Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants.

The past few years have provided important insights into the genetic architecture of systemic autoimmunity through aggregation of findings from genome-wide association studies (GWAS) and whole-exome or whole-genome sequencing studies. In the prototypic systemic autoimmune disease systemic lupus erythematosus (SLE), monogenic disease accounts for a small fraction of cases but has been instrumental in the elucidation of disease mechanisms. Defects in the clearance or digestion of extracellular or intracellular DNA or RNA lead to increased sensing of nucleic acids, which can break B cell tolerance and induce the production of type I interferons leading to tissue damage.

EBV-encoded miRNAs BHRF1-1 and BART2-5p aggravate post- transplant lymphoproliferative disorder via LZTS2-PI3K-AKT axis.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications after transplantation. Epstein-Barr virus (EBV) is a key pathogenic driver of PTLD. About 80% of PTLD patients are EBV positive.

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling.

Mesenchymal stem cells (MSCs) influence T cells in health, disease and therapy through messengers of intercellular communication including extracellular vesicles (EVs). Apoptosis is a mode of cell death that tends to promote immune tolerance, and a large number of apoptotic vesicles (apoVs) are generated from MSCs during apoptosis. In an effort to characterize these apoVs and explore their immunomodulatory potential, here we show that after replenishing them systemically, the apoV deficiency in mutant mice and pathological lymphoproliferation were rescued, leading to the amelioration of inflammation and lupus activity.

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.

Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear.

Molecular mechanisms governing the progression of nephritis in lupus prone mice and human lupus patients.

Introduction: Pathologic inflammation is a major driver of kidney damage in lupus nephritis (LN), but the immune mechanisms of disease progression and risk factors for end organ damage are poorly understood.

Methods: To characterize molecular profiles through the development of LN, we carried out gene expression analysis of microdissected kidneys from lupus-prone NZM2328 mice. We examined male mice and the congenic NZM2328.

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.

Targeting Ligand Independent Tropism of siRNA-LNP by Small Molecules for Directed Therapy of Liver or Myeloid Immune Cells.

Hepatic clearance of lipid nanoparticles (LNP) with encapsulated nucleic acids restricts their therapeutic applicability. Therefore, tools for regulating hepatic clearance are of high interest for nucleic acid delivery. To this end, this work employs wild-type (WT) and low-density lipoprotein receptor (Ldlr) mice pretreated with either a leukotriene B4 receptor inhibitor (BLT1i) or a high-density lipoprotein receptor inhibitor (HDLRi) prior to the injection of siRNA-LNP.

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.

Novel insight into miRNA biology and its role in the pathogenesis of systemic lupus erythematosus.

MicroRNAs(miRNAs) have emerged as key regulators that control and influence gene expression as well as multiple biological processes depending on their potential binding sites in human-protein coding genes and other unconventional patterns, including coding for peptides, activating Toll-like receptors as a ligand, and other manners. Accumulating evidence has demonstrated that microRNA expression is tightly regulated during phases of development, differentiation, and effector functions of immune cells, immunological disorders of systemic lupus erythematosus (SLE). This review outlines the biogenesis of miRNAs and their unconventional functions as well as underlying cellular and molecular mechanisms.

LDHA: The Obstacle to T cell responses against tumor.

Immunotherapy has become a successful therapeutic strategy in certain solid tumors and hematological malignancies. However, this efficacy of immunotherapy is impeded by limited success rates. Cellular metabolic reprogramming determines the functionality and viability in both cancer cells and immune cells.

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.

Diverging regulation of Bach2 protein and RNA expression determine cell fate in early B cell response.

During the early phase of primary humoral responses, activated B cells can differentiate into different types of effector cells, dependent on B cell receptor affinity for antigen. However, the pivotal transcription factors governing these processes remain to be elucidated. Here, we show that transcription factor Bach2 protein in activated B cells is transiently induced by affinity-related signals and mechanistic target of rapamycin complex 1 (mTORC1)-dependent translation to restrain their expansion and differentiation into plasma cells while promoting memory and germinal center (GC) B cell fates.

The NCF1 variant p.R90H aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are a professional type I IFN producer that play critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of the function of pDCs and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of the neutrophil cytosolic factor 1 (NCF1) missense variant, which is one of the most significant associated risk variants for lupus, and found that the substitution of arginine (R) for histidine (H) at position 90 in the NCF1 protein (NCF1 p.

Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus.

Background: The study of genetic predisposition to pediatric systemic lupus erythematosus (pSLE) has brought new insights into the pathophysiology of SLE, as it is hypothesized that genetic predisposition is greater in children. Furthermore, identifying genetic variants and linking disrupted genes to abnormal immune pathways and clinical manifestations can be beneficial for both diagnosis and treatment. Here, we identified genetic alterations in a patient with childhood-onset SLE and analyzed the immunological mechanisms behind them to support future diagnosis, prognosis, and treatment.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

Objective: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.

Methods: We built gene expression predictive models in blood B cells, CD4 and CD8 T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals.

Mesenchymal stem cells empower T cells in the lymph nodes via MCP-1/PD-L1 axis.

Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs.

Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery.

Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter.

Urinary galectin-3 binding protein (G3BP) as a biomarker for disease activity and renal pathology characteristics in lupus nephritis.

Objective: There is an urgent need to identify novel biomarkers of LN to reflect renal histological changes. This study aims to investigate urinary G3BP levels in LN patients and their association with renal disease activity both clinically and pathologically.

Methods: This is a cross-sectional study.

AKT2 reduces IFNβ1 production to modulate antiviral responses and systemic lupus erythematosus.

Interferon regulatory factor 3 (IRF3)-induced type I interferon (I-IFN) production plays key roles in both antiviral and autoimmune responses. IRF3 phosphorylation, dimerization, and nuclear localization are needed for its activation and function, but the precise regulatory mechanisms remain to be explored. Here, we show that the serine/threonine kinase AKT2 interacts with IRF3 and phosphorylates it on Thr207, thereby attenuating IRF3 nuclear translocation in a 14-3-3ε-dependent manner and reducing I-IFN production.

Glycine increased ferroptosis via SAM-mediated GPX4 promoter methylation in rheumatoid arthritis.

Objective: Over-proliferation of synovium is a key event of invasive pannus formation and cartilage damage in the progression of RA disease. At the same time, ferroptosis may play a pivotal role in maintaining the balance of proliferation and death of synovium. In this study, we firstly evaluated the ferroptosis level in RA fibroblast-like synoviocytes (FLS) and then explored the role of glycine in ferroptosis.

SARS-CoV-2-Encoded MiRNAs Inhibit Host Type I Interferon Pathway and Mediate Allelic Differential Expression of Susceptible Gene.

Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus-host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2.