Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.

T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development.

SPATS2L is a positive feedback regulator of the type I interferon signaling pathway and plays a vital role in lupus.

Through genome-wide association studies (GWAS) and integrated expression quantitative trait locus (eQTL) analyses, numerous susceptibility genes ("eGenes", whose expressions are significantly associated with common variants) associated with systemic lupus erythematosus (SLE) have been identified. Notably, a subset of these eGenes is correlated with disease activity. However, the precise mechanisms through which these genes contribute to the initiation and progression of the disease remain to be fully elucidated.

A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1 variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88.

Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis.

Objectives: To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting.

Methods: This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m at baseline.

Novel potential lncRNA biomarker in B cells indicates essential pathogenic pathway activation in patients with SLE.

Objectives: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity.

Serum levels of CXCL5 are decreased and correlate with circulating platelet counts in systemic lupus erythematosus.

Objective: To identify disease-specific serum chemokine profiles and potential anti-inflammatory chemokines in three rheumatic diseases.

Methods: The discovery cohort included 18 patients with rheumatoid arthritis (RA), 20 patients with primary Sjögren's syndrome (pSS), 24 patients with systemic lupus erythematosus (SLE) and 28 healthy subjects. Findings from the discovery cohort were validated in two replication cohorts, consisting of 23 patients with SLE matched with 23 healthy subjects and 62 patients with SLE, 16 patients with ANCA-associated vasculitis (AAV), and 32 healthy controls, respectively.

The transcription factor ZEB2 drives the formation of age-associated B cells.

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in haploinsufficient individuals and in mice lacking in B cells.

Efficacy and safety of abatacept for interstitial lung disease associated with antisynthetase syndrome: a case series.

Objectives: This study investigated the efficacy and safety of abatacept (ABA) in interstitial lung disease (ILD) associated with antisynthetase syndrome (ASS).

Methods: Eight patients were identified through retrospective analysis of the medical records of our centre. All patients fulfilled the Solomon criteria and had a disease complicated with ILD.

Corrigendum: Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

[This corrects the article DOI: 10.3389/fimmu.2023.

Serum Metabolic Fingerprints Characterize Systemic Lupus Erythematosus.

Metabolic fingerprints in serum characterize diverse diseases for diagnostics and biomarker discovery. The identification of systemic lupus erythematosus (SLE) by serum metabolic fingerprints (SMFs) will facilitate precision medicine in SLE in an early and designed manner. Here, a discovery cohort of 731 individuals including 357 SLE patients and 374 healthy controls (HCs), and a validation cohort of 184 individuals (SLE/HC, 91/93) are constructed.

Three-Dimensional Chromosomal Landscape Revealing miR-146a Dysfunctional Enhancer in Lupus and Establishing a CRISPR-Mediated Approach to Inhibit the Interferon Pathway.

Objective: The diminished expression of microRNA-146a (miR-146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE-affected enhancers responsible for modulating miR-146a expression.

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

Objective: There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts.

Methods: uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA.

Biomarkers for systemic lupus erythematosus - a focus on organ damage.

Introduction: Systemic lupus erythematosus (SLE) is complex autoimmune disease with heterogenous manifestations, unpredictable disease course and response to treatment. One of the critical needs in SLE management is the identification of reliable biomarkers that can aid in early diagnosis, accurate monitoring of disease activity, and assessment of treatment response.

Areas Covered: In the current review, we focus on the commonly affected organs (skin, kidney, and nervous system) in SLE to summarize the emerging biomarkers that show promise in disease diagnosis, monitoring and treatment response assessment.

The Oxysterol Receptor EBI2 Links Innate and Adaptive Immunity to Limit IFN Response and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients.

Four trajectories of 24-hour urine protein levels in real-world lupus nephritis cohorts.

Objectives: A 24-hour urine protein (24hUP) is a key measurement in the management of lupus nephritis (LN); however, trajectories of 24hUP in LN is poorly defined.

Methods: Two LN cohorts that underwent renal biopsies at Renji Hospital were included. Patients received standard of care in a real-world setting and 24hUP data were collected over time.

Control of lupus activity during pregnancy via the engagement of IgG sialylation: novel crosstalk between IgG sialylation and pDC functions.

Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy.

Involvement of Transcriptional Factor Pbx1 in Peripheral B Cell Homeostasis to Constrain Lupus Autoimmunity.

Objective: Disruption of B cell homeostasis and subsequent dominance of effector B cell subsets are critical for the development of systemic lupus erythematosus (SLE). Revealing the key intrinsic regulators involved in the homeostatic control of B cells has important therapeutic value for SLE. This study was undertaken to determine the regulatory role of the transcription factor Pbx1 in B cell homeostasis and lupus pathogenesis.

De Novo PACSIN1 Gene Variant Found in Childhood Lupus and a Role for PACSIN1/TRAF4 Complex in Toll-like Receptor 7 Activation.

Objective: Increased Toll-like receptor 7 (TLR-7) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR-7/TLR-9-mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE.

Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T-Bet-Promoted Energy Metabolism in Pathogenic Age/Autoimmune-Associated B Cells.

Objective: Emerging evidence indicates that a distinct CD11c+T-bet+ B cell subset, termed age/autoimmune-associated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC-mediated autoimmunity.

Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the IRF5 Risk Locus.

Objective: IRF5 plays a crucial role in the development of lupus. Genome-wide association studies have identified several systemic lupus erythematosus (SLE) risk single-nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. However, no comprehensive genome editing-based functional analysis exists to establish a direct link between these variants and altered IRF5 expression, particularly for enhancer variants.

Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for lupus treatment.

Excessive CD4 T helper (Th)-B-cell interactions and loss of Treg homeostasis are crucial to the pathogenesis of systemic lupus erythematosus (SLE). Targeting the SLE-specific upregulated costimulatory molecules ICOS or CD40L on Th can block Th-B reciprocal activation, but single costimulatory molecular blockade exhibited unsatisfactory therapeutic efficacy due to pathway redundancy. As ICOS and CD40L nonredundantly and cooperatively promote Th-B-cell reciprocal activation, simultaneously blocking ICOS and CD40L may achieve a synergistic effect.

Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton's Tyrosine Kinase.

Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease.

Evaluation of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in children and adults.

Objective: To evaluate the performance of the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR-2019) classification criteria for systemic lupus erythematosus (SLE) compared with the ACR-1997 and Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) patients.

Methods: We conducted a retrospective study of SLE patients (221 children and 221 adults) and controls (214 children and 214 adults) with defined rheumatic diseases to establish each ACR-1997, SLICC-2012, and EULAR/ACR-2019 criterion fulfilled. Demographic, clinical, and laboratory features were evaluated through chart review.