Abnormal Expression Of CD180 And The Mechanism Of It’s Inhibitory Effect On IFN-α Signaling In SLE B Cells

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by disorders of multiple organs and systems. The hallmarks of SLE are the high level of IFN-a and auto-antibodies targeting mainly nuclear components in patients’ serum. B cells have been proved to play crucial roles in the pathogenesis of SLE. B cells are highly activated and produce auto-antibodies in SLE. The reason why B cells are abnormally activated in SLE remains large unknown and IFN-a is considered as a key factor. In SLE B cell, the IFN-a signaling pathway is highly activated, IFN-a could affect the activation or function of B cells in various ways that participate in SLE preceding. CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies, indicating that CD 180 may influence the abnormity activation of B cell in SLE. So we ask whether there are interactions between CD 180 and IFN-a and what results in CD 180 abnormity expression in B cell in SLE? In the present study, we first detected the expression of CD 180 in B cell and identified the phenotype of CD 180-B cell in SLE, and then we explored the underlying mechanism of how CD 180 meditate IFN-α signaling that affect the function of B cell in SLE.Downregulation of CD180 on B cell in SLE and identification of the phenotype of CD180-B cellThe PBMCs from five donors and five SLE patients were analyzed by FACS, and we confirmed that CD180-B cells are dramatically increased in SLE patients, the expression of CD 180 is also decreased in SLE B cells. We next found that CD 180- B cells are also dramatically increased in bone marrow, PBMCs and spleen from MRL/lpr lupus-prone mice and the expression of CD 180 are decreased in spleen B cells. The phenotypic identification of CD 180- B cell showed that CD 180- B cell may be consisted of germinal center (GC) B cells and plasmablast/plasma cells.Ligation of CD180 inhibits IFN-a signaling, indicating that anti-CD180 may considered as an candidate for SLE treatmentWe then explored the relationship between CD 180 and IFN-α signaling and the factors that affect the expression of CD 180. We found that ligation of CD 180 could significantly inhibits the activation of IFN-α signaling and the expression of IFN-stimulated genes (ISGs) in B cell both in vitro and in vivo. Mechanistically, ligation of CD 180 could down-regulate the phosphorylation of STAT-2 via lyn-PI3K-BTK signaling axis. Furthermore, we found that activation of TLR7 and TLR9 signaling could significantly down-regulate CD 180 expression and modulate the inhibitory effect of CD 180 signaling on the activation of IFN-α signaling.In summary, our studies confirmed that CD 180- B cells are dramatically increased in MRL/lpr lupus-prone mice; we also identified the phenotype of CD180-B cell. Besides, we found that ligation of CD 180 inhibits IFN-α signaling and explored the the underlying mechanism. Moreover we found that alteration of the expression of CD 180 on B cell might be attributed to the activation of TLR7 and TLR9 signaling. Since treating SLE via targeting IFN-α has been proved to be feasible, anti-CD 180 antibody may considered as a candidate for SLE treatment.