Investigation Of Clinical Immunological Features Of Pediatric Systemic Lupus Erythematosus And MDM2 In The Pathogenesis Of Lupus Nephritis

Systemic lupus erythematosus(SLE)is a systemic autoimmune disease characterized by chronic immune inflammation.Although the incidence of SLE in children is relatively lower compared to adults,there is a significantly higher prevalence of lupus nephritis(LN)in p SLE with poor prognosis of LN.However,the clinical immunological features and the pathogenesis mechanism of LN in Chinese p SLE is not well understood.Hence the study has summarized the clinical manifestations,serological features and renal prognosis of p SLE at our center.In addition,we have also screened out a serological biomarker which can reflect overall disease activity and renal disease activity and elucidated the pathogenesis mechanism of p SLE.Our results have demonstrated that the expression of MDM2 was significantly elevated in peripheral blood mononuclear cells(PBMC)of p SLE and in the renal specimen of pediatric LN.Meanwhile,we have found that there was also a significantly increased percentage of apoptotic and necrotic cells in CD4~+T cells in SLE,which had an obvious positive correlation with elevated level of serum cell free DNA.In addition,we have also demonstrated that the levels of cell free DNA in supernatant is significantly elevated after treating PBMC and human renal mesangial cell(HRMC)with camptothecin for induction of apoptosis and necrosis.This has proved that apoptotic and necrotic cells have the capacity to release cell free DNA.Previous studies have also demonstrated that DNA can activate the immune system to secret various kinds of cytokines,while inhibition of MDM2 can alleviate the inflammatory responses.This indicated that DNA and MDM2 are closely related.Then we synthesized the immunostimulatory DNA(ISD)and transfected it into HRMC in an attempt to simulate the microenvironment in SLE.The results showed that MDM2 was significantly upregulated in HRMC after ISD transfection.Meanwhile expression of cell cycle related protein P53 and P21 was downregulated.What is more,there was significant increase in proliferation rate of HRMC upon DNA transfection.And MDM2 inhibition with nutlin3 could reverse the increased proliferation rate.Thus this has proved that MDM2 plays a key role in HRMC proliferation.We also demonstrated that this was mediated through regulation of HRMC cell cycle since MDM2 could promote cell cycle from G1 phase to S phase differentiation.We also investigated the ISD regulation of peripheral B cells.Inhibition of MDM2 altered the subsets of B lymphocytes with decreased percentage of conventional memory B cells and increased percentage of double negative B cells.In conclusion,based on previous immunological features of p SLE,we have investigated the MDM2 expression upon DNA induction as well as MDM2regulation of peripheral B cells and HRMC.The study will not only elucidate the role of MDM2 in the pathogenesis of pediatric LN,but also provide a novel target for drug development.