A Multicenter Cohort Study of Immune Dysregulation Disorders Caused by ELF4 Variants in China.

Patients with DEX (deficiency in ELF4, X-linked) were recently reported by our team and others, and cases are very limited worldwide. Our knowledge of this new disease is currently preliminary. In this study, we described 5 more cases presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anemia, or systemic lupus erythematosus. Whole exome sequencing identified potential pathogenic ELF4 variants in all cases. The pathogenicity of these variants was confirmed by the detection of ELF4 expression in peripheral blood mononuclear cells from patients and utilizing a simple IFN-b luciferase reporter assay, as previously reported. Our findings significantly contribute to the current understanding of DEX.

Safety and efficacy of telitacicept in refractory childhood-onset systemic lupus erythematosus: A self-controlled before-after trial.

OBJECTIVE: To observe the efficacy and safety of telitacicept in refractory childhood-onset systemic lupus erythematosus (cSLE). METHODS: A self-controlled before-after trial. Children with active SLE, aged 5-18 years, who cannot tolerate side effects of glucocorticoid, were enrolled in our study. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. RESULTS: Among the 15 cases of refractory cSLE, three were males (20%) and 12 were females (80%). The median age and weight were 13 years old and 52 kg, respectively. The median duration of disease was 30 months. 5-26 weeks (80 or 160 mg per week) after administration of telitacicept, 66.7% (n=10) reached SRI-4 response. 12 cases reduced their glucocorticoid intake from 40 mg/d to 17.5 mg/d. The urinary protein after treatment declined in 8 cases whose 24-h proteinuria was >0.5 g at baseline. The urinary protein in two of the eight cases turned negative and plasma albumin in five of the eight cases rose to normal. In addition, three of these eight cases demonstrated varying degrees of improvement in renal impairment, whose estimated glomerular filtration rate (eGFR, ml/min·1.73 m2) rose from 17.4 to 26.6, 40.7 to 48.2, and 63.2 to 146.0, respectively. There were mild to moderate adverse events after treatment. CONCLUSION: Telitacicept combined with the standard treatment may significantly increase the SRI-4 response rate and reduce the glucocorticoid dosage in refractory cSLE, and also shown efficacy on lupus nephritis. The related adverse drug events were controllable.

PPARα agonist exerts protective effects in podocyte injury via inhibition of the ANGPTL3 pathway.

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3-knockout mice were cultured. There was no significant difference between Angptl3-/- podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression.

Comparative proteomic analysis of children FSGS FFPE tissues.

BACKGROUND: In children, focal segmental glomerulosclerosis (FSGS) is the main cause of steroid resistant nephrotic syndrome (SRNS). To identify specific candidates and the mechanism of steroid resistance, we examined the formalin-fixed paraffin embedded (FFPE) renal tissue protein profiles via liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Renal biopsies from seven steroid-sensitive (SS) and eleven steroid-resistant (SR) children FSGS patients were obtained. We examined the formalin-fixed paraffin embedded (FFPE) renal tissue protein profiles via liquid chromatography tandem mass spectrometry (LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analysis, as well as the construction of protein-protein interaction (PPI) network were performed. Two proteins were further valiadated by immunohistochemistry staining in FSGS patients and mice models. RESULTS: In total, we quantified more than 4000 proteins, of which 325 were found to be differentially expressed proteins (DEPs) between the SS and SR group (foldchange ≥2, P<0.05). The results of GO revealed that the most significant up-regulated proteins were primarily related to protein transportation, regulation of the complement activation process and cytolysis. Moreover, clustering analysis showed differences in the pathways (lysosome, terminal pathway of complement) between the two groups. Among these potential candidates, validation analyses for LAMP1 and ACSL4 were conducted. LAMP1 was observed to have a higher expression in glomerulus, while ACSL4 was expressed more in tubular epithelial cells. CONCLUSIONS: In this study, the potential mechanism and candidates related to steroid resistance in children FSGS patients were identified. It could be helpful in identifying potential therapeutic targets and predicting outcomes with these proteomic changes for children FSGS patients.

Autophagy protects podocytes from sublytic complement induced injury.

Podocyte injury induced by sublytic complement attack is the main feature of membranous nephropathy (MN). This study aimed at investigating the impact of sublytic complement attack-related autophagy on podocyte injury in vitro. Here, we show that sublytic complement attack enhances MPC5 podocyte autophagy in vitro. Inhibition of autophagy by treatment with 3-methyladenine (3-MA) significantly increased sublytic complement attack-induced changes in the injury-related morphology, stress fiber, and podocyte apoptosis, but decreased the survival and adhesion of MPC5 podocytes. In contrast, promotion of autophagy by treatment with rapamycin mitigated sublytic complement attack-induced changes in the injury-related morphology, stress fiber, and podocyte apoptosis, but increased the survival and adhesion of MPC5 podocytes. These data suggest that autophagy may protect podocytes from sublytic complement attack-induced injury in vitro.

Juvenile dermatomyositis with central nervous system involvement: two case reports from a retrospective single-center cohort, with literature review.

Background: Juvenile dermatomyositis (JDM) is a systemic autoimmune disease primarily involving the muscles and skin; it can also affect the central nervous system (CNS). The relevant literature provides limited information regarding the characteristics of JDM with CNS involvement. Method: We reviewed patients with JDM who were hospitalized at our center between January 2016 and August 2023, with a focus on those with CNS involvement. The aim was to provide detailed case reports on these patients, and to summarize the relevant literature about the characteristics of similar cases. Results: Among 193 hospitalized patients with JDM, two (1.03%) had CNS involvement. Two patients, a 5.5-year-old girl and an 11-year-old boy, were admitted with severe proximal muscle weakness and seizures, and presented with active cutaneous vasculitis. Both were ultimately diagnosed with JDM, with CNS involvement. Both patients had confirmed presence of anti-NXP2 antibody through myositis-specific antibody analysis. Additionally, they all exhibited hyperferritinemia and thrombocytopenia. Salvage therapies like intravenous methylprednisolone (IVMP) pulse therapy and/or plasma exchange were administered successfully. At final follow-up, both patients had achieved complete clinical response and full neurological recovery. Our literature review identified nine similar case studies. CNS involvement usually occurred within the first 10 months of the disease course, and most of these patients had fatal outcomes, with a mortality rate of 66.6% (6/9). Including the two patients described herein, the median age for disease onset is 10.5 years (range 4-17 years), and the male: female ratio is 6:5. Seizures are the most common neurological symptom, accompanied by active cutaneous vasculitis. The brain biopsies showed two distinct pathological presentations: one was central nervous system vasculitis, and the other was cerebral macrophage activation syndrome. Conclusions: CNS involvement is a rare but life-threatening JDM complication. Herein, our cases and the literature indicate that it typically occurs within the first 10 months of the disease course and manifests as seizures, often accompanied by active cutaneous vasculitis, with fatal outcomes. Timely implementation of salvage therapies, like IVMP pulse therapy and plasma exchange, may significantly impact patient outcomes.

Angiopoietin-like protein 3: a novel potential biomarker for nephrotic syndrome in children.

Background: Angiopoietin-like 3 (ANGPTL3) is a secretory glycoprotein. It has been demonstrated that ANGPTL3 level was upregulated in minimal change nephrotic syndrome (MCNS) kidney tissues. Subsequently, our group found that ANGPTL3 level was closely correlated with nephropathy in vivo and in vitro. Hence, whether ANGPTL3 level could be correlated with the proteinuria level, and assessment of disease severity of nephrotic syndrome (NS) remained to be investigated. This study aimed to analyzed the correlation between the levels of ANGPTL3 in serum and urine of patients with nephrotic syndrome and proteinuria, and assessed the severity of the patients' disease. In future clinical translation, the level of ANGPTL3 in serum, urine will be used as a biomarker to better predict the development of nephrotic syndrome. Methods: A total of 200 NS patients and 80 healthy controls (age, 1-18 years) were admitted to our institution between 2021 and 2022. The etiology of NS included primary nephrotic syndrome (PNS, n = 144) and NS with other causes (n = 56). A total of 280 serum samples and 244 urinary samples were collected to determine ANGPTL3 level using enzyme-linked immunosorbent assay (ELISA). Results: Serum ANGPTL3 and urinary ANGPTL3/Cre were remarkably elevated in NS patients compared with those in healthy controls. Furthermore, serum ANGPTL3 and urinary ANGPTL3/Cre were significantly correlated with proteinuria level. Additionally, multivariate linear regression analysis demonstrated that serum ALB was independently correlated with serum ANGPTL3 and PRO/CR was independently correlated with urinary ANGPTL3/Cre in NS patients. Conclusion: Serum ANGPTL3 and urinary ANGPTL3/Cre showed a promising performance in the diagnosis of NS, and served as novel potential noninvasive biomarkers to assess disease severity of NS. Further exploration of the role of ANGPTL3 level may shed a new light on the treatment of NS.

A Chinese girl of Blau syndrome with renal arteritis and a literature review.

BACKGROUND: Blau syndrome is a rare autoinflammatory disease caused by autosomal dominant mutations in the CARD15/NOD2 gene. Vascular involvement is a rare phenotype in Blau syndrome patients. In this study, we aimed to describe a 20-year- old Chinese girl with Blau syndrome complicated by renal arteritis. In addition, we summarized a literature review of published cases of vascular involvement in patients with Blau syndrome. CASE PRESENTATION: We describe a 20-year-old girl who was initially misdiagnosed with juvenile idiopathic arthritis (JIA) almost 15 years prior. In October 2019, she developed renal arteritis at the age of 17 years and was eventually diagnosed with Blau syndrome. A de-novo M513T mutation was found in her gene testing. A review of the literature on patients with Blau syndrome and vasculitis showed that a total of 18 cases were reported in the past 40 years. The vast majority of them were predominantly involved medium and large vessel arteritis. Of the 18 patients included in our literature review, 14 patients had aorto-arteritis, and 4 of them had renal artery involvement. Two patients presented with renal artery stenosis, 1with a sinus of Valsalva aneurysm, and 1 with retinal vasculitis. CONCLUSION: A detailed medical history inquiry and a careful physical examination are helpful for the early identification of Blau syndrome, especially for infant onset refractory JIA. Medium-and large-vessel arteritis is a rare clinical manifestation in Blau syndrome patients. Careful examination of the peripheral pulse and measurement of blood pressure at every regular visit may be helpful in the early identification of Blau syndrome-arteritis. Early diagnosis and appropriate treatment may prevent or delay the occurrence of severe symptoms in patients to improve the patient's quality of life.

Childhood-onset primary Sjögren's syndrome in a tertiary center in China: clinical features and outcome.

OBJECTIVES: To characterize the clinical features and outcomes of childhood-onset primary Sjögren's syndrome (pSS). METHODS: Patients less than 18 years old who were diagnosed with pSS by paediatric rheumatologists were included, and all patients were applied the 2002 American-European Consensus Group (ACEG) criteria, the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for pSS, or the 1999 proposed juvenile pSS criteria. The electronic medical records of patients with pSS from 2013 to 2020 were collected and analysed. RESULTS: Thirty-nine patients were included. Of them, 27 (69.2%), 38 (97.4%) and 35 (89.7%) patients fulfilled the AECG criteria, ACR/EULAR criteria and proposed juvenile pSS criteria, respectively. The female:male ratio was 3.9:1. The median ages at first signs or symptoms and at diagnosis were 9.2 (4.7, 14.5) years and 10.9 (6.3, 15.0) years, respectively. The main clinical manifestations were rash or purpura (20, 51.3%), followed by fever (12, 30.8%), glandular enlargement/recurrent parotitis (10, 25.6%), and dry mouth and/or dry eyes (9, 23.1%). Twenty-eight (56.4%) patients had systemic damage, the most common of which was haematological involvement (14, 35.9%), followed by hepatic (13, 33.3%) and renal involvement (8, 20.5%). Thirty-eight (97.4%) patients underwent labial minor salivary gland biopsy, and all exhibited focal lymphocytic sialadenitis. All patients had a global ESSDAI score ≥ 1 at diagnosis, and the median total score at diagnosis was 8 (2, 31). Thirty-six (92.3%) patients were followed up for a median time of 23.6 (7.9, 79.5) months, and three patients developed systemic lupus erythematosus (SLE) at follow-up times of 13.3, 38.8 and 63.8 months. CONCLUSIONS: The presentation of childhood-onset pSS is atypical, and extraglandular manifestations and systemic involvement are more common than in adult-onset pSS. Labial salivary gland biopsy is vital for patients with probable pSS. Some patients may develop SLE over time.

Anti-ANGPTL3-FLD monoclonal antibody treatment ameliorates podocyte lesions through attenuating mitochondrial damage.

Proteinuria, an indication of kidney disease, is caused by the malfunction of podocytes, which play a key role in maintaining glomerular filtration. Angiopoietin-like 3 (ANGPTL3) has been documented to have a cell-autonomous involvement in podocytes, and deletion of Angptl3 in podocytes reduced proteinuria in adriamycin-induced nephropathy. Here, we developed a monoclonal antibody (mAb) against ANGPTL3 to investigate its effects on podocyte injury in an ADR nephropathy mouse model and puromycin (PAN) induced podocyte damage in vitro. The mAb against the human ANGPTL3-FLD sequence (5E5F6) inhibited the binding of ANGPTL3-FLD to integrin ß3. Treatment with the 5E5F6 mAb in ADR nephropathy mice mitigated proteinuria and led to a significant decline in podocyte apoptosis, reactive oxygen species (ROS) generation and mitochondrial fragmentation. In PAN-induced podocyte damage in vitro, the 5E5F6 mAb blocked the ANPGPLT3-mediated activation of integrin αvß3 and Rac1, which regulated the mitochondrial homeostasis. Altogether, anti-ANGPLT3-FLD mAb attenuates proteinuria and podocyte lesions in ADR mice models, as well as PAN-induced podocyte damage, in part through regulating mitochondrial functions. Our study provides a therapeutic approach for targeting ANGPTL3 in proteinuric kidney disease.

A novel fusion protein consisting of anti-ANGPTL3 antibody and interleukin-22 ameliorates diabetic nephropathy in mice.

Introduction: The pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvß3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism. Methods: Genes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks. Results: In this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN. Conclusion: Collectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery.

The role of HMGB1 in heart transplantation.

There has been significant progress in the field of heart transplantation over the last 45 years. Although the role of adaptive immunity in heart allograft rejection has been extensively studied for decades, there is increasing evidence that suggests that the innate immune system also contributes to the development of heart allograft rejection. The high-mobility group box (HMGB) proteins, particularly HMGB1, are self-derived innate immune activators that have multiple functions in the regulation of immunity and inflammation. Recent discoveries have illustrated the close link between HMGB1 and heart allograft rejection. In this review, we summarize current knowledge of the function of HMGB1 as a ligand that can evoke inflammatory responses and ultimately cause rejection after heart transplantation.

The advancements of heparanase in fibrosis.

Fibrosis is the endpoint in many chronic inflammatory diseases and is defined as an abnormal accumulation of extracellular matrix components. Fibrosis can affect almost any tissue, especially heart, lung, liver, and kidney, and numerous studies have been conducted to find satisfactory treatments. Since heparanase is a kind of endo-ß-D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix, which further regulate the bioavailability of growth factors (FGF-2, TGF-ß). Meanwhile, FGF-2 and TGF-ß play a major role in the fibrosis process. Recent studies including ours have consistently demonstrated that heparanase could promote fibrosis process in different organs. Thus in this mini-review, we updated the advancement of heparanase in the regulation of fibrosis generation, and discussed its impact on several critical signaling pathways relevant to fibrosis.