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 SUV39H1 at the promoter region leads to increased CREMα and accelerates autoimmune response in CD4+ T cells from patients with systemic lupus erythematosus.

BACKGROUND: Overproduction of cAMP-responsive element modulator α (CREMα) in total T cells from patients with systemic lupus erythematosus (SLE) can inhibit IL-2 and increase IL-17A. These ultimately promote progression of SLE. This study aims to investigate the expression of CREMα in SLE CD4+ T cells and find out the mechanisms for the regulation of CREMα in SLE CD4+ T cells. RESULTS: CREMα mRNA was overexpressed in CD4+ T cells from SLE patients. The levels of histone H3 lysine 9 trimethylation (H3K9me3) and suppressor of variation 3-9 homolog 1 (SUV39H1) at the CREMα promoter of SLE CD4+ T cells were markedly decreased. Down-regulating SUV39H1 in normal CD4+ T cells elevated the levels of CREMα, IL-17A, and histone H3 lysine 4 trimethylation (H3K4me3) in the CREMα promoter region, and lowered IL-2, H3K9me3, DNA methylation, and DNA methyltransferase 3a (DNMT3a) enrichments within the CREMα promoter, while no sharp change in SET domain containing 1 (Set1) at the CREMα promoter. Up-regulating SUV39H1 in SLE CD4+ T cells had the opposite effects. The DNA methylation and DNMT3a levels were obviously reduced, and H3K4me3 enrichment was greatly increased at the CREMα promoter of CD4+ T cells from SLE patients. The Set1 binding in the CREMα promoter region upgraded significantly, and knocking down Set1 in SLE CD4+ T cells alleviated the H3K4me3 enrichment within this region, suppressed CREMα and IL-17A productions, and promoted the levels of IL-2, CREMα promoter DNA methylation, and DNMT3a. But there were no obviously alterations in H3K9me3 and SUV39H1 amounts in the region after transfection. CONCLUSIONS: Decreased SUV39H1 in the CREMα promoter region of CD4+ T cells from SLE patients contributes to under-expression of H3K9me3 at this region. In the meantime, the Set1 binding at the CREMα promoter of SLE CD4+ T cells is up-regulated. As a result, DNMT3a and DNA methylation levels alleviate, and H3K4me3 binding increases. All these lead to overproduction of CREMα. Thus, the secretion of IL-2 down-regulates and the concentration of IL-17A up-regulates, ultimately promoting SLE.

Efficacy of diammonium glycyrrhizinate in the treatment of rosacea with papules and pustules: A randomized, double-blind, placebo-controlled study.

Rosacea is a kind of chronic inflammatory skin disease that usually occurs in the middle of the face. Diammonium glycyrrhizinate (DG), an effective monomer component extracted from licorice, has extensive anti-inflammatory, antioxidant, anti-allergic, and immunomodulatory effects. There is no research on its therapeutic effect on rosacea. In this study, we divided rosacea patients mainly characterized by papules and pustules randomly into three groups. Group A received clarithromycin 500 mg once a day, isotretinoin 10 mg once a day; Group B received DG 150 mg three times a day, other medicines were the same as Group A; Group C received clarithromycin 250 mg once a day, isotretinoin 10 mg once every 2 days, and DG 150 mg three times a day. All patients' symptom scores and laboratory tests were evaluated when followed up. We found that DG combined with clarithromycin and isotretinoin in the treatment of rosacea was more effective and quicker than clarithromycin and isotretinoin alone. Moreover, half common dosage of clarithromycin and isotretinoin combined with DG could achieve the same therapeutic effect as the conventional dose, and brought about lower incidences of adverse events (AEs). Therefore, it is recommended to use half common dosage of routine medication combined with DG for rosacea patients mainly characterized by papules and pustules.

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.

Interleukin-35 in autoimmune dermatoses: Current concepts.

Interleukin-35 (IL-35) is a lately observed cytokine and is part of the IL-12 cytokine family. IL-35 includes two subunits, p35 and Epstein-Barr virus-induced gene 3, and activates subsequent signaling pathways by binding to receptors to mediate signal transduction, thereby modulating the immunoregulatory functions of T cells, B cells, macrophages, and other immune cell types. Although there is currently limited research on the roles of IL-35 in human autoimmunity, many studies have demonstrated that IL-35 may mediate immunosuppression. Therefore, it plays an essential role in some autoimmune dermatoses, including systemic lupus erythematosus, psoriasis, systemic sclerosis, and dermatomyositis. We will introduce the structure and biological characteristics of IL-35 and summarize its effects on the occurrence and development of autoimmune dermatoses in this article. It is suggested that IL-35 is a possible target for therapy in the aforementioned diseases.

Reduced expression of hematopoietic progenitor kinase 1 in T follicular helper cells causes autoimmunity of systemic lupus erythematosus.

BACKGROUD: T follicular helper (Tfh) cells have been discovered to be the main CD4+ T cells assisting B cells to produce antibody. They are over activated in patients with systemic lupus erythematosus (SLE) and consequently lead to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell-mediated immune responses and TCR signal. This study aimed to investigate the roles of HPK1 in SLE Tfh cells. METHODS: HPK1 mRNA and protein levels in Tfh cells were measured by real-time quantitative PCR and western blot analysis, respectively. The production of IL-21, B cell-activating factor (BAFF), interferon γ (IFNγ), IL-17A, IgM, IgG1, IgG2, and IgG3 were analyzed using enzyme linked immunosorbent assay. Tfh cells proliferation was evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: HPK1 mRNA and protein levels were significantly reduced in SLE Tfh cells, and negatively correlated with SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for SLE (SDI). Knocking down HPK1 with siRNA in normal Tfh cells greatly elevated Tfh cells proliferation and secretions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3. There were no marked alterations in IL-17A and IgM productions. The opposite effects were observed in SLE Tfh cells transfected with HPK1 overexpressing plasmid: Tfh cells proliferation and productions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3 were all alleviated. And there were no significant changes in IL-17A and IgM levels. CONCLUSION: Our results suggest for the first time that inhibited expression of HPK1 in SLE Tfh cells leading to Tfh cells overactivation and B cells overstimulation, subsequently, the onset and progression of SLE.