MicroRNA-98-5p Inhibits IFI44L-Mediated Differentiation of Dendritic Cells and Activation of Interferon Pathway in Systemic Lupus Erythematosus.

MicroRNA-98-5p (miR-98-5p) plays a protective role in the pathogenesis of autoimmune diseases through anti-inflammatory effects, but little is known about its role in Systemic lupus erythematosus (SLE). Our previous study suggested Interferon-inducible 44 like (IFI44L) overexpressed in monocytes which contributes to the pathogenesis of SLE by enhancing the maturation and functions of monocyte-derived dendritic cells (Mo-DCs), and miR-98-5p can regulate the expression of IFI44L. In this study, we identified miR-98-5p lowly expressed in both peripheral blood mononuclear cells (PBMCs) and monocytes of SLE patients along with high expression of IFI44L. IFI44L serves as target gene of miR-98-5p which inhibits differentiation of Mo-DCs and IFI44L-mediated activation of interferon pathway. We further showed that miR-98-5p promotes methylation of the IFI44L promoter to down-regulate its expression in SLE. Our results reveal an important role for miR-98-5p in the IFI44L-mediated immune imbalance of SLE and suggest a potential therapeutic target for SLE in the future.

Sirtuin 1 overexpression contributes to the expansion of follicular helper T cells in Systemic lupus erythematosus and serves as an easy-to-intervene therapeutic target.

OBJECTIVE: SIRT1, an NAD+-dependent deacetylase, is up-regulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in Tfh cell expansion and its potential value as a therapeutic target for SLE. METHODS: Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and BCL-6 were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1-expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1, respectively, and then cultured in a Tfh-polarizing condition to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies were compared with controls. RESULTS: Expression of SIRT1 was elevated in Tfh cells from SLE patients and positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. CONCLUSION: SIRT1 overexpression contributes to the expansion of Tfh cells in SLE and may serve as a potential target for treatment.

Panoramic view of clinical features of lupus erythematosus: a cross-sectional multicentre study from China.

OBJECTIVE: Lupus erythematosus (LE) is a complicated disease with highly heterogeneous clinical manifestations. Previous studies have rarely included all subgroups of patients with lupus and have overlooked the importance of the cutaneous manifestations thereof. We aimed to compare the demographic and clinical differences among patients with different subtypes of lupus. METHODS: This is the first real-world study with a relatively large sample size that simultaneously includes patients with isolated cutaneous lupus erythematosus (iCLE) and SLE. All samples were obtained from the Lupus Erythematosus Multicenter Case-control Study in Chinese populations (LEMCSC) (registration number: ChiCTR2100048939). Comparative analyses between different LE subgroups were performed. RESULTS: A total of 2097 patients with lupus were included, with 1865 patients with SLE, 1648 with cutaneous lupus erythematosus (CLE), and 232 with iCLE. Among the patients with CLE, 1330 had acute cutaneous lupus erythematosus (ACLE); 160 had subacute cutaneous lupus erythematosus (SCLE); and 546 had chronic cutaneous lupus erythematosus (CCLE). The study included a relatively large number of patients with CCLE subtypes, including 311 with discoid lupus erythematosus (DLE), 262 with chilblain lupus erythematosus (CHLE) and 45 with lupus erythematosus profundus (LEP). Demographic characteristics, systemic involvement, mucocutaneous manifestations and autoantibodies were significantly different among the groups. CONCLUSIONS: CLE and iCLE are two distinct disease states, and the selection of broad or narrow CLE definitions should be emphasised in scientific reports. LE-non-specific cutaneous lesions imply more severity, while self-reported photosensitivity and LE-specific cutaneous manifestations imply milder severity. Generalised ACLE appears to be a more severe state than localised ACLE, and CHLE appears to be more severe than DLE. Anti-Sjögren's syndrome-related antigen B (SSB) antibodies have higher specific directivity than anti-Sjögren's syndrome-related antigen A (SSA) antibodies for SCLE lesions. Anti-double-stranded DNA antibodies have a higher co-occurrence with ACLE and a lower co-occurrence with SCLE and CCLE. Compared with DLE, CHLE has significantly higher positive rates of anti-SSA/Ro60 (71%) and anti-SSA/Ro52 (42.4%) antibodies, whereas LEP is associated with a higher positive rate of antinucleosome antibodies (31.1%).

Novel polymorphism of IFI44L associated with the susceptibility and clinical characteristics of systemic lupus erythematosus in a Chinese population.

BACKGROUND: Interferon-inducible 44 like (IFI44L) is a newly discovered gene which has been reported to associate with the susceptibility of some infectious diseases, but there is no data on IFI44L SNP polymorphism associated with Systemic lupus erythematosus (SLE). In this study, we aimed to evaluate the association of IFI44L rs273259 polymorphism with the susceptibility and clinical characteristics of SLE in a Chinese population. METHODS: 576 SLE patients and 600 controls were recruited in this case-control study. Blood DNA was extracted and IFI44L rs273259 polymorphism was detected by TaqMan SNP Genotyping Assay Kit. The expression levels of IFI44L in Peripheral blood mononuclear cells were detected by RT-qPCR. The DNA methylation levels of IFI44L promoter were detected by bisulfite pyrosequencing. RESULTS: The genotype and allele frequencies of IFI44L rs273259 in SLE patients have a significantly difference compared to healthy controls (P < 0.001). The genotype AG (vs. AA: OR = 2.849; P < 0.001) and the allele G (vs. A: OR = 1.454; P < 0.001) were associated with increased susceptibility of SLE. IFI44L rs273259 polymorphism was associated with clinical characteristics of SLE including malar rash (P < 0.001), discoid rash (P < 0.001), lupus nephritis (P < 0.001) and anti-Smith antibodies (P < 0.001). The expression levels of IFI44L were most significantly increased in genotype AG than genotype AA and GG (P < 0.01). The DNA methylation levels of IFI44L promoter were most significantly decreased in genotype AG than genotype AA and GG (P < 0.01). CONCLUSIONS: Our results indicate novel polymorphism of IFI44L rs273259 was associated with the susceptibility and clinical characteristics of SLE in the Chinese population.

Decreased Jumonji Domain-Containing 3 at the Promoter Downregulates Hematopoietic Progenitor Kinase 1 Expression and Cytoactivity of T Follicular Helper Cells from Systemic Lupus Erythematosus Patients.

T follicular helper (Tfh) cells are overactivated in systemic lupus erythematosus (SLE) patients and contribute to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1), as an inhibitor of T cells, is underexpressed in SLE Tfh cells and consequently induces autoimmunity. However, the reason for downregulation of HPK1 in SLE Tfh cells remains elusive. By combining chromatin immunoprecipitation with quantitative polymerase chain reaction assays, it was found that histone H3 lysine 27 trimethylation (H3K27me3) at the HPK1 promoter in SLE Tfh cells elevated greatly. We also confirmed jumonji domain-containing 3 (JMJD3) binding at the HPK1 promoter in SLE Tfh cells reduced profoundly. Knocking down JMJD3 in normal Tfh cells with siRNA alleviated enrichments of JMJD3, H3K4me3, and mixed-lineage leukemia (MLL) 1 at the HPK1 promoter and increased H3K27me3 number in the region. HPK1 expression was lowered, while Tfh cell proliferation activity, IL-21 and IFNγ secretions in the supernatants of Tfh cells, and IgG1 and IgG3 concentrations in the supernatants of Tfh-B cell cocultures all upregulated markedly. In contrast, elevating JMJD3 amount in SLE Tfh cells by JMJD3-overexpressed plasmid showed opposite effects. The abundances of H3K4me3 and MLL1 at the HPK1 promoter in SLE Tfh cells were greatly attenuated. Our results suggest that deficient JMJD3 binding at the promoter dampens HPK1 expression in SLE Tfh cells, thus making Tfh cells overactive, and ultimately results in onset of SLE.

Epigenetic Regulation of IFI44L Expression in Monocytes Affects the Functions of Monocyte-Derived Dendritic Cells in Systemic Lupus Erythematosus.

Background: Interferon-inducible 44 like (IFI44L) is a newly discovered interferon-induced gene and has been reported to overexpress in systemic lupus erythematosus (SLE). However, little is known about the mechanism and function of IFI44L overexpression in SLE. In this study, we aimed to investigate the epigenetic mechanism of IFI44L overexpression in SLE monocyte and its potential functions contributing to the pathogenesis of SLE. Methods: We collected peripheral blood from 20 SLE patients and 20 healthy controls. Expression of IFI44L in monocytes and effects of different signal transducers and activators of transcription (STAT) pathway inhibitors on IFI44L expression were detected. Recruitment of ten-eleven translocation protein (TET) by STAT and methylation of IFI44L promoter were evaluated. Effects of IFI44L overexpression on the expression of surface markers on monocyte-derived dendritic cells (Mo-DCs) were analyzed. T cell differentiation mediated by Mo-DCs and related cytokines production were also analyzed. Results: Expression level of IFI44L was significantly increased in SLE monocyte. IFI44L expression was decreased most significantly in STAT3 inhibitor compared with other inhibitors. STAT3 regulated IFI44L expression and interacted with TET2 which induced DNA demethylation of IFI44L promoter. Overexpression of IFI44L in monocyte enhanced the maturation and functions of Mo-DC by upregulating costimulatory receptors and inducing Th1/Th17-related cytokines when cocultured with naïve CD4+ T cells. Conclusion: TET2 recruited by STAT3 induces DNA demethylation of IFI44L promoter which promotes IFI44L overexpression in monocyte contributing to the pathogenesis of SLE by enhancing the maturation and functions of Mo-DC. IFI44L is expected to become a new target for treatment of SLE.

Generalized Eruptive Histiocytoma With S100 Protein-Positive Histiocytes and Prominent Eosinophilic Infiltration: A Rare Case Report.

ABSTRACT: Generalized eruptive histiocytoma (GEH) is a very rare benign disorder belonging to the group of non-Langerhans cell histiocytosis (non-LCH). GEH is characterized by a nearly uniform infiltrate of histiocytes with classic immunological phenotype (CD68+, S-100- and CD1a-). Prominent eosinophilic infiltration and S100-positive histiocytes are rarely associated in GEH. In this article, we reported a middle-age man presented with disseminated reddish papules distributed on the trunk and proximal extremities. A skin biopsy of the papule showed a dense histiocytic infiltration with prominent eosinophils. By immunohistochemistry, the histiocytes revealed strongly positive for CD68 and S100 protein and negative for CD1a and Langerin (CD207). Based on clinical and histopathological criteria, the diagnosis of GEH was established. We presented this rare case of GEH with such distinctive features to strengthen the awareness of this uncommon form of non-LCH. Classical histopathological and immunological features cannot reliably distinguish GEH from other non-LCH.

A Rare Case of Pediatric Xanthoma Disseminatum With Diabetes Insipidus and BRAF p.V600E Mutation.

ABSTRACT: Xanthoma disseminatum (XD) is a rare non-Langerhans cell histiocytosis characterized by xanthomatous lesions in the absence of hyperlipidemia. XD usually develops in young adults, and there are rare cases among children. BRAF mutations are frequent in Langerhans cell histiocytosis and Erdheim-Chester disease but absent or only rarely detected in other histiocytosis. Herein, we described a 6-year-old Chinese girl presented with generalized skin lesions and diabetes insipidus for 5 months. There were multiple periorbital xanthelasma with histopathological features of foamy histiocytes infiltration with Touton cells. Pituitary magnetic resonance imaging showed pituitary enlargement and pituitary stalk thickening. The presence of BRAF p.V600E mutation makes this case distinctive and also offers a potential therapeutic target. According to our review of the literature, this is the first pediatric XD with diabetes insipidus and BRAF mutation.

Systematic Review and Meta-analysis of the Association Between Metabolic Syndrome and Androgenetic Alopecia.

The association of androgenetic alopecia with metabolic syndrome has been investigated in several studies, with conflicting results. We conducted a meta-analysis to quantitatively evaluate the risk grade of metabolic syndrome and the metabolic profile in patients with androgenetic alopecia compared with controls. In total, 19 articles (2,531 participants) satisfied the inclusion criteria. The pooled odds ratio for the prevalence rate of metabolic syndrome between the group with androgenetic alopecia and controls was 3.46 (95% CI 2.38-5.05; p < 0.001). Female sex, early onset, and African ethnicity were associated with an increased risk of metabolic syndrome. Furthermore, patients with androgenetic alopecia had significantly poorer metabolic profiles, such as body mass index, waist circumference, fasting glucose, blood lipids, and blood pressure. It is important for physicians to screen metabolism-related indicators in patients with androgenetic alopecia. More rigorously designed studies and larger sample sizes are required in future studies.

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Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.

MiR-301a-3p Advances IRAK1-Mediated Differentiation of Th17 Cells to Promote the Progression of Systemic Lupus Erythematosus via Targeting PELI1.

Systemic lupus erythematosus (SLE) is a common autoimmune disease with high incidence in females. The pathogenesis of SLE is complex, and healing SLE has become a serious challenge for clinical treatment. Aberrant expression of miR-301a-3p involves the progressions of multiple diseases, and some studies have indicated that increased miR-301a-3p could induce the inflammatory injury of some organs. However, the role and molecular mechanism of miR-301a-3p in SLE remain unclear. In this study, the miR-301a-3p levels in peripheral blood mononuclear cells (PBMCs) of the patients with SLE and health subjects were measured with qRT-PCR. The ELISA assay was used to investigate the effect of miR-301a-3p on the levels of inflammatory factors in PBMCs, and flow cytometry assays were used to observe the effect of miR-301a-3p on the levels of CD4+ T cells and Th17 cells in PBMCs. Moreover, TargetScan, dual-luciferase reporter assay, and western blot were used to reveal the downstream targets and regulation mechanism of miR-301a-3p in SLE. The results showed that miR-301a-3p was significantly upregulated in PBMCs of the SLE patients, and increased miR-301a-3p could boost the expression of IL-6, IL-17, and INF-γ in PBMCs and promote the differentiation of Th17 cells. It was found that PELI1 was a target of miR-301a-3p, and PELI1 upregulation could effectively reverse the effect of miR-301a-3p on PBMCs. Besides, this study also found that miR-301a-3p could promote the expression of IRAK1 to involve the progression of SLE via targeting PELI1. In conclusion, this study suggests that increased miR-301a-3p serves as a pathogenic factor in SLE to promote IRAK1-mediated differentiation of Th17 cells via targeting PELI1.

Abnormalities in Gut Microbiota and Metabolism in Patients With Chronic Spontaneous Urticaria.

Background: Increasing evidence suggests that the gut microbiome plays a role in the pathogenesis of allergy and autoimmunity. The association between abnormalities in the gut microbiota and chronic spontaneous urticaria (CSU) remains largely undefined. Methods: Fecal samples were obtained from 39 patients with CSU and 40 healthy controls (HCs). 16S ribosomal RNA (rRNA) gene sequencing (39 patients with CSU and 40 HCs) and untargeted metabolomics (12 patients with CSU and 12 HCs) were performed to analyze the compositional and metabolic alterations of the gut microbiome in CSU patients and HCs. Results: The 16S rRNA gene sequencing results showed a significant difference in the ß-diversity of the gut microbiota, presented as the Jaccard distance, between CSU patients and HCs. No significant differences were found in the α-diversity of the gut microbiota between patients and HCs. At the phylum level, the major bacteria in the gut microbiome of patients with CSU were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At the genus level, Lactobacillus, Turicibacter, and Lachnobacterium were significantly increased and Phascolarctobacterium was decreased in patients with CSU. PICRUSt and correlation analysis indicated that Lactobacillus, Turicibacter, and Phascolarctobacterium were positively related to G protein-coupled receptors. Metabolomic analysis showed that α-mangostin and glycyrrhizic acid were upregulated and that 3-indolepropionic acid, xanthine, and isobutyric acid were downregulated in patients with CSU. Correlation analysis between the intestinal microbiota and metabolites suggested that there was a positive correlation between Lachnobacterium and α-mangostin. Conclusions: This study suggests that disturbances in the gut microbiome composition and metabolites and their crosstalk or interaction may participate in the pathogenesis of CSU.

Case of Generalized Tumor-Type Rosai-Dorfman Disease With Sarcoidosis-Like Histological Features and IgG4-Positive Plasma Cells.

ABSTRACT: Rosai-Dorfman disease (RDD, also known as sinus histiocytosis with massive lymphadenopathy) is a rare and benign non-Langerhans cell histiocytosis. Skin biopsy usually shows nodular or diffuse dermatitis. Rosai-Dorfman cells (RDD cells) and emperipolesis are the key to diagnosis. RDD cells express S-100 antigen, CD68, CD163, α1-antitrypsin, α1-antichymotrypsin, and ham-56, whereas Langerhans cell markers such as CD1a and langerin are negative. We presented a case of a 55-year-old man with varying sizes of many dark red nodules and lumps over the face, trunk, and limbs for approximately 1 year but without systemic involvement. The results of the laboratory evaluations were notable for an increased level of serum IL-6 and serum IgG4. Histopathological examination showed a diffused dense nodular infiltration of "nude" epithelioid histiocytes with infiltration of minimal lymphocytes and plasm cells around the epithelioid nodules. Immunohistochemistry identified nodular histiocytes being stained strongly positive for S-100 and CD68 but negative for CD1a. Plasma cells showed focally positive for IgG, IgG4, and CD38 and with a ratio of IgG4/IgG >40%. Considering these findings, we believe that our case meets the diagnostic description of "cutaneous Rosai-Dorfman disease" and is, therefore, a rare case with clinical features of multiple tumor-like nodules, sarcoidosis-like histological features, and immunohistochemistry of IgG4-positive plasma cells.

Recent advances in understanding pathogenesis and therapeutic strategies of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system-involving autoimmune disorder mainly affecting young and middle-aged women. Autoantibodies formation and immune complex deposition as well as other immune mechanisms contribute to heterogeneous clinical presentation, which leads to challenges for diagnosis and management. Although the exact pathogenesis of SLE is highly complicated, the pathophysiological understanding of SLE is constantly evolving and relevant studies were continually published, providing a better understanding of the molecular mechanisms. Moreover, new therapeutic strategies and management plans targeting pivotal factors involved in the pathogenesis of SLE got well established recently. In this article, we reviewed recent studies to provide an update in understanding pathogenesis and therapeutic strategies of SLE.