IL-21 And The B Cell PTEN/PI3K/Akt Signaling Pathway Abnormalities In The Pathogenesis Of Systemic Lupus Erythematosus

Both IL-21/IL21R signaling and PI3K-PTEN (the lipid phosphatase and tensin homolog protein) molecules are involved in maintaining normal humoral immunity and deletion of autoreactive B cells. To determine whether IL-21 can regulate PTEN/PI3K/Akt signaling pathway and if this has effects on systemic lupus erythematosus (SLE), we investigated the differences in HC and SLE B cells reactived to IL-21 stimulation.We first compared the expressions of p-Akt and p-STAT3 in B cells stimulated by IL-21 with or without CD40L/anti-IgM coactivation in the part one. We found that co stimulation with IL-21 can downregulated the Phosphorylation levels of Akt induced by CD40L/anti-IgM.and this effect disappeared in SLE B cells.In the partâ…¡,we detected the expression level of PTEN and IL-21 R in fresh isolated B cells and compared the expression level of PTEN in B cells stimulated by IL-21 after 72h from HC and SLE. Consist to the low expression level in fresh isolated SLE B cells,the PTEN expression could not be induced in the active SLE B cells.Down regulation the chemokine receptor CXCR4 expressed on activated B cells is important to maintain the light zone in germinal center and control the excessive activation in B cells. In the partâ…¢,we found that either IL-21 or CD40L/anti-IgM stimulation will reduce the CXCR4 expressed on B cells. Not surprisingly, the CXCR4 expression could not be reduced by IL-21 in the activated SLE B cells independ on CD40L/anti-IgM stimulation.In the partâ…£, we compared the activation,proliferation and differentiation to antibody secreting cells induced by IL-21 with or without the costimulated by CD40L/anti-IgM in HC and SLE B cells. The results show that all changes involved previously will occur by IL-21 alone.In the last,we found that CD19+IgD+CD38hi transitional B cells have the ability to secret IL-10 under the IL-21 coculture condition. But in lupus, this subtype B cells have the higher percentage and the more activated phenotype but lose the ability to product IL-10.1. Summary of these results derived from the study in this paper, we could get the conclusion that 1L-21/IL-21R signaling control the activation of human autoreactive B cells may through the PTEN/PI3K/Akt pathway. And the intrinsic defection to downregulation the activation of Akt in SLE, will aggravate the auto-reactivation to self-antigen related to IL-21.