• CD27
• CD4+ T cells
• Regulatory T cells
• Systemic lupus erythematosus

• Humans
• Lupus Erythematosus, Systemic/immunology
• Lupus Erythematosus, Systemic/diagnosis
• Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
• Female
• Adult
• Male
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism
• Middle Aged
• Young Adult
• Biomarkers
• Immunophenotyping

• Humans
• Lupus Nephritis/therapy
• Lupus Erythematosus, Systemic/therapy
• Kidney
• Endoplasmic Reticulum Stress
• Autophagy

• ICOS
• PCR
• RNA expression level
• association
• gene polymorphisms
• genetic susceptibility
• systemic lupus erythematosus

• Humans
• Case-Control Studies
• Leukocytes, Mononuclear
• Polymorphism, Single Nucleotide
• Lupus Erythematosus, Systemic/genetics
• Genotype
• Genetic Predisposition to Disease
• RNA, Messenger
• Gene Frequency
• Inducible T-Cell Co-Stimulator Protein/genetics

• Humans
• Lupus Erythematosus, Cutaneous/diagnosis
• Lupus Erythematosus, Cutaneous/drug therapy
• Lupus Erythematosus, Cutaneous/etiology
• Skin/pathology
• Keratinocytes/pathology
• Immunosuppressive Agents/therapeutic use
• Lupus Erythematosus, Systemic/complications

• grant 2022-1A-08 Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn
• Universitätsklinikum Bonn (8930)

• Anifrolumab
• Belimumab
• Biologics
• Clinical trial
• Systematic review
• Targeted treatments

The phenotypic and functional complexities of T cells engender complicated and often confusing concepts as to how T cells ignite, accelerate and brake the inflammatory processes involved in systemic lupus erythematosus (SLE), let alone the plasticity of T cells that takes place under different immunological contexts. Nevertheless, being one of the prime survival factors of T cells, interleukin (IL)-2 plays a potentially critical role in many immunological scenarios during the pathophysiological process of SLE. Here, the pathophysiology of lupus T cells and current, as well as ongoing, therapeutic approaches of SLE that involve low-dose IL-2 administration will be highlighted. The mechanisms of IL-2 deficiency in SLE pathophysiology, the effects of low-dose IL-2 on T cells and restoration of lupus manifestations in murine SLE models, as well as the efficacy and safety of clinical trials that evaluated low-dose IL-2-containing regimens in patients with SLE will be discussed.

Pregnancy in the setting of systemic lupus erythematosus can worsen the condition from the stable to active stage, with quality of life and fertility desire being particular concerns. Pregnancy in the active stage of systemic lupus erythematosus (ASLE), although rare and complicated to manage, can be treated favorably with immunotherapies ifs used properly. Here we report such a success case.

A 31-year-old primigravida patient, diagnosed with SLE seven years ago, was induced ASLE after a cold at 21 + weeks. The patient’s vital signs on presentation were normal. Her laboratory exam was remarkable for significant proteinuria, liver and renal dysfunction, and low C3 and C4 levels. Infectious work-up was negative. The patient was diagnosed with ASLE. She was given immunosuppressive agents (methylprednisolone, gamma globulin and azathioprine etc.) and plasma adsorption therapy, monitoring blood pressure every 8 h, fetal heart rate twice a day, and liver and renal function at least twice a week. Successful maternal and fetal outcomes are presented here.

Child-bearing in ASLE has become more promising, even for this difficult case of ASLE with multiple organ damage. Thorough antepartum counseling, cautious maternal-fetal monitoring, and multi-organ function monitoring by multidisciplinary specialties are keys to favorable pregnancy outcomes.

• Pregnant women
• Systemic lupus erythematosus
• Immunotherapies
• Case report
• Active stage of systemic lupus erythematosus
• Literature review

This study aims to determine the prevalence of vitamin D deficiency in Pakistani systemic lupus erythematosus (SLE) patients and the effect of vitamin D deficiency on the severity and outcomes of SLE.

This retrospective study evaluated SLE patients presenting to our hospital between January 2009 and December 2018. A total of 98 patients (13 males, 85 females; mean age 39.8±14.9 years; range, 16 to 73 years) with vitamin D levels available at the time of diagnosis were included in the study. Disease activity was measured using SLE disease activity score at the time of diagnosis and at the two-year mark.

Sixty-five patients were deficient in Vitamin D and out of those 46 were severely deficient. The severe disease group had more patients with vitamin D deficiency at both visits (43/78 and 33/46) while patients in remission all had normal vitamin D (12/12 and 14/14) (p≤0.001).

Vitamin D deficiency is common in SLE patients and also significantly associated with increased disease activity at the time of diagnosis and at the two-year mark. We hope this study becomes a platform for the global medical community to come together and implement early screening and monitoring of vitamin D levels and to determine the optimal level of supplementation for prevention of poor outcomes in SLE.

• Autoimmune disease
• rheumatology
• systemic lupus erythematosus
• vitamin D

We used bioinformatic tools to dichotomize 157 non-M3 AML patients from the TCGA dataset based on the presence or absence of TP53 mutations, and screened out a key gene related to TP53 mutation for future analysis.

DEGs were analyzed by R package “DESeq2” and then run GSEA, GO enrichment, KEGG pathway and PPI network. Hub genes were selected out according to MCC. Log-rank (Mantel–Cox) test was used for survival analysis. Mann–Whitney U’s nonparametric t test and Fisher’s exact test was used for continuous and categorical variables respectively. p value< 0.05 was considered to be statistical significance.

TNFRSF4 was final screened out as a key gene. Besides TP53 mutation (p = 0.0118), high TNFRSF4 was also associated with FLT3 mutation (p = 0.0102) and NPM1 mutation (p = 0.0024). Elevated TNFRSF4 was significantly related with intermediate (p = 0.0004) and poor (p = 0.0011) risk stratification as well as relapse statute (p = 0.0099). Patients with elevated TNFRSF4 expression had significantly shorter overall survival (median survival: 2.35 months vs. 21 months, p < 0.0001). Based on our clinical center data, TNFRSF4 expression was significantly higher in non-M3 AML patients than HDs (p = 0.0377) and MDS patients (EB-1, 2; p = 0.0017).

Elevated TNFRSF4 expression was associated with TP53, FLT3 and NPM1 mutation as well as poor clinical outcome. TNFRSF4 expression was significantly higher in non-M3 AML patients than HDs and MDS (EB-1, 2) patients. TNFRSF4 is need for future functional and mechanistic studies to investigate the role in non-M3 AML.

• AML
• Bioinformatics
• TCGA
• TNFRSF4

Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE.

• CD137
• CD137 ligand
• SLE
• cerebral
• lupus
• renal

• CD137 ligand
• SLE
• Th17
• glomerulonephritis
• skin lesions
• synaptic plasticity

• 4-1BB Ligand/deficiency
• 4-1BB Ligand/immunology
• Animals
• Brain/immunology
• Brain/pathology
• Gene Deletion
• Interleukin-10/genetics
• Interleukin-10/immunology
• Kidney/immunology
• Kidney/pathology
• Lupus Nephritis/genetics
• Lupus Nephritis/immunology
• Lupus Nephritis/pathology
• Mice
• Mice, Knockout
• Skin/immunology
• Skin/pathology
• T-Lymphocytes, Helper-Inducer/immunology
• T-Lymphocytes, Helper-Inducer/pathology

• CD80
• CTLA-4
• apoptosis
• autoimmunity
• coinhibitory pathway
• costimulatory pathway
• immune evasion
• immunotolerance

• Interferon λ
• Lupus nephritis
• Systemic lupus erythematosus

• Adult
• Asian People/genetics
• Biomarkers/blood
• Female
• Gene Frequency
• Genetic Predisposition to Disease/ethnology
• Genetic Predisposition to Disease/genetics
• Genotype
• Haplotypes
• Humans
• Interferons
• Interleukins/blood
• Interleukins/genetics
• Lupus Erythematosus, Systemic/blood
• Lupus Erythematosus, Systemic/ethnology
• Lupus Erythematosus, Systemic/genetics
• Lupus Nephritis/blood
• Lupus Nephritis/ethnology
• Lupus Nephritis/genetics
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Taiwan
• Young Adult

• R21 AI125729 NIAID NIH HHS
• Chang Gung Memorial Hospital, Linkou
• Ministry of Science and Technology, Taiwan
• National Institutes of Health

Over the past two decades it has been increasingly recognized that vitamin D, aside from its crucial involvement in calcium and phosphate homeostasis and the dynamics of the musculoskeletal system, exerts its influential impact on the immune system. The mechanistic roles that vitamin D plays regarding immune activation for combating infection, as well as pathologically and mediating autoimmune conditions, have been progressively unraveled. In vitro and in vivo models have demonstrated that the action of vitamin D on various immunocytes is not unidirectional. Rather, how vitamin D affects immunocyte functions depends on the context of the immune response, in the way that its suppressive or stimulatory action offers physiologically appropriate and immunologically advantageous outcomes. In this review, the relationship between various aspects of vitamin D, starting from its adequacy in circulation to its immunological functions, as well as its autoimmune conditions, in particular systemic lupus erythematosus (SLE), a prototype autoimmune condition characterized by immune-complex mediated inflammation, will be discussed. Concurring with other groups of investigators, our group found that vitamin D deficiency is highly prevalent in patients with SLE. Furthermore, the circulating vitamin D levels appear to be correlated with a higher disease activity of SLE as well as extra-musculoskeletal complications of SLE such as fatigue, cardiovascular risk, and cognitive impairment.

• disease activity
• disease damage
• lupus
• systemic lupus erythematosus
• vitamin D

• Animals
• Humans
• Lupus Erythematosus, Systemic/complications
• Lupus Erythematosus, Systemic/immunology
• Lupus Erythematosus, Systemic/pathology
• Musculoskeletal Diseases/genetics
• Musculoskeletal Diseases/immunology
• Musculoskeletal Diseases/pathology
• Vitamin D/immunology
• Vitamin D Deficiency/complications
• Vitamin D Deficiency/immunology
• Vitamin D Deficiency/pathology

The aim of the present study was to explore the roles of OX40/OX40 ligand (OX40L) signaling and OX40⁺ T cells in ovalbumin (OVA)-induced mouse asthma model. Asthma was induced by OVA exposure and subsequent co-treatment with OX40L protein, neutralizing anti-OX40L blocking antibody, OX40⁺ T cells or PBS. The protein expression levels of interleukin (IL)-4, IL-6, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in bronchoalveolar lavage fluid (BALF) were examined using murine cytokine-specific ELISA. Eosinophil accumulation as well as proliferation and apoptosis of T cells in BALF were detected by Cell Counting kit-8 and flow cytometric assays. Expression of the apoptosis-related protein cleaved caspase-3 was examined in OX40⁺ T cells using western blot assay. Flow cytometric analysis revealed that OVA-treated mice that were co-treated with OX40L or OX40⁺ T cells exhibited higher eosinophil infiltration compared with control mice treated only with OVA, whereas neutralizing anti-OX40L blocking antibody inhibited eosinophil infiltration. ELISA assays demonstrated that the expression of IL-4, IL-6, IL-13, IL-17, TNF-α and IFN-γ in BALF in OX40L-treated and OX40⁺ T cell-treated mice was increased compared with expression levels in control mice. Treatment with OX40L protein effectively reduced apoptosis of T cells and the expression of cleaved caspase-3 in T cells. OX40L-treated and OX40⁺ T cell-treated mice exhibited increased asthma through OX40/OX40L signaling, which probably promoted inflammatory factor expression, eosinophil infiltration and T cell proliferation.

Thousands of long noncoding RNAs (lncRNAs) have been reported and represent an important subset of pervasive genes associated with a broad range of biological functions. Abnormal expression levels of lncRNAs have been demonstrated in multiple types of human disease. However, the role of lncRNAs in systemic lupus erythematosus (SLE) remains poorly understood. In the present study, the expression patterns of lncRNAs and messenger RNAs (mRNAs) were investigated in peripheral blood mononuclear cells (PBMCs) in SLE using Human lncRNA Array v3.0 (8×60 K; Arraystar, Inc., Rockville, MD, USA). The microarray results indicated that 8,868 lncRNAs (3,657 upregulated and 5,211 downregulated) and 6,876 mRNAs (2,862 upregulated and 4,014 downregulated) were highly differentially expressed in SLE samples compared with the healthy group. Gene ontology (GO) analysis of lncRNA target prediction indicated the presence of 474 matched lncRNA-mRNA pairs for 293 differentially expressed lncRNAs (fold change, ≥3.0) and 381 differentially expressed mRNAs (fold change, ≥3.0). The most enriched pathways were ‘Transcriptional misregulation in cancer’ and ‘Valine, leucine and isoleucine degradation’. Furthermore, reverse transcription-quantitative polymerase chain reaction data verified six abnormal lncRNAs and mRNAs in SLE. The results indicate that the lncRNA expression profile in SLE was significantly changed. In addition, a range of SLE-associated lncRNAs were identified. Thus, the present results provide important insights regarding lncRNAs in the pathogenesis of SLE.

• Autoantibodies
• Autoimmune diseases
• Biologic therapies
• Monoclonal antibodies
• Systemic lupus erythematosus

• Biomarker
• Diagnosis
• Epigenetics
• Epigenomics
• Genomics
• Rheumatic diseases

• Autoimmunity
• Extracellular vesicles
• Ion channels
• Lipids
• Lupus nephritis
• Pattern recognition receptors
• Systemic lupus erythematosus

We report pharmacokinetics, pharmacodynamics, and safety of a novel anti‐CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single‐ or multiple‐dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single‐ascending‐dose (SAD), double‐blind, first‐in‐human study. Part 1 included 9 intravenous (IV; 0.01‐100 mg) and 3 subcutaneous (SC; 9‐50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9‐100 mg) or placebo. In a double‐blind, multiple‐ascending‐dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9‐mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.

• biologics
• clinical trials (CTR)
• immunopharmacology (imm)
• pharmacodynamics (PDY)
• pharmacokinetics and drug metabolism
• rheumatology

• CVD
• SLE
• immune mechanisms
• immunotherapy

• Histone modification
• IL-17
• Systemic lupus erythematosus
• T cells
• TLR2

The pathogenesis of systemic lupus erythematosus (SLE) has not yet been completely elucidated. One of the hallmarks of SLE is the production of autoantibodies by uncontrolled over-activated B cells. Early B cell factor 1 (EBF1) contributes to the development, activation, and proliferation of B cells through activation of the AKT signaling pathway. Accumulating evidence has demonstrated that several microRNAs (miRNAs) contribute to the pathogenesis of autoimmune diseases through the regulation of B cells in SLE. We aim to investigate the expression patterns of miR-1246 in B cells and its contribution to pathogenesis of SLE.

Our results showed that the expression of miR-1246 was significantly decreased in B cells from SLE patients. We verified that miR-1246 specifically targeted the EBF1 messenger RNA (mRNA) by interacting with its 3′-untranslated region (3′-UTR) and regulated the expression of EBF1. Transfection of miR-1246 inhibitors into healthy B cells upregulated the expression of EBF1, enhanced B cell function, and increased the production of B cell surface co-stimulatory molecules CD40, CD80, and CD86. We also observed that abnormal activation of the AKT signaling pathway was associated with decreased P53 expression, leading to the downregulation of the miR-1246 expression; and upregulation of the miR-1246 expression reversed the responsiveness of B cells by inhibiting EBF1 expression.

Activated B cells in lupus could decrease the expression of miR-1246 through the AKT-P53 signaling pathway, which in turn enhances the expression of EBF1, thereby promoting further activation of B cells. Conversely, upregulation of miR-1246 could interrupt this amplification pathway. Our findings thus provide a theoretical framework towards the research of novel biological targets in SLE treatment.

The online version of this article (doi:10.1186/s13148-015-0063-7) contains supplementary material, which is available to authorized users.

• AKT
• B cell
• Co-stimulatory molecules
• EBF1
• Has-miR-1246
• P53
• Systemic lupus erythematosus

• zaire ebola virus
• ebola virus disease
• cell-mediated immune surveillance
• vaccine
• blood–brain barrier
• m1 & m2 macrophages
• epidemic
• pandemic
• syndemic
• zoonotic

• Animals
• Ebolavirus/physiology
• Hemorrhagic Fever, Ebola/epidemiology
• Hemorrhagic Fever, Ebola/pathology
• Hemorrhagic Fever, Ebola/virology
• Humans
• Pandemics
• Telemedicine
• Translational Research, Biomedical

• K23 MH095661 NIMH NIH HHS

To assess the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA).

The primary endpoint of this 1-year, open-labeled, prospective, observational multicenter study of RA-associated secondary SS was the rate of SDAI remission at 52 weeks after initiation of abatacept therapy. The secondary endpoints included that of Saxson's test and Schirmer's test. Adverse events during the study period were also analyzed.

Thirty-two patients (all females) were enrolled in this study. Interim analysis at 24 weeks included assessment of efficacy (n = 31) and safety (n = 32). The mean SDAI decreased from 19.8 ± 11.0 (± SD) at baseline to 9.9 ± 9.9 at 24 weeks (P < 0.05). Patients with clinical remission, as assessed by SDAI, increased from 0 patient (0 week) to 8 patients (25.8%) at 24 weeks. Saliva volume (assessed by Saxson's test) increased slightly from 2232 ± 1908 (0 week) to 2424 ± 2004 (24 weeks) mg/2 min (n = 29). In 11 patients with Greenspan grading 1/2 of labial salivary glands biopsy, saliva volume increased from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min (P < 0.05). Schirmer's test for tear volume showed increase from 3.6 ± 4.6 (0 week) to 5.5 ± 7.1 (24 weeks) mm/5 min (n = 25; P < 0.05). Five adverse events occurred in five of 32 patients (15.6%), and three of these events were infections.

Abatacept seems to be effective for both RA and RA-related secondary SS.

• Abatacept
• Rheumatoid arthritis
• Sjögren's syndrome

• Autoimmunity
• B cells
• Cancer
• TNF superfamily

• Gene ontology analysis
• Microarray
• Pathway analysis
• SLE
• miRNA

• Animals
• Autoantibodies/biosynthesis
• B-Lymphocytes/immunology
• B-Lymphocytes/pathology
• Calcineurin Inhibitors/therapeutic use
• Cell Communication
• Clinical Trials as Topic
• Gene Expression Regulation
• Humans
• Immunologic Factors/therapeutic use
• Lupus Erythematosus, Systemic/drug therapy
• Lupus Erythematosus, Systemic/genetics
• Lupus Erythematosus, Systemic/immunology
• Lupus Erythematosus, Systemic/pathology
• Mice
• Receptors, Antigen, T-Cell/genetics
• Receptors, Antigen, T-Cell/immunology
• Signal Transduction
• T-Lymphocytes, Helper-Inducer/immunology
• T-Lymphocytes, Helper-Inducer/pathology
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology