Comparison of effectiveness of methotrexate in patients with late-onset versus younger-onset rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

OBJECTIVE: To compare the effectiveness of methotrexate (MTX) as initial therapy in patients with late-onset and younger-onset rheumatoid arthritis (LORA and YORA). METHODS: Of 114 patients with YORA and 96 patients with LORA, defined as RA occurring at ≥65 years of age, enrolled in a multicentre RA inception cohort study, 71 and 66 patients who had been followed up to 6 months after starting MTX treatment were included in this study. RESULTS: Proportions of patients on MTX treatment at 6 months were 96% and 92% in the YORA and LORA groups, respectively. Despite lower doses of MTX in the LORA group compared with the YORA group, no significant difference was observed in clinical disease activity index scores between the two groups throughout the follow-up period. The proportion of patients in clinical disease activity index remission at 6 months was 35% in both groups. Logistic regression analysis revealed that knee joint involvement and high Health Assessment Questionnaire-Disability Index were significant negative predictors of achieving clinical disease activity index remission at 6 months in the LORA group. CONCLUSION: Observations up to 6 months revealed that the effectiveness of MTX administered based on rheumatologist discretion in patients with LORA is comparable to that in patients with YORA in clinical settings.

Choice of and response to treatment in patients with early-diagnosed rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

OBJECTIVE: Various guidelines recommend that patients with early rheumatoid arthritis (RA) try to achieve clinical remission within 6 months, and early therapeutic intervention is important to this end. This study aimed to investigate short-term treatment outcomes of patients with early-diagnosed RA in clinical practice and to examine predictive factors for achieving remission. METHODS: Of the 210 patients enrolled in the multicenter RA inception cohort, 172 patients who were followed up to 6 months after treatment initiation (baseline) were included. Logistic regression analysis was used to examine the impact of baseline characteristics on achievement of Boolean remission at 6 months. RESULTS: Participants (mean age, 62 years) initiated treatment after a mean of 19 days from RA diagnosis. At baseline and 3 and 6 months after treatment initiation, proportions of patients using methotrexate (MTX) were 87.8%, 89.0%, and 88.3%, respectively, and rates of Boolean remission were 1.8%, 27.8%, and 34.5%, respectively. Multivariate analysis revealed that physician global assessment (PhGA) (Odds ratio (OR): 0.84, 95% confidence interval (CI): 0.71-0.99) and glucocorticoid use (OR: 0.26, 95% CI: 0.10-0.65) at baseline were independent factors that predicted Boolean remission at 6 months. CONCLUSION: After a diagnosis of RA, satisfactory therapeutic effects were achieved at 6 months after the initiation of treatment centered on MTX according to the treat to target strategy. PhGA and glucocorticoid use at treatment initiation are useful for predicting the achievement of treatment goals.

Clinical characteristics of COVID-19 infection in a dialysis center during a nosocomial outbreak.

BACKGROUND: Blood purification therapy is a treatment method, wherein many patients gather in the same space to receive regular treatments, possibly increasing the risk of contracting the coronavirus disease 2019 (COVID-19) through contact, droplet, and aerosol. We experienced a nosocomial outbreak and evaluated the clinical characteristics of COVID-19 infection in patients undergoing blood purification therapy. METHODS: We retrospectively analyzed 28 patients who underwent blood purification therapy at the dialysis center of our hospital from April 2, 2020, to April 29, 2020. Logistic regression analysis was performed to identify clinical factors related to COVID-19 for 18 patients who were tested using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Of the 28 patients, seven were COVID-19 positive, as confirmed by RT-PCR. The median age was 77 years, 22 patients were male (79%), four patients had acute kidney injury (14%), and six patients were bedridden (21%). All infected patients had been admitted to the wards where the nosocomial outbreak had occurred. Logistic regression analysis revealed that being bedridden (odds ratio 13.33, 95% confidence interval 1.05-169.56, p < 0.05) was significantly related to COVID-19 infection. However, the Charlson comorbidity index, receiving dialysis in the same room, and adjacency of the dialysis bed to COVID-19-positive patients before the confirmation of infection did not reveal any significant relationship. CONCLUSION: Bedridden patients admitted to nosocomial infection wards were associated with COVID-19 infection, and transmission within the dialysis center was not observed. More rigorous infection control measures need to be implemented for bedridden patients undergoing blood purification therapy.

Recurrent membranous nephropathy with a possible alteration in the etiology: a case report.

BACKGROUND: Phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major pathogenic antigens for membranous nephropathy (MN). It has been reported that THSD7A-associated MN has a higher prevalence of comorbid malignancy than PLA2R1-associated MN. Here we present a case of MN whose etiology might change from idiopathic to malignancy-associated MN during the patient's clinical course. CASE PRESENTATION: A 68-year-old man with nephrotic syndrome was diagnosed with MN by renal biopsy. Immunohistochemistry showed that the kidney specimen was negative for THSD7A. The first course of corticosteroid therapy achieved partial remission; however, nephrotic syndrome recurred 1 year later. Two years later, his abdominal echography revealed a urinary bladder tumor, but he did not wish to undergo additional diagnostic examinations. Because his proteinuria increased consecutively, corticosteroid therapy was resumed, but it failed to achieve remission. Another kidney biopsy was performed and revealed MN with positive staining for THSD7A. PLA2R1 staining levels were negative for both first and second biopsies. Because his bladder tumor had gradually enlarged, he agreed to undergo bladder tumor resection. Pathological examination indicated that the tumor was THDS7A-positive bladder cancer. Subsequently, his proteinuria decreased and remained in remission. CONCLUSIONS: This case suggests that the etiology of MN might be altered during the therapeutic course. Intensive screening for malignancy may be preferable in patients with unexpected recurrence of proteinuria and/or change in therapy response.

Low-Temperature-Processed Brookite-Based TiO2 Heterophase Junction Enhances Performance of Planar Perovskite Solar Cells.

In the design of electron-transport layers (ETLs) to enhance the efficiency of planar perovskite solar cells (PSCs), facile electron extraction and transport are important features. Here, we consider the effects of different titanium oxide (TiO2) polymorphs, anatase and brookite. We design and fabricate high-phase-purity, single-crystalline, highly conductive, and low-temperature (<180 °C)-processed brookite-based TiO2 heterophase junctions on fluorine-doped tin oxide (FTO) as the substrate. We test and compare single-phase anatase (A) and brookite (B) and heterophase anatase-brookite (AB) and brookite-anatase (BA) as ETLs in PSCs. The power-conversion efficiencies (PCEs) of PSCs with low-temperature-processed single-layer FTO-B as the ETL were as high as 14.92%, which is the highest reported efficiency of FTO-B-based single-layer PSC. This implies that FTO-B serves as an active phase and can be a potential candidate as an n-type ETL scaffold in planar PSCs. Moreover, the surface of highly crystalline brookite TiO2 exhibits a tendency toward interparticle necking, leading to the formation of compact scaffolds. Furthermore, PSCs with heterophase junction FTO-AB ETLs exhibited PCEs as high as 16.82%, which is superior to those of PSCs with single-phase anatase (FTO-A) and brookite (FTO-B) as the ETLs (13.86% and 14.92%, respectively). In addition, the PSCs with FTO-AB exhibited improved efficiency and decreased hysteresis compared with those with FTO-BA (13.45%) due to the suitable band alignment with the perovskite layer, which resulted in superior photogenerated charge-carrier extraction and reduced charge accumulation at the interface between the heterophase junction and perovskite. Thus, the present work presents an effective strategy by which to develop heterophase junction ETLs and manipulate the interfacial energy band to further improve the performance of planar PSCs and enable the clean and eco-friendly fabrication of low-cost mass production.

VEGF-A Links Angiolymphoid Hyperplasia With Eosinophilia (ALHE) to THSD7A Membranous Nephropathy: A Report of 2 Cases.

Autoantibodies against thrombospondin type 1 domain-containing 7A (THSD7A) cause membranous nephropathy (MN); however, the mechanisms involved in THSD7A expression and immunization are uncertain. We present 2 cases of THSD7A-associated MN accompanied by angiolymphoid hyperplasia with eosinophilia (ALHE), a benign tumor characterized by proliferation of plump endothelial cells. Prednisolone therapy, but not surgical resection of ALHE tumors, successfully suppressed eosinophilia and proteinuria in both cases. Because ALHE is characterized by the proliferation of plump endothelial cells, we focused on the roles of vascular endothelial growth factor A (VEGF-A) in MN pathogenesis. We found that plump endothelial cells in ALHE modestly expressed THSD7A in both cases. We also found that eosinophils in ALHE expressed VEGF-A, which upregulated THSD7A expression, especially under T-helper type 2-prone conditions in cultured endothelial cells. Furthermore, double-positive cells for THSD7A and CD83 surrounded the proliferated small vessels. Our results suggest that VEGF-A-induced THSD7A expression outside the kidney may be important for MN pathogenesis.

High-sensitivity simultaneous quantification of tacrolimus and 13-O-demethyl tacrolimus in human whole blood using ultra-performance liquid chromatography coupled to tandem mass spectrometry.

Blood concentrations of tacrolimus show large variability among patients and the narrow therapeutic range is related to adverse effects. Therefore, therapeutic drug monitoring is needed for strict management. 13-O-Demethyl tacrolimus (13-O-DMT) was reported as the major metabolite formed by cytochrome P450 (CYP)3A such as CYP3A5. In previous studies, the best lower limit of quantification (LLOQ) was 0.1 ng/mL for both substances. However, this LLOQ may not be low enough now because the dosage of tacrolimus has decreased in recent years. The purpose of this study was to develop and validate a high-sensitivity and high-throughput assay for simultaneous quantification of tacrolimus and 13-O-DMT in human whole blood using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). Thirty-five stable kidney transplant recipients receiving tacrolimus were recruited in this study. The calibration curve range was 0.04-40 ng/mL. All calibration samples and quality control samples fulfilled the requirements of the US Food and Drug Administration and the European Medicines Agency guidelines for assay validation. Trough concentrations of tacrolimus and 13-O-DMT in 35 stable kidney transplant recipients receiving tacrolimus were within the range of the respective calibration curve. Our novel UPLC-MS/MS method is more sensitive than previous methods for quantification of tacrolimus and 13-O-DMT.

Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates with Maleates and Its Application to the Enantioselective Synthesis of Tricarboxylic Acid Derivatives.

The Michael reaction of malonates with maleates afforded the corresponding adducts in high yields with high enantioselectivities (up to 98% enantiomeric excess (ee)) by using dilithium 3,3'-dichlorobinaphtholate as a catalyst. The obtained Michael adducts could be converted to optically active tricarboxylic acid (TCA) derivatives via the Krapcho reaction.

The three-year efficacy of iguratimod in clinical daily practice in patients with rheumatoid arthritis.

Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients. Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed. Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years. Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.

Optimal Trough Concentration of Teicoplanin in Febrile Neutropenic Patients with Hematological Malignancy.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic currently used for the treatment of methicillin-resistant Staphylococcus aureus. The need for therapeutic drug monitoring of teicoplanin has been increasingly highlighted as important. It is generally accepted that whereas a plasma trough concentration (Cmin) of ≥10 mg/L is appropriate for the majority of infections, it should exceed 20 mg/L for severe infections. The target Cmin of teicoplanin in patients with febrile neutropenia (FN) has not been reported. The aim of this study was to estimate the target Cmin for the treatment of FN in patients with hematological malignancy. METHODS: In this retrospective, single-center, observational cohort study, the records of 52 hospitalized patients with hematological malignancy who were treated with teicoplanin for FN due to bacteriologically documented or presumptive gram-positive infections were analyzed. RESULTS: A significant difference in the first Cmin of teicoplanin was observed between the response and nonresponse groups in patients with bacteremia. The areas under the receiver operating characteristic curves were 0.80 for clinical efficacy. The cut-off value of teicoplanin Cmin on days 4-6 was 15.2 mg/L (sensitivity 80.0%, specificity 75.0%). CONCLUSIONS: The authors propose a target teicoplanin Cmin of ≥15.2 mg/L for FN in patients with hematological malignancy.

Comparison of whole-blood tacrolimus concentrations measured by different immunoassay systems.

INTRODUCTION: Different measured values for tacrolimus were obtained with different automated immunoassays. We aimed to examine the differences in the blood tacrolimus concentrations measured by the major immunoassay systems commercially available in Japan. METHODS: Whole-blood samples from 118 patients were assayed by 3 commercial assays: chemiluminescent enzyme immunoassay (CLIA), affinity column-mediated immunoassay (ACMIA), and enzyme-multiplied immunoassay technique (EMIT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for reference. KEY FINDINGS: The correlation coefficient of immunoassay vs LC-MS/MS was excellent for ACMIA (.83) and CLIA (.81) and good for EMIT (.71). The mean error was negative for ACMIA and positive for CLIA and EMIT. The mean absolute error and root-mean-square error were almost the same for ACMIA and CLIA and lower than those for EMIT. CONCLUSIONS: The ACMIA and CLIA yield considerably better results than the EMIT for monitoring blood tacrolimus concentrations.

Short-term daily teriparatide in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to compare the efficacy of six-month teriparatide treatment followed by six-month bisphosphonate therapy with 12-month bisphosphonate monotherapy in Japanese rheumatoid arthritis (RA) patients who had not been previously treated for osteoporosis. METHODS: A total of 34 RA patients with osteoporosis were enrolled. Thirteen patients received six-month teriparatide prior to six-month minodronate therapy (PTH group), and 21 patients received 12-month minodronate therapy (BP group). Bone mineral density (BMD), and bone turnover markers were measured prior to and 6 and 12 months after the initiation of treatment. RESULTS: Bone mineral density of the spine was significantly increased after 12 months of treatment in both groups. In the PTH group, the mean percent change of BMD of the spine was significantly higher at 12 months after the initiation of treatment, as compared to the BP group (PTH group: 9.9 ± 1.5%, BP group: 5.5 ± 0.7%). Femoral neck BMD was significantly increased only in the PTH group after 12 months. CONCLUSION: Therapy involving six-month teriparatide followed by six-month minodronate therapy increased spine BMD to a greater degree than 12-month minodronate monotherapy. The strategy of short-term administration of teriparatide for RA patients with osteoporosis might be useful when additional bisphosphonate therapy is considered.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient.

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Predictive factors associated with the progression of large-joint destruction in patients with rheumatoid arthritis after biologic therapy: A post-hoc analysis using FDG-PET/CT and the ARASHI (assessment of rheumatoid arthritis by scoring of large-joint destruction and healing in radiographic imaging) scoring method.

OBJECTIVE: To investigate the associations between large-joint damage and findings on fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) using the "assessment of rheumatoid arthritis by scoring of large-joint destruction and healing in radiographic imaging (ARASHI)" scoring system. METHODS: A total of 270 large joints (shoulders, elbows, hips, knees, and ankles) in 27 rheumatoid arthritis patients were assessed. FDG-PET/CT was performed at the initiation of biologics. Radiographs at baseline and at 3 years were evaluated using the ARASHI score. RESULTS: Radiographic progression of damage was detected in 35 by Larsen grade vs. 87 by the ARASHI score. The maximum standardized uptake value (SUVmax) at baseline, Steinbrocker stage at baseline, concomitant prednisolone use, and disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at 6 months were significantly higher in the radiographic progression group. An SUVmax higher than 1.65 at baseline was a significant predictive factor for progressive damage at 3 years. CONCLUSIONS: The ARASHI score may allow more detailed evaluation of large joints than the Larsen method. Joint destruction is likely to have progressed at 3 years in large joints, which had a higher SUVmax at the initiation of biologics.

Predictive factors related to shoulder joint destruction in rheumatoid arthritis patients treated with biologics: A prospective study.

OBJECTIVE: The aim of this study was to assess the risk factors for shoulder joint destruction in rheumatoid arthritis (RA) patients treated with biologics. METHODS: Thirty shoulders of 29 patients with RA were assessed using 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) before starting biologics and 6 months later. The mean age (range) was 54 (18-72) years, and the mean disease duration was 7 (0.8-30) years. The radiographic findings were assessed at baseline and 3 years later. The inflammation markers and RA disease activity were also assessed. These parameters were compared between the progression of joint destruction group and the no progression group. RESULTS: The SUVmax on PET, the rate of synovitis, and the rate of rotator cuff tear on MRI before biologic treatment were significantly higher in the progression of joint destruction group. SUVmax and synovitis on MRI after 6 months were also significantly higher in the progression of joint destruction group. On logistic regression analysis, the SUV at baseline of the shoulder joint was the main risk factor for joint destruction. CONCLUSION: The detection of synovitis by imaging was more important than disease activity and inflammation markers for assessing the progression of shoulder joint destruction.

[18F]fluorodeoxyglucose uptake as a predictor of large joint destruction in patients with rheumatoid arthritis.

The present retrospective study investigated the relationship between [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET) findings and subsequent progression of joint destruction on plain X-ray. Nineteen rheumatoid arthritis (RA) patients (59 joints) who underwent FDG-PET and whose joints could be evaluated on plain X-ray 5 years later were included in this retrospective investigation. The relationship between the standardized uptake value (SUV) on FDG-PET and Larsen grade progression on plain X-ray was investigated for each joint. Factors related to progression of joint destruction were also investigated. Joints with advanced joint destruction (Larsen grades IV and V) on X-ray imaging at the time of FDG-PET were excluded. On initial plain X-ray images taken at the time of FDG-PET, a significant correlation was observed between the initial SUV of each joint and the progression of joint destruction 5 years later (R = 0.47, P < 0.01). Significant correlations between the SUV and progression of joint destruction were observed in both load-bearing (R = 0.52, P < 0.01) and non-load-bearing joints (R = 0.52, P < 0.01). On logistic regression analysis, higher SUV and lower prednisolone dose were associated with greater risk of progressive joint destruction (P < 0.05). On receiver operating characteristics curve analysis, the optimum threshold for identifying preceding joint destruction was an SUVmean of 1.33. In RA joints, FDG uptake was seen mostly by inflammatory cells; therefore, FDG uptake reflected joint inflammation. Additionally, the activity seen on FDG-PET might be associated with future radiographic changes in RA patients.

Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter, cohort study.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA). METHODS: The subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17-87) years; median (range) disease duration, 8 (0.6-48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2-16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group). Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM. RESULTS: There were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group. CONCLUSIONS: GLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.

Autoimmune animal models in the analysis of the CD47-SIRPα signaling pathway.

Signal regulatory protein α (SIRPα), also known as SHPS-1/SIRPA, is an immunoglobulin superfamily protein that binds to the protein tyrosine phosphatases Shp1 and Shp2 through its cytoplasmic region and is predominantly expressed in dendritic cells and macrophages. CD47, a widely expressed transmembrane protein, is a ligand for SIRPα, with the two proteins constituting a cell-cell communication system. It was previously demonstrated that the CD47-SIRPα signaling pathway is important for prevention of clearance by splenic macrophages of red blood cells or platelets from the bloodstream. In addition, this signaling pathway is also implicated in homeostatic regulation of dendritic cells and development of autoimmunity. Here we describe the detailed protocols for methods that were used in our recent studies to study the role of the CD47-SIRPα signaling pathway in autoimmunity. We also demonstrate that hematopoietic SIRPα as well as nonhematopoietic CD47 are important for development of experimental autoimmune encephalomyelitis. Thus, we here strengthen the importance of experimental animal models as well as other methods for the study of molecular pathogenesis of autoimmunity.

Histochemical and immunoelectron microscopic analysis of ganglioside GM3 in human kidney.

BACKGROUND: Gangliosides are amphipathic lipids ubiquitously expressed in all vertebrate cells. They have been reported to play pivotal roles in cell morphology, cell adhesion, signal transduction, and modulation of immune reaction. Although human kidney contains various kinds of ganglioside, their physiological and pathophysiological roles have not been elucidated yet. As ganglioside GM3 is the most abundant ganglioside in human kidney, we tried to reveal the distribution of GM3 using histological analysis. METHODS: Macroscopically normal parts of operatively resected kidney from renal cell carcinoma patients were used for analyses. Immunohistochemical and immunoelectron microscopic analyses were performed with anti-GM3 antibody. RESULTS: Immunohistochemical analyses showed that GM3 was observed in glomeruli and renal proximal tubules. Immunoelectron microscopy demonstrated that GM3 was localized on the foot process of podocyte and also in Golgi region of renal proximal tubule cells. CONCLUSIONS: Ganglioside GM3 might take a part of the negative electric charge on the surface of podocyte and its multiple physiological actions may play pivotal roles for maintaining glomerular function.

Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity.

Dendritic cells (DCs) promote immune responses to foreign Ags and immune tolerance to self-Ags. Deregulation of DCs is implicated in autoimmunity, but the molecules that regulate DCs to protect against autoimmunity have remained unknown. In this study, we show that mice lacking the protein tyrosine phosphatase Shp1 specifically in DCs develop splenomegaly associated with more CD11c(+) DCs. Splenic DCs from the mutant mice showed upregulation of CD86 and CCR7 expression and of LPS-induced production of proinflammatory cytokines. The mice manifested more splenic Th1 cells, consistent with the increased ability of their DCs to induce production of IFN-γ by Ag-specific T cells in vitro. The number of splenic CD5(+)CD19(+) B-1a cells and the serum concentrations of Igs M and G2a were also increased in the mutant mice. Moreover, aged mutant mice developed glomerulonephritis and interstitial pneumonitis together with increased serum concentrations of autoantibodies. Shp1 is thus a key regulator of DC functions that protects against autoimmunity.