| Background:Primary Sjogren Syndrome(pSS)is an autoimmune disease involving multiple systems,among which renal involvement is often characterized as renal tubular acidosis,interstitial nephritis.Currently,there are limited numbers of studies regarding the clinical manfestation,pathology,prognosis and pathogenesis of the glomerular involvement of pSS.In our previous study,we found that membranous nephropathy was the most common type of the glomerular involvement of pSS.Anti-PL A2R antibody,an antibody that was thought to be specific to idiopathic membranous nephropathy(iMN),was not significantly different between pSS patients with MN(pSS-MN)and iMN patients.The relationship between pSS and MN in pSS-MN patients is not clear.Besides anti-PLA2R antibody,high expression of exostosin 1/2(EXT 1/2)antigen in glomeruli of secondary MN and the pathogenic role of interleukin-34(IL-34)in lupus nephritis had recently been noted,but no validation in pSS-MN had been conducted.In recent year,the genetic background of iMN patients had attracted much attention.It had been confirmed that HLA-DRB1*15:01 was a high-site for iMN in two large-scale studies.Furthermore,several single nucleotide polymorphism(SNP)sites related to iMN or pSS had been confirmed in genome-wide association study(GWAS)and subsequent studies.However,there is still no studys regarding the genetic background of MN.Therefore,we summarized the clinical,pathlogical and prognostic features of pSS-MN patients from Peking Union Medical College Hospital in recent 20 years,and compared them with iMN and lupus nephritis(type V)(LN).Expression of IL-34 and EXT1/2 were evaluated in pSS-MN.HLA and SNP of pSS-MN were compared with iMN,pSS patients and normal control reported in literatures.We aimed to explore the relationship between pSS and MN in pSS-MN patients,providing some clues for further research on the pathogenesis and potential interventions.Purpose:1.To summarize the clinical feature,pathology,treatment and prognosis of pSS-MN patients.2.By investigating immulogical mechanism(PLA2R,EXT1/2,IL-34 and its receptor PTPRZ)to differentiate whether pSS-MN are primary or secondary membranous nephropathy.3.By investigating genetic background(HLA,SNP),to differentiate whether pSS-MN are primary or secondary membranous nephropathy.MethodsThe medical records and follow-up data of patients with pSS-MN in Peking Union Medical College Hospital from January 1993 to December 2018 were reviewed.iMN patients from June 2017 to June 2018,LN(type V)from January 2013 to December 2018 were used as control.All diagnoses were confirmed by biopsy,with complete clinical data.The pSS activity was evaluated;glomerular and tubulointerstitial lesions were evaluated semi-quantitatively;expression of IL-34,PTPRZ,EXT1/2 were evalutated by immunohistostaining;HLA class Ⅱ alleles and SNP were typed by Sanger tests;their correlation with clinicopathologic parameters and prognosis were also studied.Stastitical methods including t test,Mann-Whiteney test,Kruskal-Wallis test,ANOVA,Fisher test,Spearman or Pearson correlation coefficients,logistic regression,Kaplan-Meier analysis and expectation maxium algorithm.Modified p<0.05 were considered significant.Statistical analysis was performed by SPSS(version 19.0,IBM,USA),R(version 3.5.3).Reuslts1.Clinical and pathological features of pSS-MN patients In total,82 pSS-MN patients were enrolled in the study,accounting for 33.6%renal biopies in the same period.a.Clinically,the majority were female(80.5%),with average age of 53.4±13.5 years.The clinical manifestations were nephrotic syndrome(72.0%)and microscopic hematuria(72.0%),24-hour urine protein(24hUpro)at biopsy was 4.05±2.96g,serum albumin level was 27.8±6.2g/L,and eGFR was 89.4±24.9mL/min.Compared with iMN patients,demographic characteristics(gender,age)and extra-renal clinical indicators(Hgb,PLT,WBC,ESR)were significantly different from those in iMN and LN patients,and their 24hUpro was significantly lower than that of iMN patients.Serum IgG and IgA were significantly higher than the other two groups,while the level of complement C3 was significantly lower than iMN but higher than LN.b,Pathological features:Compared with iMN,the proportion of atypical membranous nephropathy in pSS-MN was significantly higher.There was no significant difference in MN staging in typical membranous nephropathy between pSS-MN and iMN.Significant difference was observed in tubulointerstial lesions between iMN and pSS-MN but only endothelial injury is different in glomrualr lesions.The deposition of C1q in pSS-MN patients was significantly more than that in iMN patients,and there was no significant difference in IgG4 deposition.Compared with the LN group,the glomerular involvement of pSS-MN was significantly less damaged than the that of LN group,while the tubulointerstitial involvement was heavier in the LN group,and the immunofluorescence was significantly different in nearly every aspect between pSS-MN and LN group,except for IgG deposition.2.Expression of PLA2R,EXT1/2,IL-34 and PTPRZ in renal tissuesThe positive rate of serum anti-PLA2R antibody in the pSS-MN group was not significantly different from that in the iMN group(41.5%vs 51.9%,p=0.052),while that of PLA2R antigen was lower than that of iMN(60.7%vs 87.3%,p=0.005).The serum anti-PLA2R antibody positive group had higher 24hUpro,and the atypical membranous nephropathy had lower anti-PLA2R antigen positive rate.Immunohistochemical staining of EXT1/2 was performed on 15 cases of pSS-MN.No expression of EXT1/2 deposited along the basement membrane of the glomeruli was observed.IL-34 and PTPRZ staining were performed on 15 patients with different degrees of pSS-MN lymphocyte infiltration.The results of semi-quantitative analysis of immunohistochemistry showed that IL-34 and PTPRZ levels were not significantly different in GML,iMN and pSS-MN.3.Prognosis of pSS-MNSteroid-based immunosuppressive therapy was the most employed treatment,with a median follow-up of 24 months.Compared with iMN and LN groups,there was no significant difference in complete remission rate within 2 years.24hUpro at the time of biopsy was a risk factor for complete remission.There was no significant relationship between serum anti-PLA2R antibody positivity and prognosis,but 24hUpro decreased after antibody turn to negative.4.Genetic characteristics of HLA and SNP in SS-MN patientsFifty-eight patients with pSS-MN completed the typing of HLA-DQA1,DQB1,DRB1 and DRB3 and sequencing of 8 SNP sites.Compared with data in literatures,there was no significant difference between pSS-MN and iMN in HLA alleles.DQA1*01:02,DQB1*06:02,and DRB1*15:01 were significantly higher than the normal control group.There was no significant difference between DRB 1*03:01 and iMN group and normal control.DRB3*02:02 was significantly lower than iMN group and higher than normal control.pSS-MN was significantly different between rs2187668(p<0.001)and rs9271588(p<0.001)when compare with case group.When compared with normal controls,except rs5029939 showed no significant difference(p=0.492),the other 7 locus all showed significant differences.Relationship with clinical parameters:The higher positive rate of serum anti-PLA2R antibody(57.1%vs 10%,p=0.012)and higher 24hUpro during biopsy(4.73±3.56g vs 2.82±1.71,p=0.020)were observed in DRB1*15:01 positive patients.No significant difference in other clinicopathological parameters and prognosi were observed.The significance of SNP mutations for clinical and prognostic parameters had not been observed.ConclusionIn current study,we observed:1.The glomerular injury of pSS-MN patients is similar to that of iMN patients,but significantly different from LN patients.The prognosis of the three groups is not significantly different;2.There are no significant differences between pSS-MN and iMN in anti-PLA2R antibody and EXT1/2.No significant differences in expression of IL-34 and its receptor PTPRZ were observed.3.pSS-MN has a similar genetic background to iMN in HLA and SNP.HLA-DRB 1*15:01 is a high-risk site for its pathogenesis.One SNP related to iMN and one related to pSS show significant linkage disequilibrium. |
PDF Full Text Request