HMGB1 Promotes Systemic Lupus Erythematosus by Enhancing Macrophage Inflammatory Response

Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE); however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure.Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues.Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-αand IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response.Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE.

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Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

Genes ◽

10.3390/genes12050680 ◽

2021 ◽

Vol 12 (5) ◽

pp. 680

Author(s):

Rujuan Dai ◽

Zhuang Wang ◽

S. Ansar Ahmed

Keyword(s):

Systemic Lupus Erythematosus ◽

Dna Methylation ◽

Lupus Erythematosus ◽

Critical Role ◽

Methylation Status ◽

Transcriptional Level ◽

Dna Hypomethylation ◽

Systemic Lupus ◽

Multiple Organs ◽

Genetic Imprinting

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

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Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

10.1101/2021.02.09.430558 ◽

2021 ◽

Author(s):

Hui Ma ◽

Lin Wang ◽

Zilu Wen ◽

Xinchun Chen ◽

Haiying Liu ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Inflammatory Response ◽

Pulmonary Tuberculosis ◽

Autoimmune Diseases ◽

Metabolic Activity ◽

Lupus Erythematosus ◽

Immune Complexes ◽

Systemic Lupus ◽

Dsdna Antibodies

ABSTRACTMetabolic activity in pulmonary lesion is associated with disease severity and relapse risk in tuberculosis. However, the nature of the metabolic activity associated with tuberculosis in humans remains unclear. Previous works indicate that tuberculosis bears resemblance transcriptionally with systemic lupus erythematosus in peripheral blood, except that the plasma cell component was absent in tuberculosis. Here we reported that the missing transcriptional component was present within the metabolic active tissues in the lung of patients with sputum culture-negative tuberculosis, within which increased levels of circulating immune complexes and anti-dsDNA antibodies were found relative to nearby non-metabolic active tissues. Histological examination revealed specific vascular deposition of immune complexes, neutrophil extracellular traps, and vascular necrosis in the metabolic-active tissue. Thus, tuberculosis-initiated metabolic activity was associated with hyperactive antibody responses and vascular pathology, and shared features with systemic lupus erythematosus and other autoimmune diseases. We discussed these observations in the context of earlier literatures demonstrating that similar effects could be induced in humans and animal models by complete freund’s adjuvant, the most potent antibody response inducer ever reported. Our small case series, if verified in a larger size study, might help inform host-directed therapies to alleviate disease progression and augment treatment efficacy.IMPORTANCEIn patients with pulmonary tuberculosis, lung tissues were destroyed by a hyperactive inflammatory response towards M. tuberculosis. The mechanisms underlying the inflammatory response are still poorly understood. Using 18F-FDG avidity as a surrogate marker of inflammation, we have identified that hyper-inflamed tissues possessed features associated with systemic lupus erythematosus: gene expression signatures of plasma cell and immunoglobulins and increased levels of anti-dsDNA antibodies, immune deposits, and vasculopathy. This observation might suggest an explanation to why patients with tuberculosis share more gene expression signatures with autoimmune diseases than infectious diseases and why they are more likely to develop autoimmune diseases. Defining the inflammatory responses at the lesion could help inform host-directed therapies to intervene disease progression or even accelerate cure.

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Association of the PINX1 Variant rs6984094, Which Lengthens Telomeres, with Systemic Lupus Erythematosus Susceptibility in Chinese Populations

Journal of Immunology Research ◽

10.1155/2021/7079359 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Yuan-yuan Qi ◽

Xin-ran Liu ◽

Ying-xin He ◽

Min Zhou ◽

Xiang-hui Ning ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Genetic Association ◽

Lupus Erythematosus ◽

Genome Wide Association Study ◽

Mononuclear Cells ◽

Critical Role ◽

Systemic Lupus ◽

Peripheral Blood Mononuclear ◽

Chinese Populations ◽

Genetic Heritability

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified ( P discovery = 4.13 × 10 − 2 , OR = 0.58 , 95% CI 0.35-0.98) and successfully replicated ( P replication = 5.73 × 10 − 3 , OR = 0.45 , 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

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Association between IgG4 Autoantibody and Complement Abnormalities in Systemic Lupus Erythematosus

Mediators of Inflammation ◽

10.1155/2016/2196986 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Qingjun Pan ◽

Linjie Guo ◽

Jing Wu ◽

Jun Cai ◽

Huanjin Liao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Inflammatory Response ◽

Lupus Erythematosus ◽

Serum Levels ◽

Clinical Parameters ◽

Newly Diagnosed ◽

Systemic Lupus ◽

Novel Therapeutic

In order to investigate the association between IgG4 autoantibody and complement abnormalities in systemic lupus erythematosus (SLE), 72 newly diagnosed SLE patients, 67 rheumatoid arthritis (RA) patients, and 41 healthy normals were employed. Serum levels of antinuclear IgG4 and IgG4-specific IgM-rheumatoid factor (RF) were measured, and the correlations between serum levels of antinuclear IgG4 and several clinical parameters were analyzed. Also, the levels of IgG subclasses, C1q, and C3 deposition in lupus nephritis (LN) were detected. The results showed that serum levels of antinuclear IgG4 were higher in SLE patients relative to healthy normals (P<0.01). Serum levels of antinuclear IgG4 in SLE patients were positively correlated with serum levels of total IgG4, albumin, and C3 (r=0.61,P<0.05;r=0.40,P<0.05; andr=0.54,P<0.05, resp.) and negatively correlated with 24-hour urinary protein (r=0.49,P<0.05). Serum levels of IgG4-specific IgM-RF were higher in RA patients than in SLE patients (P<0.001). Also, the ratio of the deposition score for IgG4/(IgG1 + IgG2 + IgG3 + IgG4) was negatively correlated with the score for C1q and C3 deposition in LN (r=0.34,P<0.05;r=0.51,P<0.01, resp.). In summary, the IgG4 autoantibody may dampen the inflammatory response in SLE, thus maybe providing a novel therapeutic target for SLE.

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Dysregulated T Cell Activation and Aberrant Cytokine Expression Profile in Systemic Lupus Erythematosus

Mediators of Inflammation ◽

10.1155/2019/8450947 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Haiyan Zhou ◽

Bojiang Li ◽

Jing Li ◽

Tongqian Wu ◽

Xiaoqian Jin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

T Cell ◽

Lupus Erythematosus ◽

Critical Role ◽

Cytokine Expression ◽

Healthy Controls ◽

Systemic Lupus ◽

Hla Dr ◽

Dsdna Antibody

Accumulating evidence indicates a critical role for T cells and relevant cytokines in the pathogenesis of systemic lupus erythematosus (SLE). However, the specific contribution of T cells together with the related circulating cytokines in disease pathogenesis and organ involvement is still not clear. In the current study, we investigated relevant molecule expressions and cytokine levels in blood samples from 49 SLE patients and 22 healthy control subjects. The expression of HLA-DR and costimulatory molecules on T cells was evaluated by flow cytometry. Concentrations of serum C-reactive protein, erythrocyte sedimentation rate, anti-double-stranded DNA (anti-dsDNA) antibody, total lgG, complement 3, and complement 4 were measured. Serum cytokines and chemokines were measured by a cytometric bead array assay. Elevated frequencies of HLA-DR+ T cells and ICOS+ T cells were observed in SLE patients with positive anti-dsDNA antibodies compared with those in healthy controls (P<0.001). The expression of HLA-DR+ T cells was positively correlated with SLEDAI (r=0.15, P<0.01). Furthermore, levels of serum IL-6, MCP-1, TNFRI, IL-10, IL-12, and CCL20 were higher in SLE patients compared with healthy controls. In addition, patients with hematologic manifestations displayed elevated frequencies of HLA-DR+ T cells and ICOS+ T cells. Patients with renal manifestations had a decreased frequency of TIGIT+ T cells. These results suggested a dysregulated T cell activity and cytokine expression profiles in SLE subjects. We also developed a chemokine and cytokine profiling strategy to predict the activity of SLE, which has clinical implication for better monitoring the flares and remission during the course of SLE and for assessing therapeutic interventions.

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UnMASking the diagnosis: Acute severe necrotizing pancreatitis in the setting of systemic lupus erythematosus complicated by macrophage activation syndrome

Case Reports in Internal Medicine ◽

10.5430/crim.v5n4p1 ◽

2018 ◽

Vol 5 (4) ◽

pp. 1

Author(s):

Cyrus Ashraf Askin ◽

Jerome Craig Edelson ◽

Guy Smith Dooley ◽

Amy Nicole Stratton

Keyword(s):

Systemic Lupus Erythematosus ◽

Acute Pancreatitis ◽

Inflammatory Response ◽

Lupus Erythematosus ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Necrotizing Pancreatitis ◽

Adult Onset ◽

Systemic Lupus ◽

Activation Syndrome

Systemic lupus erythematosus (SLE) is a common rheumatologic condition with known GI involvement. Acute pancreatitis (AP) is a rare GI complication of SLE and is typically associated with increased disease activity. Macrophage activation syndrome (MAS) is an unusual, hyper-inflammatory response to a rheumatologic stimulus characterized by hyperferritinemia, pancytopenia, thermal dysregulation and multi-organ dysfunction. MAS, more commonly seen in children, has been reported to complicate both adult onset SLE and AP. We present a case of necrotizing AP secondary to an SLE flare complicated by MAS in an adult patient successfully treated with anakinra.

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Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus

Journal of Experimental Medicine ◽

10.1084/jem.20050914 ◽

2005 ◽

Vol 202 (8) ◽

pp. 1131-1139 ◽

Cited By ~ 635

Author(s):

Franck J. Barrat ◽

Thea Meeker ◽

Josh Gregorio ◽

Jean H. Chan ◽

Satoshi Uematsu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Rna Viruses ◽

Critical Role ◽

Serum Levels ◽

Systemic Lupus ◽

Tlr Signaling ◽

Dna And Rna ◽

Mammalian Origin ◽

Protein Particles

Raised serum levels of interferon (IFN)-α have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-α is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-α. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-α production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-α production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-α by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.

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