Activation of Platelet mTORC2/Akt Pathway by Anti-ß2GP1 Antibody Promotes Thrombosis in Antiphospholipid Syndrome.

BACKGROUND: Anti-ß2GP1 (ß2-glycoprotein 1) antibodies are the primary pathogenic antibody to promote thrombosis in antiphospholipid syndrome (APS), yet the underlying mechanism remains obscure. We aimed to explore the intracellular pathway that mediated platelet activation. METHODS: Platelets were isolated from patients with APS and subjected to RNA sequencing. Platelet aggregation, the release of platelet granules, platelet spreading, and clot retraction were detected to evaluate platelet activation. We purified anti-ß2GP1 antibodies from patients with APS and the total IgG from healthy donors to stimulate platelets with/without FcγRIIA (Fcγ receptor IIA) blocking antibody or Akt (protein kinase B) inhibitor. Platelet-specific Sin1 (stress-activated protein kinase-interacting protein) deficiency mice were established. The thrombus model of inferior vena cava flow restriction, ferric chloride-induced carotid injury model, and laser-induced vessel wall injury in cremaster arterioles model were constructed after administration of anti-ß2GP1 antibodies. RESULTS: Combined RNA sequencing and bioinformatics analysis suggested that APS platelets exhibited increased levels of mRNA associated with platelet activation, which was in line with the hyperactivation of APS platelets in response to stimuli. Platelet activation in APS platelets was accompanied by upregulation of the mTORC2 (mammalian target of the rapamycin complex 2)/Akt pathway and increased levels of SIN1 phosphorylation at threonine 86. Anti-ß2GP1 antibody derived from patients with APS enhanced platelet activation and upregulated the mTORC2/Akt pathway. Moreover, the Akt inhibitor weakened the potentiating effect of the anti-ß2GP1 antibody on platelet activation. Notably, Sin1 deficiency suppresses anti-ß2GP1 antibody-enhanced platelet activation in vitro and thrombosis in all 3 models. CONCLUSIONS: This study elucidated the novel mechanism involving the mTORC2/Akt pathway, which mediates the promotion of platelet activation and induction of thrombosis by the anti-ß2GP1 antibody. The findings suggest that SIN1 may be a promising therapeutic target for the treatment of APS.

Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus.

Although extracellular DNA is known to form immune complexes (ICs) with autoantibodies in systemic lupus erythematosus (SLE), the mechanisms leading to the release of DNA from cells remain poorly characterized. Here, we show that the pore-forming protein, gasdermin D (GSDMD), is required for nuclear DNA and mitochondrial DNA (mtDNA) release from neutrophils and lytic cell death following ex vivo stimulation with serum from patients with SLE and IFN-γ. Mechanistically, the activation of FcγR downregulated Serpinb1 following ex vivo stimulation with serum from patients with SLE, leading to spontaneous activation of both caspase-1/caspase-11 and cleavage of GSDMD into GSDMD-N. Furthermore, mtDNA oxidization promoted GSDMD-N oligomerization and cell death. In addition, GSDMD, but not peptidyl arginine deiminase 4 is necessary for extracellular mtDNA release from low-density granulocytes from SLE patients or healthy human neutrophils following incubation with ICs. Using the pristane-induced lupus model, we show that disease severity is significantly reduced in mice with neutrophil-specific Gsdmd deficiency or following treatment with the GSDMD inhibitor, disulfiram. Altogether, our study highlights an important role for oxidized mtDNA in inducing GSDMD oligomerization and pore formation. These findings also suggest that GSDMD might represent a possible therapeutic target in SLE.

Differential diagnostic performance of PET/CT in adult-onset still's disease and lymphoma: a retrospective pilot study.

Background: Adult-onset still's disease (AOSD) and lymphoma are the common causes of fever of unknown origin (FUO) and show some similar clinical symptoms. This study aimed to establish a reliable and easy-to-used scoring model based on clinical information, laboratory characteristics and 18F-fluorodeoxyglucose positron emission tomography/computer tomography (18F-FDG PET/CT) images for the differential diagnosis of these two diseases. Methods: A development cohort including 70 AOSD and 37 lymphoma patients was used to establish a scoring model based on the features of PET/CT images. The scoring model was then validated in a validation cohort of 15 AOSD and 12 lymphoma patients. The features of involved bone marrow, spleen, lymph nodes, and other organs or tissues displayed on PET/CT images were compared. Multiple logistics regression and decision tree analysis were used to establish the scoring model. Results: Four features that could significantly differentiate these two diseases were selected to establish a scoring model discriminating AOSD from lymphoma, including (I) white blood cell (WBC) count ≤10×109/L (1 point); (II) ferritin ≤ upper limit of normal (ULN) (1 point); (III) no abnormal bone marrow metabolism (1 point); (IV) total lesion glycolysistotal (TLGtotal) >9.0 (1 point). After decision tree analysis, it showed that a score ≤1 indicates AOSD. A score ≥3 strongly suggested lymphoma, with a sensitivity of 81.1% and specificity of 90.0% in the development cohort, and a sensitivity of 58.3% and specificity of 100% in the validation cohort. Conclusions: Our scoring model showed good diagnosis performance in distinguishing AOSD from lymphoma.

The use of high-sensitivity cardiac troponin I in assessing cardiac involvement and Disease prognosis in idiopathic inflammatory myopathy

Abstract Objectives Cardiac involvement is one of the most serious complications of idiopathic inflammatory myopathy (IIM) that indicates poor prognosis. However, there is a lack of effective biomarkers for the identification of cardiac involvement and the prediction of prognosis in IIM. Here, we aimed to explore the value of different cardiac biomarkers in IIM patients. Methods A total of 142 IIM patients in the Department of Rheumatology and Immunology, Ruijin Hospital from July 2019 to October 2022 were included in this study. The clinical characteristics, laboratory tests, treatments and prognosis were recorded. The disease activity was assessed according to the core set measures. The correlations of the serum cardiac biomarkers levels with disease activity were analyzed by the Spearman correlation test. Risk factors for cardiac involvement were evaluated by multivariate logistic regression analysis. Results Higher high-sensitivity cardiac troponin I (hs-cTnI) levels were associated with cardiac involvement (n = 41) in IIM patients [adjusted OR 7.810 (95% CI: 1.962-31.097); p = 0.004], independent of other serum cardiac biomarkers. The abnormal hs-cTnI had the highest AUC for distinguishing of cardiac involvement in IIM patients (AUC = 0.848, 95% CI: 0.772,0.924; p < 0.001). Besides, we found that high serum levels of hs-cTnI were significantly correlated with disease activity. Moreover, patients with higher serum levels of hs-cTnI tended to suffer from poor prognosis. Conclusions Serum hs-cTnI testing may play a role in screening for cardiac involvement in IIM patients. Abnormal levels of serum hs-cTnI were associated with increased disease activity and poor prognosis. Key Points Among all the cardiac biomarkers, the serum levels of hs-cTnI were independently associated with cardiac involvement in IIM patients. The serum levels of hs-cTnI were significantly correlated with disease activity in IIM patients. The abnormal hs-cTnI levels were correlated with poor prognosis in IIM patients.

Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage.

OBJECTIVE: Liver damage is a common manifestation and can be life-threatening in adult-onset Still's disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD. METHODS: Transcriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed. RESULTS: LCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694. CONCLUSION: Our results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.

Anti-Tyro3 IgG Associates with Disease Activity and Reduces Efferocytosis of Macrophages in New-Onset Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a disease characterized by the production of a large number of autoantibodies. Defected phagocytosis of macrophage plays an important role in innate immunity in the pathogenesis of SLE. Tyro3 is a receptor responsible for the recognition of apoptotic cells during efferocytosis by macrophages. To investigate the role of Tyro3 receptor in macrophages' efferocytosis of apoptotic cells in SLE, we aimed to reveal the clinical relevance and impact of Tyro3 autoantibody on SLE. METHODS: The serum levels of IgG-type autoantibody against Tyro3 receptor were detected in new-onset, treatment-naïve SLE patients (n = 70), rheumatoid arthritis (RA) (n = 24), primary Sjögren's Syndrome (pSS) (n = 21), and healthy controls (HCs) (n = 70) using enzyme-linked immunosorbent assay (ELISA). The effects of purified Tyro3 autoantibody from SLE patients on the efferocytosis of human monocyte-derived macrophages were measured by flow cytometry and immunofluorescence. RESULTS: The serum levels of IgG-type autoantibody against Tyro3 receptor were significantly elevated in patients with SLE compared to RA, pSS, and HCs (all p < 0.0001). The levels of anti-Tyro3 IgG were positively associated with the SLE disease activity index (SLEDAI) score (r = 0.254, p = 0.034), erythrocyte sedimentation rate (ESR) (r = 0.430, p < 0.001), C-reactive protein (CRP) (r = 0.246, p = 0.049), and immunoglobulin G (IgG) (r = 0.408, p = 0.001) and negatively associated with haemoglobin (Hb) (r = -0.294, p = 0.014). ROC curves illustrated that the anti-Tyro3 antibody could differentiate patients with SLE from HCs. Furthermore, flow cytometry and immunofluorescence demonstrated that purified anti-Tyro3 IgG inhibited the efferocytosis of macrophages (p = 0.004 and 0.044, respectively) compared with unconjugated human IgG. CONCLUSIONS: These observations indicated that autoantibody against Tyro3 was associated with disease activity and could impair efferocytosis of macrophages. It might be a potential novel disease biomarker and might be involved in the pathogenesis of SLE.

Urinary Proteomics Identifying Novel Biomarkers for the Diagnosis of Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a systemic, multigenic autoinflammatory disease, and the diagnosis of AOSD must rule out neoplasms, infections, and other autoimmune diseases. Development of a rapid and efficient but non-invasive diagnosis method is urgently needed for improving AOSD therapy. In this study, we first performed a urinary proteomic study using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis in patients with AOSD and healthy control (HC) subjects. The urinary proteins were enriched in pathways of the innate immune system and neutrophil degranulation, and we identified that the α-1-acid glycoprotein 1 (LRG1), orosomucoid 1 (ORM1), and ORM2 proteins were highly expressed in patients with AOSD. The elevated urine levels of LRG1, ORM1, and ORM2 were further validated by enzyme-linked immunosorbent assay in active patients with AOSD, disease controls, and HC subjects. Receiver operating characteristic curves showed that the areas under the curve of LRG1, ORM1, and ORM2 were 0.700, 0.837, and 0.736, respectively (all p < 0.05). Furthermore, we found that the urine levels of LRG1, ORM1, and ORM2 were positively correlated with the systemic score and erythrocyte sedimentation rate and that the urine levels of LRG1 were positively correlated with interleukin 1ß (IL-1ß), IL-6, and IL-18 levels, whereas the urine levels of ORM1 were positively correlated with the IL-1ß level. Together, our study identified novel urinary markers for non-invasive and simple screening of AOSD.

Serum sTREM-1 in adult-onset Still's disease: a novel biomarker of disease activity and a potential predictor of the chronic course.

OBJECTIVES: Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of inflammatory signals. Recently, a soluble form of TREM-1 (sTREM-1) was described. This study aimed to investigate the role of serum sTREM-1 in patients with adult-onset Still's disease (AOSD). METHODS: Serum sTREM-1 levels were detected in 108 AOSD patients, 88 RA patients and 112 healthy controls (HC). The correlations of sTREM-1 with disease activity, clinical characteristics and laboratory parameters in AOSD patients were analysed by the Spearman correlation test. Risk factors for the chronic course of AOSD were evaluated by multivariate logistic regression analysis. RESULTS: AOSD patients had significantly higher serum sTREM-1 levels than RA patients and HC, and serum sTREM-1 levels were correlated with the systemic score, ferritin, leucocyte count, CRP, IL-1ß and IL-6. The elevation in the initial sTREM-1 level by itself could discriminate patients developing the chronic course from patients developing the nonchronic course. Moreover, an elevated sTREM-1 level (> 526.4475 pg/ml) was an independent risk factor for the chronic course in active AOSD patients. Furthermore, interfering with TREM-1 engagement led to reductions in the secretion of pro-inflammatory cytokines, such as IL-1ß, IL-6 and TNF-α, in neutrophils and monocytes from active AOSD patients. CONCLUSION: Serum sTREM-1 levels are correlated with disease activity, and an elevation in the initial serum sTREM-1 level is a potential predictor of the chronic course in AOSD patients, which currently provides the best predictive model for identifying patients prone to developing the chronic course of AOSD.

Pathogenesis, disease course, and prognosis of adult-onset Still's disease: an update and review.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare but clinically well-known polygenic systemic autoinflammatory disease. In this review, we aim to present frontiers in the pathogenesis, clinical features, diagnosis, biomarkers, disease course, prognosis, and treatment in AOSD. DATA SOURCES: We retrieved information from the PubMed database up to July 2019, using various search terms and relevant words, including AOSD and Still's disease. STUDY SELECTION: We included data from peer-reviewed journals. Both basic and clinical studies were selected. RESULTS: Pathogenesis of AOSD involves genetic background, infectious triggers, and immunopathogenesis, mainly the activation of macrophages and neutrophils followed by a cytokine storm. Diagnosis and prognosis evaluation of AOSD is still challenging; therefore, there is an urgent need to identify better biomarkers. Biologic agents, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α antagonists in the treatment of AOSD, have good prospect. CONCLUSION: This review highlights the advances in pathogenesis, potential biomarkers, disease course, and treatment in AOSD.

Cysteine-Rich Angiogenic Inducer 61 Serves as a Potential Serum Biomarker for the Remission of Adult-Onset Still's Disease.

Objective: Adult-onset Still's disease (AOSD) is a rare, polygenic, systemic autoinflammatory disease. The aim of this study is to evaluate the serum levels of cysteine-rich angiogenic inducer 61 (Cyr61), a secreted, extracellular protein in AOSD patients. Methods: A total of 60 AOSD patients (39 of active phase and 21 of inactive phase), 16 rheumatoid arthritis patients as a disease control, and 34 sex- and age-matched healthy control subjects (HC) were enrolled in the study. The data of the clinical manifestations and laboratory examinations were collected. The serum levels of Cyr61, interleukin (IL)-17, and IL-37 were detected by ELISA assay, and the serum levels of IL-10, IL-1ß, IL-6, IL-18, and tumor necrosis factor (TNF)-α were examined by electrochemiluminescence assay. Results: The serum levels of Cyr61 were significantly increased in inactive AOSD than those in active patients and HCs, and the levels of Cyr61 were dramatically increased after treatment. The levels of Cyr61 were inversely correlated with systemic score, the counts of leukocyte and neutrophil, and the levels of inflammatory cytokines (IL-1ß, IL-6, and IL-17). Moreover, the levels of Cyr61 were higher in patients without the clinical symptoms of fever, skin rash, sore throat, arthralgia, and lymphadenopathy compared with those in patients with these symptoms. Conclusion: The serum levels of Cyr61 were inversely correlated with disease activity in AOSD patients; thus, we proposed that Cyr61 was a biomarker for the remission of AOSD.

Cytomegalovirus Infection May Trigger Adult-Onset Still's Disease Onset or Relapses.

Previous studies have revealed that several micro-organisms, especially DNA viruses, have been associated with adult-onset Still's disease (AOSD). However, there are no studies on the relationship between the presence of viral infections in AOSD patients with disease occurrence and reactivation. In the present study, we aimed to investigate the presence of antibodies against virus, virus DNA load and nucleic acid sensors in AOSD patients. Anti-viral antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in plasma samples from 100 AOSD patients and 70 healthy controls (HCs). The copy number of cytomegalovirus (CMV) DNA in 100 AOSD patients was detected by PCR. The expression levels of nucleic acid sensors interferon gamma-inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) in peripheral blood mononuclear cell (PBMC) and skin from AOSD patients and HCs were analyzed by PCR and immunohistochemistry. The levels of antibodies against CMV were significantly higher in AOSD patients compared to HCs. Moreover, the level of anti-CMV IgM antibody was significantly increased in patients with fever, sore throat, arthralgia and rash. CMV DNA was found in plasma of AOSD patients with disease new-onset and relapse. Furthermore, the copy number of CMV DNA significantly increased in patients with fever, sore throat, arthralgia and rash. And the significant associations of the CMV DNA level with the levels of leukocytes, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were observed. Moreover, we found an upregulation of cytoplasmic DNA-sensing receptor IFI16 and AIM2 in PBMC and skin from AOSD patients. In conclusion, our results showed that CMV infection may play a role in the initiation or amplification of inflammatory responses in AOSD.

Increased neutrophil extracellular traps activate NLRP3 and inflammatory macrophages in adult-onset Still's disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by neutrophilia and NLRP3 inflammasome and macrophage activation. We investigated the role of neutrophil extracellular traps (NETs) in the pathogenesis of AOSD, and explored the effect of NETs on activating NLRP3 inflammasome and proinflammatory macrophages. METHODS: The sera of 73 AOSD patients and 40 healthy controls were used to detect the level of cell-free DNA and NET-DNA complexes. NET formation ex vivo was analyzed using immunofluorescence and flow plates. The activation of NLRP3 inflammasome in THP-1 cells and proinflammatory macrophages stimulated with DNA purified from NETs was measured using RT-PCR, ELISA, Western blotting and flow cytometry. RESULTS: The levels of cell-free DNA and NET-DNA complexes were significantly increased in the circulation of patients with AOSD compared with healthy controls, and freshly isolated neutrophils from patients with AOSD were predisposed to high levels of spontaneous NET release. Interestingly, enhanced NET release was abrogated with NADPH oxidase inhibitors and a mitochondrial scavenger. Furthermore, DNA purified from AOSD NETs activated NLRP3 inflammasomes. NET DNA from AOSD also exerted a potent capacity to accelerate the activation of CD68+CD86+ macrophages and increased the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. Finally, the copy number of mitochondrial DNA (mtDNA) in NETs and plasma was significantly increased in AOSD patients, suggesting that mtDNA may be involved in the activation of NLRP3 and inflammatory macrophages. CONCLUSIONS: These findings implicate accelerated NET formation in AOSD pathogenesis through activation of NLRP3 and proinflammatory macrophages, and identify a novel link between neutrophils and macrophages by NET formation in AOSD.

Causes of death in hospitalized patients with systemic lupus erythematosus: a 10-year multicenter nationwide Chinese cohort.

To estimate the mortality and describe the causes of death in a large multicenter cohort of hospitalized patients with SLE in China. This was a retrospective study of a nationwide SLE cohort (10 centers, 29,510 hospitalized patients) from 2005 to 2014 in China. Standardized mortality ratios (SMRs) were calculated for all death and were stratified by sex and age. Chi-square test was used to determine whether the major causes of death vary in age, sex, duration of SLE, disease activity, or medications. Comparison between dead patients and survival controls was used to identify the risk factors for mortality. Logistic regression analysis was used to evaluate the risk factors for mortality. A total of 360 patients died during the study period, accounting for 1.22%. The overall SMR was 2.13 (95% CI 1.96, 2.30), with a particularly high SMR seen in subgroups characterized by younger age. Infection (65.8%) was the most common cause of death, followed by lupus nephritis (48.6%), hematological abnormality (18.1%), neuropsychiatric lupus/NPSLE (15.8%), and interstitial pneumonia (13.1%). Cardiovascular disease and malignancy contributed little to the causes of death. Infection, in particular severe pulmonary infection, emerged as the foremost risk factor for mortality, followed by lupus encephalopathy. However, lupus nephritis and hematological abnormalities occurred more frequently in survival patients. SLE patients at a younger age of diagnosis have a poorer prognosis. Infection dominated the causes of death in recent China. Ethnicity and medications might account for the differences in causes of death compared with western populations.

Anti-SIRT1 autoantibody is elevated in ankylosing spondylitis: a potential disease biomarker.

BACKGROUND: Little is known about the presence of specific autoantibodies in ankylosing spondylitis (AS), an immune-mediated inflammatory disease. The object of this study was to explore potential autoantibody profiles in AS patients. RESULTS: Levels of anti-SIRT1 autoantibodies were significantly higher in AS (P < 0.001) and psoriatic arthritis (PsA) (P < 0.01) patients but not rheumatoid arthritis (RA) patients compared with healthy controls. Additionally, titers of anti-NAD-dependent protein deacetylase sirtuin-1(SIRT1) antibodies were significantly higher in AS patients than in RA (P < 0.05) and PsA (P < 0.05) patients. Moreover, levels of anti-SIRT1 (P < 0.001) antibodies were significantly higher during the first year in patients with hip joint involvement. The anti-SIRT1 antibody positivity rate was 18.9% in AS patients. CONCLUSIONS: Our findings indicate that anti-SIRT1 autoantibodies may serve as a marker for diagnosing AS and predicting hip joint involvement at an early stage.

Interleukin-37 is increased in adult-onset Still's disease and associated with disease activity.

BACKGROUND: Interleukin (IL)-37 has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of adult-onset Still's disease (AOSD) has not been investigated. In this study, we examined serum IL-37 levels and their clinical association with AOSD, and we explored the anti-inflammatory effects of IL-37 on peripheral blood mononuclear cells (PBMCs) from patients with AOSD. METHODS: Blood samples were collected from 62 patients with AOSD and 50 healthy control subjects (HC). The serum IL-37 levels were determined using an enzyme-linked immunosorbent assay (ELISA). The correlations of serum IL-37 levels with disease activity, laboratory values, and inflammatory cytokines in AOSD were analyzed by Spearman's correlation test. The correlations between serum IL-37 levels and clinical manifestations were analyzed by Mann-Whitney U test. PBMCs from ten patients with AOSD were stimulated with recombinant human IL-37 protein, and expression levels of tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-1ß, and IL-18 were determined by qRT-PCR and ELISA. RESULTS: A significantly higher IL-37 protein level was observed in patients with AOSD than in HC. Serum IL-37 levels correlated with systemic score, laboratory values, IL-1ß, IL-18, and IL-10 in patients with AOSD. The expression levels of IL-37 were closely related to the patients with AOSD who also had fever, skin rash, lymphadenopathy, splenomegaly, myalgia, and arthralgia. Moreover, the production of proinflammatory cytokines such as IL-6, IL-1ß, TNF-α, and IL-18 in PBMCs from patients with AOSD was obviously attenuated after recombinant human IL-37 stimulation. CONCLUSIONS: Increased expression of IL-37 and its positive correlation with disease activity suggest its involvement in AOSD pathogenesis. More importantly, IL-37 inhibits the expression of proinflammatory cytokines in PBMCs from patients with AOSD, indicating the potential anti-inflammatory role of IL-37 in AOSD. Thus, IL-37 may be a novel disease activity biomarker and research target in AOSD.

Delayed-onset of progressive pseudorheumatoid dysplasia in a Chinese adult with a novel compound WISP3 mutation: a case report.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disease that is characterized by pain, stiffness and enlargement of multiple joints with an age of onset between 3 and 8 years old. Mutations in the WISP3 (Wnt1-inducible signal pathway) gene are known to be the cause of PPD. CASE PRESENTATION: We present a case of delayed-onset PPD in a Chinese man. The 35-year-old proband presented with an almost 20-year history of pain and limitations in mobility in multiple joints. Based on the clinical manifestations, the patient was diagnosed with PPD; however, there was no specific evidence to confirm this diagnosis. Through mutational analyses, two WIPS3 mutations in exon 4, including a novel frameshift mutation (c.670dupA) in the paternal allele and an already described nonsense mutation (c.756C > A, p.Cys252*) in the maternal allele, were identified in the proband. Thus, the patient was diagnosed with PPD. Furthermore, we found that the proband's son only carried one of the mutations (c.670dupA) and therefore determined that he would not be affected by PPD in the future. CONCLUSIONS: In this case, we successfully diagnosed the disease that the proband was affected precisely after the reunion of clinical diagnosis and genetic analysis. These findings demonstrate the clinical utility of genetic analysis to diagnose skeletal dysplasia and guide genetic counseling.

Demethylzeylasteral (T-96) Treatment Ameliorates Mice Lupus Nephritis Accompanied by Inhibiting Activation of NF-κB Pathway.

BACKGROUND: Inflammation plays a vital role in the pathogenesis in lupus nephritis (LN), which is largely attributable to the activation of nuclear factor kappa B (NF-κB) signal pathway. NF-κB up-regulates pro-inflammatory mediators, such as TNF-α, cyclo-oxygenase-2 (COX-2) and ICAM-1, and promotes macrophage infiltration into renal tissue, further inducing the progression of LN. Over the past 30 years, research has demonstrated that Tripterygium wilfordii Hook F (TWHF) possesses potent anti-inflammatory and immunosuppressive activities, and that demethylzeylasteral (T-96), an extract of TWHF, may be one of the responsible compounds. Here, we investigate the pharmacodynamic role and therapeutic mechanism by which T-96 suppresses inflammation and reduces renal pathology in the lupus-prone MRL/lpr mice. METHODS: Forty-eight MRL/lpr mice were equally randomly divided into 6 groups (1.2, 0.6 or 0.3 mg/10 g T-96, 0.022 pills/10 g kang lang chuang san (one of Traditional Chinese herb as positive control), 0.125 mg/10 g prednisone and 0.1 ml/10 g normal saline as the LN disease control group). Also, eight WT C57BL/6 mice were used as normal control. After treatment by gavage with 0.10 ml/10 g/day volumes for 8 weeks, all mice were sacrificed and renal tissues were collected. The amount of 24 h proteinuria and the levels of anti-dsDNA antibody in serum were assessed respectively at weeks 0, 4 and 8. Inflammation, cytokines and NF-κB levels were assessed by histological examinations, immunohistochemical analyses and Western blot analyses. RESULTS: In comparison with untreated MRL/lpr mice, mice treated with 1.2 and 0.6 mg/10 g of T-96 showed a significant improvement in 24 h proteinuria and the levels of anti-dsDNA antibody in serum. In addition, T-96 reduced the secretion of pro-inflammatory mediators such as TNF-α, COX-2 and ICAM-1, and the infiltration of macrophages in renal tissue. Moreover, T-96 significantly suppressed phosphorylations of cytoplasmic IKK and nuclear p65. CONCLUSION: This study suggests that T-96 exhibits reno-protective effects in LN accompanied by inhibiting the activation of NF-κB, reducing the downstream pro-inflammatory mediators and thus restricting macrophage infiltration. Because of these potent properties, T-96 should be considered as a promising therapeutic drug for LN.