that CH25H, APY29 CYP7B1, and HSD3B7 constitute a metabolic pathway that is required in lymphoid stromal cells for establishing B cell-guiding 7α,25-OHC gradients. We also have provided evidence that FDCs are needed to maintain a low-EBI2-ligand zone in the follicle interior and that HSD3B7 restricts EBI2 ligand production by T zone DCs. We propose the following model for how B cell-guiding EBI2 ligand gradients are established in lymphoid tissues. CH25H and CYP7B1 are needed in radiation-resistant stromal cells, are abundantly expressed and active in CXCL13+ and CCL21+ FRCs, but not lymphocytes, and are poorly expressed in the inner follicle compared to surrounding regions. This enzyme distribution results in more ligand production at the follicle perimeter than at the follicle center, accounting for the propensity of EBI2hi cells to be attracted to the follicle perimeter (Gatto et al., 2011; Kelly et al., 2011; Pereira et al., 2009). HSD3B7, by contrast, is present in similar amounts in the inner follicle and at the perimeter, and thus we propose that by shortening the 7α,25-OHC half-life, this enzyme ensures that the concentration of ligand closely mirrors the distribution of the biosynthetic enzymes. CYP7B1 and CH25H are also abundant in the T zone, but in this compartment HSD3B7 is highly expressed, causing T zone 7α,25-OHC to be relatively low. As a result, ligand concentrations are most likely higher along the follicle-T zone interface than within the T zone proper. In the first hours after B cell activation, CCR7 and EBI2 are both upregulated, and B cells move to the T zone in a CCR7-dependent manner (Gatto et al., 2009; Kelly et al., 2011; Pereira et al., 2009; Reif et al., 2002); however, their propensity to remain at and distribute along the length of the B-T zone interface is promoted by the abundance of EBI2 ligand in this region. Later, after activation (∼day 2), when B cells have received T cell help, they maintain high EBI2 function (Figure 1) and CXCR5 expression but downregulate CCR7 function (Chan et al., 2009; Coffey et al., 2009; Kelly et al., 2011). As a result, these cells are less strongly attracted to the B-T zone interface and relocate to the outer follicle in an EBI2-dependent manner. A recent study suggested EBI2 transmits proproliferative signals to B cells (Benned-Jensen et al., 2011). We have not found 7α,25-OHC to have mitogenic effects on B cells (T.Y., L.M.K., and J.G.C., unpublished data). Our findings of similar B cell positioning and antibody response defects in mice that are unable to make 7α,25-OHC (CH25H- and CYP7B1-deficient) and in mice that have an elevated abundance of 7α,25-OHC (HSD3B7-deficient) are most consistent with B cell EBI2 functioning principally as a guidance receptor.