Differential Expression of Toll-Like Receptors 1 and 3 in Patients With Systemic Lupus Erythematosus and Systemic Sclerosis

Abstract Background: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases with some overlapping clinical manifestations. Recent studies have revealed that Toll-like receptors (TLRs) play essential roles in autoimmune diseases' pathogenesis. To investigate the expression of TLR genes in SLE and SSc that are specific to the character of these diseases' pathogenesis.Methods: We recruited patients with SLE (n = 15) and SSc (n = 9) from China Medical University Hospital hospital in Taiwan from 2016 to 2017. Included were healthy reference controls and SLE datasets from the NCBI database. RNA was extracted from peripheral blood cells of the patients for next-generation sequencing (NGS). Results in identified differentially expressed genes were compared to explore TLRs' association with SLE and SSc pathogenesis. Housekeeping genes, including ACTB, GAPDH, PGK1, PPIB, SDHA, and TBP, were used to normalize the expression levels of the TLR genes. Results: There were significant differences in raw gene expression for patients with SLE and SSc (p < 0.05). No significant difference between patients with SLE and control datasets with SLE (p >0.05). The expression levels of TLR1 (p = 0.018) and TLR3 (p = 0.031) were significantly upregulated in the patients with SSc compared with those with SLE, normalized by GAPDH. Compared with many housekeeping genes, ACTB, GAPDH, and TBP indicated a significant difference (p < 0.05) in the expression of TLR1and TLR3. Conclusions: TLR1 and TLR3 can serve as biomarkers to distinguish the gene expression between SLE and SSc, normalized with housekeeping genes such as ACTB, GADPH, and TBP.

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Differential expression of Toll-like receptors 1 and 3 in patients with systemic lupus erythematosus and systemic sclerosis

10.21203/rs.3.rs-85965/v1 ◽

2020 ◽

Author(s):

Ang-Jun Liu ◽

Po-Chang Wu ◽

Jian-Ruei Ciou ◽

Pu-Wei Hou ◽

Chung-Ming Huang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Systemic Sclerosis ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Clinical Manifestations ◽

Housekeeping Genes ◽

Low Grade ◽

Toll Like Receptors ◽

Systemic Lupus ◽

Expression Levels

Abstract Background: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases with some overlapping clinical manifestations. SLE is characterized by systemic inflammation with vasculitis and multiple organ damage, whereas SSc manifests as low-grade inflammation with vasculopathy and tissue fibrosis. Recent studies have revealed that Toll-like receptors (TLRs) play essential roles in the pathogenesis of autoimmune diseases. This study investigated the expression of TLR genes in SLE and SSc to determine their roles in the pathogenesis of these diseases.Methods: Patients with SLE (n = 15) and SSc (n = 9) were recruited from a hospital in Taiwan from 2016 to 2017. RNA was extracted from peripheral blood cells of the patients for next-generation sequencing (NGS). Then, We identified differentially expressed genes and associated pathways to explore the association of TLRs with SLE and SSc pathogenesis. Several housekeeping genes, including ACTB, GAPDH, PGK1, PPIB, SDHA, and TBP, were used to normalize the expression levels of the TLR genes.Results: GAPDH, PGK1, PPIB and SDHA are significantly different (p < 0.05) in patients of SLE and SSc. The expression levels of TLR1 (p = 0.018) and TLR3 (p = 0.031) were significantly upregulated in the patients with SSc compared with those with SLE, normalized by GAPDH.Conclusions: TLR1 and TLR3 can serve as biomarkers to distinguish the gene expression between SLE and SSc, normalized with housekeeping genes such as ACTB, GADPH and TBP.

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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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Upregulated PD-1 Expression Is Associated with the Development of Systemic Lupus Erythematosus, but Not the PD-1.1 Allele of the PDCD1 Gene

International Journal of Genomics ◽

10.1155/2014/950903 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Qingqing Jiao ◽

Cuiping Liu ◽

Ziliang Yang ◽

Qiang Ding ◽

Miaomiao Wang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Activity Index ◽

Disease Activity Index ◽

Peripheral Tolerance ◽

Systemic Lupus ◽

Peripheral Blood Mononuclear ◽

Expression Levels ◽

Significant Difference

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with complicated genetic inheritance. Programmed death 1 (PD-1), a negative T cell regulator to maintain peripheral tolerance, induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of SLE. In order to examine whether expression levels of PD-1 contribute to the pathogenesis of SLE, 30 patients with SLE and 30 controls were recruited and their PD-1 expression levels in peripheral blood mononuclear cells (PBMCs) were measured via flow cytometry and quantitative real-time-reverse transcription polymerase chain reaction (RT-PCR). Also, whether PD-1 expression levels are associated with the variant of the SNP rs36084323 and the SLE Disease Activity Index (SLEDAI) was studied in this work. The PD-1 expression levels of SLE patients were significantly increased compared with those of the healthy controls. The upregulated PD-1 expression levels in SLE patients were greatly associated with SLEDAI scores. No significant difference was found between PD-1 expression levels and SNP rs36084323. The results suggest that increased expression of PD-1 may correlate with the pathogenesis of SLE, upregulated PD-1 expression may be a biomarker for SLE diagnosis, and PD-1 inhibitor may be useful to SLE treatment.

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A Systematic Literature Review of the Association of Lipoprotein(a) and Autoimmune Diseases and Atherosclerosis

International Journal of Rheumatology ◽

10.1155/2012/480784 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 30

Author(s):

I. Missala ◽

U. Kassner ◽

E. Steinhagen-Thiessen

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Systemic Sclerosis ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Systemic Vasculitis ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Systemic Lupus ◽

Lipoprotein A

Objective. To investigate the association of lipoprotein(a) and atherosclerosis-related autoimmune diseases, to provide information on possible pathophysiologic mechanisms, and to give recommendations for Lp(a) determination and therapeutic options.Methods. We performed a systematic review of English language citations referring to the keywords “Lp(a)” AND “autoimmune disease” AND “atherosclerosis,” “Lp(a)” AND “immune system” OR “antiphospholipid (Hughes) syndrome (APS)” OR “rheumatoid arthritis” OR “Sjögren’s syndrome” OR “systemic lupus erythematosus” OR “systemic sclerosis” OR “systemic vasculitis” published between 1991 and 2011 using Medline database.Results. 22 out of 65 found articles were identified as relevant. Lp(a) association was highest in rheumatoid arthritis (RA), followed by systemic lupus erythematosus (SLE), moderate in APS and lowest in systemic sclerosis (SSc). There was no association found between Lp(a) and systemic vasculitis or Sjögren’s syndrome.Conclusion. Immune reactions are highly relevant in the pathophysiology of atherosclerosis, and patients with specific autoimmune diseases are at high risk for CVD. Elevated Lp(a) is an important risk factor for premature atherosclerosis and high Lp(a) levels are also associated with autoimmune diseases. Anti-Lp(a)-antibodies might be a possible explanation. Therapeutic approaches thus far include niacin, Lp(a)-apheresis, farnesoid x-receptor-agonists, and CETP-inhibitors being currently under investigation.

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AB0126 EXPRESSION CHARACTERISTICS OF ADENOSINE DEAMINASES ACTING ON RNA-1 IN SYSTEMIC LUPUS ERYTHEMATOSUS AND ITS CORRELATION WITH SERUM IFN-Α

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4361 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1363-1364

Author(s):

X. Di ◽

F. Gao ◽

C. Gao ◽

C. Zhang ◽

W. Sun ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Rna Editing ◽

Lupus Erythematosus ◽

Class Iii ◽

Systemic Lupus ◽

Expression Levels ◽

Serum Igg ◽

Significant Difference ◽

Expression Rate

Background:SLE is a multisystem autoimmune disease characterized by the production of multiple autoantibodies and loss of immunity against autoantigens in various tissues. SLE patients have significantly elevated RNA editing levels and the potential to produce new autoantigens.1ADAR1 is an RNA A-I editing enzyme that converts adenine to hypoxanthine and contributes to SLE pathogenesis.2Objectives:Dama demonstrated the upregulation of ADAR1p150 expression in SLE T cells, B cells, PBMCs, and NK cells;3however, the following issues were not reported in detail: 1. specific alterations in ADAR1 expression in PBMCs collected from SLE patients with varying degrees of the disease and its correlation with serum IFN-α levels; 2. association between ADAR1 and clinical indicators; and 3. ADAR1 expression in renal tissue of LN patients. Our study therefore aimed to elucidate the abovementioned points.Methods:We used qRT-PCR to determine ADAR1 expression levels in PBMCs and renal tissues of controls and SLE patients. We also conducted immunohistochemical studies to detect positive ADAR1 expression rate in renal cells of controls and LN patients.Results:ADAR1 expression was higher in PBMCs of SLE patients than in those of controls and was positively correlated with SLEDAI. When serum IFN-α levels in SLE patients decreased <260.0 pg/mL, ADAR1 expression in PBMCs increased with the increase in IFN-α concentration, and serum IFN-α may regulate ADAR1 level in PBMC in SLE patients, which may require the participation of serum IgG antibody and related immune complex. However, there was no significant difference between the expression in renal tissues in all patients.Conclusion:There was a certain correlation between ADAR1 expression and serum IFN-α levels in PBMCs of SLE patients.References:[1]Roth SH, Danan-Gotthold M, Ben-Izhak M, et al. Increased RNA Editing May Provide a Source for Autoantigens in Systemic Lupus Erythematosus.Cell Rep2018; 23: 50-57.[2]Hogg M, Paro S, Keegan LP and O’Connell MA. RNA editing by mammalian ADARs.Adv Genet2011; 73: 87-120.[3]Laxminarayana D, Khan IU, O’Rourke KS and Giri B. Induction of 150-kDa adenosine deaminase that acts on RNA (ADAR)-1 gene expression in normal T lymphocytes by anti-CD3-epsilon and anti-CD28.Immunology2007; 122: 623-633.Figure 1.Analysis of ADAR1 expression levels. a. The ADAR1 expression in PBMCs was higher in SLE patients (n=30) than in healthy controls (n = 30) (p<0.05). b. SLE patients were divided into three groups: NSLE (SLEDAI 0–4, n = 6), LSLE (SLEDAI 5–9, n = 12), and SSLE (SLEDAI ≥10, n = 12) according to SLEDAI score. c. Based on the effect of the disease on the kidneys, the patients were divided into the SLE#group (#:SLE patient group without the kidney involved, n = 17) and LN group (lupus nephritis group, n = 13). d. There was no significant difference observed between the renal tissues of controls (n = 5) and LN patients (n = 10) (p>0.05).Figure 2.a. Immunohistochemical image of renal tissues from the two groups (200×). b. There was no significant difference in the ADAR1 cell positive rate between controls (n = 5), LN patients(n = 20), and different pathological subgroups (class III, n = 5; class IV, n = 5; class V, n = 5; class III+IV, n = 5) (p>0.05). c. The positive expression rate of ADAR1 in renal tubular cells was higher than that in glomerular cells both in the two groups (p<0.05).Figure 3.a. Correlation between ADAR1 and serum IFN-α levels in PBMCs of SLE patients. b. Correlation between ADAR1p150 and serum IFN-α levels in PBMCs of SLE patients.Figure 4.In vitroPBMCs assay. a. Western blot (WB) analysis of ADAR1p150 and ADAR1p110 in PBMCs using different concentrations of IFN-α, combined with 1.5 mg/mL IgG purified from the serum of SLE patients or without it, and cultured for 24 hours. b. The line graph depicts the trend of ADAR1, ADAR1p150, and ADAR1p110 expression with increase in IFN-α concentrationin vitroPBMCs co-cultured with serum IgG from SLE patients.Disclosure of Interests:None declared

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Author response for "Cytometry by Time of Flight identifies distinct signatures in patients with systemic sclerosis, systemic lupus erythematosus and Sjögrens syndrome"

10.1002/eji.201948129/v3/response1 ◽

2019 ◽

Author(s):

Maarten der Kroef ◽

Lucas L. den Hoogen ◽

Jorre S. Mertens ◽

Sofie L.M. Blokland ◽

Scott Haskett ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Systemic Sclerosis ◽

Lupus Erythematosus ◽

Time Of Flight ◽

Author Response ◽

Systemic Lupus ◽

Sjogrens Syndrome

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OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2955 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 4-5

Author(s):

A. Aue ◽

F. Szelinski ◽

S. Weißenberg ◽

A. Wiedemann ◽

T. Rose ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Autoimmune Diseases ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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