Refractory autoimmune hemolytic anemia in a patient with systemic lupus erythematosus and ulcerative colitis:A case report

BACKGROUND Ulcerative colitis(UC)and systemic lupus erythematosus(SLE)are both systemic immunoreactive diseases,and their pathogenesis depends on the interaction between genes and environmental factors.There are no reports of UC with SLE in China,but six cases of SLE with UC have been reported in China.The combination of these two diseases has distinct effects on the pathogenesis of both diseases.CASE SUMMARY A female patient(30 years old)came to our hospital due to dull umbilical pain,diarrhea and mucous bloody stool in August 2018 and was diagnosed with UC.The symptoms were relieved after oral administration of mesalazine(1 g po tid)or folic acid(5 mg po qd),and the patient were fed a control diet.On June 24,2019,the patient was admitted for treatment due to anemia and tinnitus.During hospitalization,the patient had repeated low-grade fever and a progressively decreased Hb level.Blood tests revealed positive antinuclear antibody test,positive anti-dsDNA antibody,0.24 g/L C3(0.9-1.8 g/L),0.04 g/L C4(0.1-0.4 g/L),32.37 g/L immunoglobulin(8-17 g/L),and 31568.1 mg/24 h total 24-h urine protein(0-150 mg/24 h).The patient was diagnosed with SLE involving the joints,kidneys and blood system.Previously reported cases of SLE were retrieved from PubMed to characterize clinicopathological features and identify prognostic factors for SLE.CONCLUSION The patient was discharged in remission after a series of treatments,such as intravenous methylprednisolone sodium succinate,intravenous human immunoglobulin,cyclophosphamide injection,and plasma exchange.After discharge,the patient took oral prednisone acetate tablets,cyclosporine capsules,hydroxychloroquine sulfate tablets and other treatments for symptoms and was followed up regularly for 1 month,after which the patient's condition continued to improve and stabilize.

Retrospective Analysis of Plasma Exchange Combined with Glucocorticosteroids for the Treatment of Systemic Lupus Erythematosus-related Acute Pancreatitis in Central China

Systemic lupus erythematosus-related acute pancreatitis（SLEAP） has a poor prognosis with a high mortality. We described the clinical features of SLEAP, and discussed the feasibility of plasma exchange（PE） combined with glucocorticosteroids（GC） in short-term prognosis and possible mechanism in reducing serum inflammatory cytokine IL-6 and removing serum lipids. A retrospective study was performed by an independent rheumatologist. Medical records of SLEAP from March 2010 to December 2014 were retrieved from Tongji Hospital information system, and patients were divided into two groups according to whether PE therapy was adopted. Sixteen patients treated with PE in combination with GC were classified as group A, and the other 10 patients who were treated with merely GC were classified as group B. Patients＇ clinical remission rate and average daily GC dosage after two-week therapy were compared between the two groups. Patients＇ serum inflammatory cytokines and lipid concentration were compared between baseline and after two-week treatment in both groups. Pearson correlation test was performed to determine association between serum cytokines and Ranson score. SLEDAI score in group A patients at baseline（14.8±3.1） showed no statistical difference from that in group B（14.1±3.3）. At baseline serum IL-6 levels had no significant difference between group A [13.14（11.12, 16.57） mg/L] and group B [14.63（11.37, 16.37） mg/L]; after two-week therapy IL-6 decreased significantly in group A [9.16（7.93, 10.75）mg/L] while it did not show decreasing trend in group B [13.62（9.29,17.63） mg/L]. Serum lipid concentration after two-week therapy in group A [（TC=5.02±0.53, TG=1.46±0.44） mmol/L] decreased significantly compared to baseline [（TC=6.11±0.50, TG=2.14±1.03） mmol/L], while similar tendency was not observed in group B. The remission rate after two-week therapy was higher in group A（70.0%） than in group B（25.0%）. Acute pancreatitis（AP） was one of the clinical manifestations of active SLE. PE combined with GC could reduce serum IL-6 level, and remove serum lipid to improve short-term prognosis. Therefore, it might be a safe and effective way in treating SLEAP and was worth continuing to explore its feasibility.

Circulating Levels of Hypoxia-regulating MicroRNAs in Systemic Lupus Erythematosus Patients with Hemolytic Anemia

Objective MicroRNAs are fine regulators for gene expression during the post-transcriptional stage in many autoimmune diseases.HypoxamiRs(miR-210 and miR-21)play an important role in hypoxia and in inflammation-associated hypoxia.Systemic lupus erythematosus(SLE)is a chronic systemic autoimmune disease that would potentiate many pathological complications,including hemolytic anemia.This study aimed to investigate the role of hypoxamiRs in SLE/hemolytic anemia patients.Methods This work was designed to analyze the circulating levels of↱the miR-210 and miR-21 expressions and hypoxia-inducible factor-1α(HIF-α)in SLE/hemolytic anemia patients.SLE activity was evaluated for all patients by SLE Disease Activity Index(SLEDAI).Clinical manifestations/complications and serological/hematological investigations were reported.HIF-αconcentration was assayed by ELISA and expression of miR-21 and miR-210 was analyzed by qRT-PCR.Results The results indicated that the fold change of the miR-210/miR-21 expressions in plasma was significantly elevated in SLE/hemolytic anemia patients.A strong positive correlation between the miR-210 and miR-21 expression levels was also recorded.Among the associated-disease complications,hypertension,arthritis,oral ulcers,and serositis were associated with a high circulating miR-210 expression,while the occurrence of renal disorders was associated with the increased miR-21 expression.Furthermore,the HIF-αlevel was remarkably elevated in SLE/hemolytic anemia patients.A high positive correlation was recorded between the HIF-αconcentration and miR-210/miR-21 expression levels.The occurrence of oral ulcers,arthritis,and hypertension was associated with the increased HIF-αconcentration.On the other hand,SLEDAI and white blood cell count were positively correlated with miR-21/miR-210.The erythrocyte sedimentation rate was positively correlated with miR-21.Conclusion The dysregulation of the circulating miR-210/miR-210/HIF-1αlevels in SLE/hemolytic anemia patients advocated that the hypoxia pathway might have an essential role in the pathogenesis and complications of these diseases.

The expression of PD-1 and level of CXCL10 in patients with systemic lupus erythematosus

The aim of this study was to investigate the expression of PD-1 on peripheral blood mononuclear cells (PBMCs) and the serum level of CXCL10 and those of roles in the pathogenesis in SLE patients. The expression of PD-1 on PBMCs was tested by flow cytometry and the serum level of CXCL10 was determined by ELISA in 47 SLE patients and 21 healthy controls. The correlation between PD-1, CXCL10 and ANA, anti-dsDNA antibody and SLEDAI (SLE disease activity index) were evaluated. The expression of PD-1 on PBMCs in SLE patients was significantly different from that of controls. The percentage of PD-1 on neutrophiles in SLE patients was decreased compared with that of healthy controls (P<0.01), and that on lymphocyte from inactive SLE was significantly lower than that of controls (P<0.02). However, the PD-1 expression and the level of serum CXCL10 in active SLE were significantly increased (P<0.01) than those of controls. Positive correlations were found between PD-1, CXCL10 and anti-dsDNA antibody, SLEDAI in active SLE. The abnormal expression of PD-1 on PBMCs and serum level of CXCL10 in SLE patients may impair the auto-immunological tolerance, and play an important role in the pathogenesis of SLE.

Gene testing for osteonecrosis of the femoral head in systemic lupus erythematosus using targeted next-generation sequencing:A pilot study

BACKGROUND Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head(ONFH)in systemic lupus erythematosus(SLE).Some gene loci such as complement C3d receptor 2(CR2),nitric oxide synthase 3(NOS3),collagen type II alpha 1 chain(COL2A1),protein tyrosine phosphatase non-receptor type 22(PTPN22),and transient receptor potential cation channel subfamily V member 4(TRPV4)were reported to be involved in this process.AIM To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations(SNVs)in these five genes.METHODS SNVs in the CR2,NOS3,COL2A1,PTPN22,and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH.Burrows–wheeler aligner was used to align the sequencing reads to hg19,and GATK and Varscan programs were used to perform SNV calling.PolyPhen-2,SIFT,and MutationTaster were used to assess the functional effects of non-synonymous SNVs.RESULTS Six of the 49 patients were confirmed to have low frequency SNVs,including one patient with SNVs in NOS3(exon 6:c.814G>A:p.E272K and exon 7:c.814G>A:p.E272K.),four in COL2A1(rs41263847:exon 29:c.1913C>T:p.T638I,exon 28:c.1706C>T:p.T569I,and rs371445823:exon 8:c.580G>A:p.A194T,exon 7:c.373G>A:p.A125T),and one in CR2(rs45573035:exon 2:c.200C>G:p.T67S).CONCLUSION The onset of ONFH in SLE might be associated with the identified SNVs in NOS3,COL2A1,and CR2.

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

Plasma cells, which secrete auto-antibodies, are considered to be the arch-criminal of autoimmune diseases such as systemic lupus erythematosus, but there are many cytokines involved in inducing the differentiation of B-cell subsets into plasma cells. Here, we emphasize IL-21, which has emerged as the most potent inducer of plasma cell differentiation. In this review, we focused on the promoting effects of IL-21 on plasma cell differentiation and discuss how these effects contribute to B cell-mediated autoimmune disease.

The relationship between Th1/Th2-type cells and disease activity in patients with systemic lupus erythematosus

Obejctive To investigate the imbalance of Th1/Th2 type cytokines in patients with systemic lupus erythematosus (SLE) and its relation to disease activity Methods Intracellular cytokines were determined by flow cytometry following whole blood culture Results Patients with systemic lupus erythematosus disease activity index (SLEDAI) >10 had statistically significantly fewer CD4 + or CD8 + T cells producing IFN γ than patients with SLEDAI =0, SLEDAI 1-10 or healthy controls ( P <0 01, P <0 01 or P <0 05, respectively) Patients with SLEDAI>10 also had decreased ratio of IFN γ/IL 4 positive CD4 + or CD8 + T cells, compared with patients with SLEDAI =0, SLEDAI 1-10 or healthy controls ( P <0 05) The decreased Th1 or Tc1 cells and the ratios of IFN γ: IL 4 positive CD4 + T cells were significantly correlated with disease activity ( P <0 05) Conclusion SLE is characterized by an imbalance of Th1/Th2 and Tc1/Tc2 cytokines The decreased Th1 or Tc1 cells and the Th1/Th2 ratio are related to disease activity

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

Evaluating Anti-SmDl-amino-acid 83-119 Peptide Reactivity in Children with Systemic Lupus Erythematosus and Other Immunological Diseases

Background： SmD1-amino-acid 83-119 peptide （SmD183-119） is the major epitope of Smith （Sm） antigen, which is specific for adult systemic lupus erythematosus （SLE）. The anti-SmD183-119 antibody has exhibited higher sensitivity and specificity than anti-Sm antibody in diagnosing adult SLE. However, the utility of anti-SmD183-119 antibodies remains unclear in children with SLE （cSLE）. This study aimed to assess the characteristics of anti-StuD 183-119 antibody in the diagnosis of cSLE. Methods： Samples from 242 children with different rheumatological and immunological disorders, including autoimmune diseases （SLE [n = 46] and ankylosing spondylitis [AS, n = 11]）, nonautoimmune diseases （Henoch-Schonlein purpura [HSP, n = 60], idiopathic thrombocytopenia purpura [n = 27], hematuria [n = 59], and arthralgia [n = 39]） were collected from Shanghai Children＇s Medical Center from March 6, 2012 to February 27, 2014. Seventy age- and sex-matched patients were enrolled in this study as the negative controls. All the patients＇ sera were analyzed for the anti-SmD 183-119, anti-Sm, anti-U 1-nRNP, anti-double-stranded DNA （dsDNA）, anti-nucleosome, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB, anti-Scl-70, and anti-histone antibodies using the immunoblotting assay. The differences in sensitivity and specificity between anti-SmD183-119 and anti-Sm antibodies were compared by Chi-square test. The correlations between anti-SmD183-119 and other auto-antibodies were analyzed using the Spearman＇s correlation analysis. A value of P 〈 0.05 was considered statistically significant. Results： Thirty-six out of 46 patients with cSLE were found to be positive for anti-SmD183-119, while 12 patients from the cSLE cohort were found to be positive for anti-Sm. Compared to cSLE, it has been shown that anti-SmD183-119 was only detected in 27.3% of patients with AS and 16.7% of patients with HSP. In comparison with anti-Sm, it has been demonstrated that anti-StuD 183-119 had a higher sensitivity （78.3% vs. 26.1%, 2＇2 = 25.1, P 〈 0.05） and a lower specificity （90.8% vs. 100%, x^2 = 13.6, P 〈 0.05） in the diagnosis of cSLE. Further analysis revealed that anti-StuD 183-119 antibodies were positively correlated with anti-dsDNA, anti-nucleosome, and anti-histone antibodies in cSLE. Moreover, it has been clearly shown that anti-SmD183-119was more sensitive than anti-Sm in discriminating autoimmune diseases from nonautoimmune disorders in patients with arthralgia or hematuria. Conclusions： Measurement of anti-SmD183-119 in patients with cSLE has a higher sensitivity and a marginally lower specificity than anti-Sin. It has been suggested that inclusion of anti-SmD183-119 testing in the integrated laboratory diagnosis ofcSLE may significantly improve the overall sensitivity in child populations.

Siglec genes confer resistance to systemic lupus erythematosus in humans and mice

A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus(SLE).However,no specific Siglec(sialic acid-binding immunoglobulin-like lectin)genes(Siglecs)have been implicated in the pathogenesis of SLE.Here,we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene.These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations.Consistent with human genetic data,we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3(Sle1–3)mice in Siglece,which is the murine Siglec with the greatest homology to human SIGLEC12.Since the mutations resulted in reduced binding of Siglec E to splenic cells,we evaluated whether Siglece−/−mice had SLE phenotypes.We found that Siglece−/−mice showed increased autoantibody production,glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy.Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.

E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis

Systemic lupus erythematosus(SLE)is a systemic autoimmune disease,and the pathogenesis of SLE has not been fully elucidated.The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor that can promote the ubiquitination and subsequent degradation of various oncoproteins;however,the potential role of FBXW7 in autoimmune diseases is unclear.In the present study,we identified that FBXW7 is a crucial exacerbating factor for SLE development and progression in a mouse model induced by 2,6,10,14-tetramethylpentadecane(TMPD).Myeloid cell-specific FBXW7-deficient(Lysm+FBXW7f/f)C57BL/6 mice showed decreased immune complex accumulation,glomerulonephritis,glomerular mesangial cell proliferation,and basemembrane thickness in the kidney.Lysm+FBXW7f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells.In Lysm+FBXW7f/f mice,we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chi inflammatory monocytes were recruited to the peritoneal cavity.Consistently,diffuse pulmonary hemorrhage(DPH)was also decreased in Lysm+FBXW7f/f mice.Mechanistically,we clarified that FBXW7 promoted TMPD-induced cell apoptosis by catalyzing MCL1 degradation through K48-linked ubiquitination.Our work revealed that FBXW7 expression in myeloid cells played a crucial role in TMPD-induced SLE progression in mice,which may provide novel ideas and theoretical support for understanding the pathogenesis of SLE.

Expression of matrix metalloproteinase-1 mRNA in peripheral blood mononuclear cells of systemic lupus erythematosus patients and its relationship with atherosclerosis

Background Matrix metalloproteinase-1 （MMP-1） plays an important role in atherosclerosis. This study was to examine expression of MMP-1 mRNA in peripheral blood mononuclear cells （PBMCs） of patients with systemic lupus erythematosus （SLE）, and to explore its relationship with atherosclerosis in SLE. Methods Fluorescent quantitative reverse transcription polymerase chain reaction （RT-PCR） was used to examine the expression of MMP-1 mRNA in PBMCs in 80 SLE patients, including 39 prone to atherosclerosis （Group A） and 41 unprone to atherosclerosis （Group B）. Meanwhile, 30 patients who were free of cardiovascular diseases and 30 healthy individuals were selected as disease and normal control group （Groups C and D）. The changes of MMP-1 gene expression were analyzed by differences of cycle threshold （ACt）, with the following formula： ACt = Cttarget gene - Ctreference gene. Results The expression level of MMP-1 mRNA in Group A was significantly higher than that of group B （ACt=8.64±2.43 vs ACt=12.09±2.26, t=6.588, P 〈0.01）. The expression level of MMP-1 mRNA of SLE patients was significantly higher than that of Group C （ACt=10.41±2.90 vs ACt=12.29±2.51, t=3.135, P 〈0.01） and Group D （ACt=10.41±2.90 vs ACt=12.48±1.69, t=3.675, P 〈0.01）. Conclusions In comparison to disease and control group, expression of MMP-1 mRNA in PBMCs of SLE patients was significantly elevated, and significant difference of MMP-1 mRNA expression was also found between SLE patients prone and unprone to atherosclerosis, indicating that expression of MMP-1 mRNA may be correlated with the pathogenesis and activity of atherosclerosis in SLE.

Elevated levels of serum antibodies against alpha-1,6-glucan in patients with systemic lupus erythematosus or rheumatoid arthritis

This study was undertaken to investigate whether levels of anti-alpha-1,6-glucan antibodies in human sera correlate with rheumatoid arthritis(RA)and systemic lupus erythematosus(SLE).Serum samples were collected from patients with SLE(n=30),RA(n=30)and healthy adult volunteers.IgG,IgA and IgM levels against alpha-1,6-glucan were measured using enzyme linked immunosorbent assays.Anti-alpha-1,6-glucan IgG prevalence was raised in patients with active SLE(73.3%)and RA(60%)compared with healthy controls(13.3%).Strong correlation between anti-alpha-1,6-glucan-IgG levels and anti-perinuclear factor(r=0.642;p<0.05)in RA patients or anti-nuclear antibodies(r=0.675;p<0.05)in SLE patients was observed.No significant differences in anti-alpha-1,6-glucan-IgA or-IgM levels were noted between different groups.We conclude that anti-alpha-1,6-glucan-IgG levels were significantly elevated in patients with SLE or RA and positively correlated with disease activity.

Phenotypic characterization of patients with activated PI3Kδ syndrome 1 presenting with features of systemic lupus erythematosus

Activated phosphoinositide 3-kinase d syndrome 1(APDS1)is a primary immunode-ficiency disease caused by gain-of-function mutations in PIK3CD.Clinical features of autoimmune disease have been reported in patients with APDS1.In this study,we reported three patients with APDS1 presenting with systemic lupus erythematosus(SLE)phenotype.The clinical manifestations included recurrent respiratory tract infection,lymphoproliferation,Coombs-positive hemolytic anemia,decreased complement fractions,positive antinuclear antibodies,renal complications related to SLE associated diseases,which met the clinical spectrum of APDS1 and the classification criteria of SLE.The immunological phenotype included an inversion in the CD4:CD8 ratio,an increase in both non-circulating Tfh CD4^(+)memory T and circulating Tfh populations,a low level of recent thymic emigrant T cells,overexpression of CD57 on T cells,and a decrease in B cells with fewer antibody class switch recombination.These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE.Meanwhile,we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1.The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy,including two who presented with SLE phenotype.The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy.Here,we showed the coexistence of immunodeficiency and SLE phenotype in APDS1,and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.

Dual autoimmune diseases:Rheumatoid arthritis with systemic lupus erythematosus and Type 1 diabetes mellitus with multiple sclerosis

Autoantibodies and inflammation are the hallmarks of autoimmune diseases(ADs).Organ-specific and nonorgan-specific ADs are divided according to whether the autoimmune reaction is directed against a specific tissue(e.g.,thyroid in Hashimoto's thyroiditis)or widely expressed antigens(e.g.,cell nuclei in systemic lupus erythematosus[SLE]).SLE is distinguished by the presence of circulating autoantibodies and immune complex deposition,both of which can induce inflammatory damage to many organs.Rheumatoid arthritis(RA),sometimes called inflammatory arthritis,is a systemic AD that affects the joints and causes synovitis.Multiple sclerosis(MS)is a central nervous system inflammatory disease with various neurological and autoimmune symptoms.Links have been reported between RA and SLE as well as between Type 1 diabetes mellitus and MS.Identification of shared genes and biological processes could aid in the discovery of possible treatment targets in these dual ADs.This review article explores the molecular nature and familial inheritance of dual ADs.

Association of HLA-DR3 and HLA-DR15 Polymorphisms wi Risk of Systemic Lupus Erythematosus

Background:Systemic lupus erythematosus (SLE)is an autoimmune disease under genetic control.Growing evidences support the genetic predisposition ofHLA-DRB1 gene polymorphisms to SLE,yet the results are not often reproducible.The purpose of this study was to assess the association of two polymorphisms ofHLA-DRB1 gene (HLA-DR3and HLA-DR15)with the risk of SLE via a comprehensive meta-analysis. Methods:This study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Case-control studies on HLA-DRB1 and SLE were searched from PubMed,Elsevier Science,Springer Link,Medline,and Cochrane Library database as of June 2018.Analysis was based on the random-effects model using STATA software version 14.0. Results:A total of 23studies were retained for analysis,including 5261cases and 9838controls.Overall analysis revealed that HLA-DR3 and HLA-DR15 polymorphisms were associated with the significant risk of SLE (odds ratio [OR]:1.60,95%confidence interval (CI):1.316-1.934,P =0.129and OR:1.68,95%CI:1.334-2.112,P =0.001,respectively).Subgroup analyses demonstrated that for both HLA-DR3and HLA-DR15polymorphisms,ethnicity was a possible source of heterogeneity.Specifically,HLA-DR3polymorphism was not associated with SLE in White populations (OR:1.60,95%CI:1.320-1.960,P =0.522)and HLA-DR15polymorphism in East Asian populations (OR:1.65,95%CI:1.248-2.173,P =0.001).In addition,source of control was another possible source for both HLA-DR3and HLA-DR15polymorphisms,with observable significance for HLA-DR3in only population-based studies (OR:1.65,95% CI:1.370-1.990,P =0.244)and for HLA-DR15in both population-based and hospital-based studies (OR:1.38,95%CI:1.078-1.760, P =0.123and OR:2.08,95%CI:1.738-2.490,P =0.881,respectively). Conclusions:HLA-DRB1 gene may be a SLE-susceptibility gene,and it shows evident ethnic heterogeneity.Further prospective validations across multiple ethnical groups are warranted.

Successful use of plasma exchange in fulminant lupus myocarditis coexisting with pneumonia: A case report

BACKGROUND Fulminant lupus myocarditis is a rare but fatal manifestation of systemic lupus erythematosus.Aggressive immunosuppressive treatments are important in its successful management.However,they can significantly damage the immunity and are associated with a considerable risk of infection development and spread.We present a rare and complicated case of a 20-year-old female diagnosed with fulminant lupus myocarditis accompanied by pneumonia.The patient was successfully treated with plasma exchange(PE)for fulminant lupus myocarditis.CASE SUMMARY A 20-year-old Chinese woman presented to the Hematology Department complaining of fatigue and knee pain.Blood test showed anemia and thrombocytopenia.On the second day of hospitalization,she was transferred to the ICU due to dyspnea and hypotension.Autoimmune profiles showed hypocomplementemia and positive antinuclear antibodies.Computer tomography showed an enlarged heart and pneumonia.Ultrasound revealed an enlarged heart with a low left ventricular ejection fraction.Fulminant lupus myocarditis with cardiogenic shock was initially considered.Due to the accompanying pneumonia,aggressive immunosuppression was contraindicated.Her cardiac function remained critical after the initial therapy of intravenous immunoglobulin and corticosteroids at a conventional dose,but she responded well to later PE therapy plus corticosteroids administration.The patient fully recovered with normal cardiac function.CONCLUSION This case indicates that PE is a valuable treatment choice without adverse effects of immunosuppression in patients with fulminant lupus myocarditis and coexisting infection.

Lupus-associated thrombotic thrombocytopenic purpura-like microangiopathy

Recently reported cases of lupus complicated by a thrombotic thrombocytopenic purpura （TTP）-like syndrome suggest a survival beneft to early treatment with plasma exchange. The following is a report of the eighth such case in the last ten years. A 44-year-old lady known for lupus presented with the nephrotic syndrome and a renal biopsy was consistent with class 4G lupus nephritis. She was given high-dose steroids and cytotoxic therapy, but her induction therapy was complicated by the classic pentad of TTP. She was subsequently treated with another course of high-dose steroids, a different cytotoxic agent, and plasma exchange, with clinical resolution shortly thereafter. Similar to seven recently reported cases of microangiopathy in lupus, this lady’s TTP-like syndrome improved dramatically after initiation of plasma exchange, despite not having a severely deficient ADAMTS13. This has implications on both current clinical practice and on the pathogenesis of TTP-like syndromes in lupus.

Renal Expression and Clinical Significance of High Mobility Group Box 1 in Lupus Nephritis

Objective: To evaluate the clinical significance of high mobility group box 1 (HMGB1) expression in nephridial tissues of lupus nephritis (LN). Methods: Sixty-three patients with active LN and 15 systemic lupus erythematosus (SLE) (combined without LN) were included. Renal biopsies were performed in the two groups. The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index. Serum levels of HMGB1 were analyzed by western blot. HMGB1 expression in renal tissue was assessed by immunohistochemistry in the two groups. The correlation between HMGB1 and renal active index (AI), chronicity index (CI), pathological type of LN was analyzed. Results: LN biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B). The HMGB1 expression was higher in the LN groups than the control groups (t = 9.263, P < 0.05). It showed positive correlation between HMGB1 expression and SLE DAI classification (r = 0.579, P P < 0.05) and renal tubule interstitial (TIL) classification (r = 0.815, P < 0.05), and negative correlation between HMGB1 expression and CI classification (r = 0.582, P < 0.05). In all patients, serum levels of HMGB1 increased only slightly in the patients only with SLE;however, in patients with LN WHO class IV a significant decrease was observed (P = 0.02). Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium. There were significant differences in HMGB1 expression between LN and control biopsies and it existed with apparent association to histopathological classification and clinical outcome. Conclusions: Renal tissue expression and serum levels of HMGB1 were elevated in LN. The unusual elevation of HMGB1 in serum and tissue in LN may reflect persistent inflammatory activity, which clearly indicates a role for HMGB1 in pathogenesis of LN.

HMGB1中和抗体抑制细胞焦亡改善系统性红斑狼疮小鼠肺损伤的机制研究

目的探究高迁移率族蛋白1(high-mobility group box 1,HMGB1)中和抗体对系统性红斑狼疮(systemic lupus erythematosus,SLE)小鼠肺损伤的影响及机制。方法30只MRL/lpr小鼠随机分为MRL/lpr组、MRL/lpr+HMGB1中和抗体(anti-HMGB1)组、MRL/lpr+MCC950组,每组10只,另取10只野生型C57BL/6小鼠作为对照组,给药4周。苏木精-伊红(HE)染色和马松三色(Masson)染色观察各组小鼠肺组织病理学变化及胶原纤维沉积情况,酶联免疫吸附法(ELISA)检测各组小鼠肺泡灌洗液中白细胞介素-1β(IL-1β)、IL-6、IL-18及肿瘤坏死因子-α(TNF-α)含量,免疫荧光染色观察各组小鼠肺组织内核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)荧光表达,蛋白质免疫印记(Western blotting)检测各组小鼠肺组织中HMGB1及NLRP3、凋亡相关斑点样蛋白(ASC)、含半胱氨酸的天冬氨酸蛋白水解酶-1(Caspase-1)、gasdermin D(GSDMD)的蛋白表达水平。结果与对照组比较,MRL/lpr组小鼠肺组织呈现严重病理损伤症状,胶原纤维沉积面积显著增加(P<0.05),肺泡灌洗液中IL-1β、IL-6、IL-18、TNF-α含量显著升高(P<0.05),肺组织内NLRP3平均荧光强度显著增加(P<0.05),HMGB1蛋白相对表达量及NLRP3、ASC、Caspase-1、GSDMD蛋白相对表达量均显著上调(P<0.05);与MRL/lpr组比较,MRL/lpr+anti-HMGB1组和MRL/lpr+MCC950组小鼠肺组织损伤得到明显改善,胶原纤维沉积面积显著减少(P<0.05),肺泡灌洗液中IL-1β、IL-6、IL-18、TNF-α含量显著降低(P<0.05),肺组织内NLRP3平均荧光强度显著减小(P<0.05),同时,肺组织中HMGB1蛋白相对表达量及NLRP3、ASC、Caspase-1、GSDMD蛋白相对表达量均显著下调(P<0.05)。结论HMGB1中和抗体能够改善SLE模型小鼠肺损伤,该作用可能是通过抑制细胞焦亡实现的。