Mechanisms of Tumor Necrosis Factor-Alpha Inhibitor-Induced Systemic Lupus Erythematosus
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SUBMITTER: Yen C
PROVIDER: S-EPMC9208548 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor ? (TNF?) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNF? levels, clinical manifestations of SLE, autoantibodies, and serum interferon-? (IFN?) levels in a large multiancestral SLE cohort.We studied serum TNF? levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNF? was measured using an enzyme-linked immunosorbent assay, and IFN? was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate.Serum TNF? levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNF? levels were positively correlated with high serum IFN? levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNF? levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNF? and IFN? was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNF? levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling.Serum TNF? levels are high in many SLE patients, and we observed a positive correlation between serum TNF? and IFN? levels. These data support a role for TNF? in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease.
| S-EPMC3396783 | biostudies-literature
Project description:ObjectiveTo define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).MethodsTumor necrosis factor α (TNFα) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNFα(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-α/β/ω receptor-knockout (IFNAR(-/-) ), and B cell-deficient (μmt) mice treated with pristane. Flow cytometry was used to examine TNFα production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.ResultsBM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNFα overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNFα production was abolished in pristane-treated TLR-7(-/-) and μmt mice but was restored in μmt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNFα(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNFα(-/-) mice.ConclusionAlthough autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNFα driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNFα production mediating glomerulonephritis and hematologic involvement, respectively.
| S-EPMC3990233 | biostudies-literature
Project description:In rare cases, clinical inhibitors of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) can induce symptoms of lupus erythematosus (drug-induced lupus, DIL), but this adverse response usually resolves rapidly upon drug withdrawal. We report the case of a 25-year-old Asian woman with rheumatoid arthritis exhibiting severe prolonged DIL even after the termination of TNF-α inhibitor treatment. The patient had been treated intermittently using Traditional Chinese Medicine for 11 years, but this therapy failed to effectively control her clinical symptoms. Subsequently, methotrexate and hydroxychloroquine were prescribed, but a reduced white blood cell count was detected. Finally, the TNF-α inhibitor Anbainuo was prescribed. However, after 2 months of treatment, the patient exhibited elevated serum creatinine, anti-double-stranded DNA (+++), anti-nuclear antibody (1:1000), and urine protein (+++) accompanied by buccal erythema, hair loss, and hand shaking, consistent with Anbainuo-induced lupus, lupus nephritis, and lupus encephalopathy. Moreover, her serum creatinine level remained high after Anbainuo withdrawal and prolonged steroid and immunosuppressive therapy. Careful and sustained monitoring for adverse reactions to Anbainuo (and other TNF-α inhibitors) is recommended.
| S-EPMC8216383 | biostudies-literature
Project description:IntroductionPlasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.MethodsPeripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry.ResultsAfter TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01).ConclusionsTreatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.
| S-EPMC3446541 | biostudies-literature
Project description:Antimalarials are used to treat dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Although hydroxychloroquine (HCQ) is frequently used, addition of quinacrine (QC) has shown additional clinical effects when combined with HCQ. To quantify the effects of HCQ versus QC in suppressing secretion of tumor necrosis factor-α (TNF-α) and IFN-α from the peripheral blood mononuclear cells of DM and CLE patients, lipopolysaccharide-stimulated and control peripheral blood mononuclear cells from DM and CLE patients and control subjects were analyzed for the effect of HCQ and QC on TNF-α and IFN-α production using ELISA testing. Flow cytometry showed the effects of these therapies on intracellular TNF-α in myeloid dendritic cells and monocytes of DM patients and control subjects. QC significantly suppressed TNF-α relative to HCQ from unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). It suppressed IFN-α as significantly as HCQ from cytosine phosphodiester guanine-stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). Flow cytometry showed that QC significantly suppressed intracellular expression of TNF-α from the lipopolysaccharide-stimulated myeloid dendritic cells and monocytes of DM patients (P-values ≤ 0.0008). In conclusion, QC likely has a different mechanism of action than HCQ, given the broader inhibition of proinflammatory cytokines, including both TNF-α and IFN-α.
| S-EPMC5645024 | biostudies-literature
Project description:Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.
| S-EPMC2989495 | biostudies-literature
Project description:ObjectiveTo conduct a case-control study to investigate whether there are independent tumour necrosis factor alpha (TNFalpha) or lymphotoxin alpha (LTalpha) haplotype associations with SLE or with any of the major serological subsets of SLE.Methods157 patients with SLE were genotyped for HLA-DRB1, HLA-DQB1, TNFalpha, and LTalpha alleles by polymerase chain reaction and compared with 245 normal white controls. For TNFalpha, six single nucleotide polymorphisms (SNPs) at positions -1031, -863, -857, -308, -238, and +488 and for LTalpha three SNPs at positions +720, +365, and +249 were studied to assign six TNFalpha haplotypes (TNF1-6) and four LTalpha haplotypes (LTA1-4). All SLE patients had full serological profiles on serial samples.ResultsThe most significant association with SLE overall was with HLA-DR3 (p<0.001; odds ratio (OR) = 2.5 (95% confidence interval, 1.6 to 3.8)) and the extended haplotype HLA-DQB1*0201;DRB1*0301;TNF2;LTA2 (p<0.001; OR = 2.3 (1.4 to 3.7)). Associations were strongest in the anti-La positive group (13%) of SLE patients (HLA-DR3, OR = 71 (9 to 539); HLA-DQB1*0201, OR = 35 (5 to 267); TNF2, OR = 10 (2.8 to 36), and LTA2, OR = 4.9 (1.1 to 21)). There was an increase in the HLA-DR2 associated extended haplotype (HLA-DQB1*0602;DRB1*1501;TNF1;LTA1) in patients with anti-Ro in the absence of anti-La (p<0.005; OR = 3.9 (1.5 to 10)). The HLA-DR7 extended haplotype (HLA-DQB1*0303;DRB1*0701/2;TNF5;LTA3) was decreased in SLE overall (p<0.02; OR = 0.2 (0.05 to 0.8)).ConclusionsThe strongest association in this predominantly white population with SLE was between HLA-DR3 and anti-La, which seemed to account for any associations with TNFalpha alleles on an extended DR3 haplotype.
| S-EPMC1798099 | biostudies-literature
Project description:OBJECTIVES: The etiology and pathogenesis of systemic lupus erythematosus remains unknown, evidence exists for the involvement of mycobacterial antigen. This study is aimed to determine the effect of Mycobacterium tuberculosis on clinical course of SLE patients and the role of ROS and TNF-α in the pathogenesis of tuberculosis associated SLE patients. METHODS: This study was done on 100 patients divided into SLE group (n=30), TB group (n=30), SLE-TB group (n=30) and control group (n=10). All patients underwent clinical, biochemical and immunological evaluation by employing techniques such as SDS-PAGE, direct binding and competition ELISA, PBMC and cell culture. RESULTS: Fever, arthritis, skin rash, photosensitivity were more common in both SLE and SLE-TB group. Reduced glutathione showed amelioration of ROS and TNF-α induced action, which in turn, subsequently suppressed the immune-bindings observed in monocytes of TB and SLE patients cultured without glutathione. CONCLUSION: Data shows that SLE patients are more susceptible to developing Mycobacterium tuberculosis, as ROS and TNF-α in SLE patients could activate the replication of mycobacterial Ag85B (30 kDa) after bacilli infection.
| S-EPMC3282130 | biostudies-other
Project description:ObjectivesThe goal of our study was to evaluate the potential role of sTNF-RI as a biomarker of renal involvement in SLE patients and active SLE.MethodsThe study sample consisted of two cohorts. The discovery cohort included 16 SLE patients without renal involvement (non-LN), 60 lupus nephritis (LN) patients and 21 healthy controls (HCs) and the replication cohort included 18 SLE non-LN patients, 116 LN patients and 36 HCs.ResultsThe sTNF-RI levels differed significantly in the discovery cohort. The plasma sTNF-RI levels were higher in LN patients than in non-LN patients (p = .009) and HCs (p = 4 × 10-6). Plasma sTNF-RI levels were significantly higher in non-LN patients than in HCs (p = .03). The finding was confirmed in independent replication cohort (LNs vs. non-LN, p = 4.053 × 10-7; LNs vs. HCs, p = 2.395 × 10-18; non-LN vs. HCs, p = 2.51 × 10-4). The plasma sTNF-RI levels were associated with disease activity, renal function in SLE patients and urine protein in LN patients. The multivariate analysis revealed that high sTNF-RI was an independent risk factor for renal involvement. The multivariate logistic regression results suggested that high TNF-RI, high systolic blood pressure, high serum creatinine, low C4 and positive anti-dsDNA were independent risks of active SLE patients. A nomogram was constructed based on the results of multivariate logistic regression analysis and it was practical in predicting the risk of the active SLE patients. Immunohistochemistry suggested that the expression of TNF-RI in the kidney was increased.ConclusionsPlasma sTNF-RI might be a good biomarker of renal involvement and disease activity in SLE patients.
| S-EPMC10035946 | biostudies-literature
Project description:Tumor necrosis factor-alpha (TNF-α) plays an important role in autoimmune diseases. Previous studies have investigated the association of TNF-α-238G/A (rs361525) and -308G/A (rs1800629) polymorphisms with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, no agreed conclusion had been made. Therefore, this meta-analysis was conducted to assess the associations of TNF-α-238G/A and -308G/A polymorphisms with RA and SLE risk. A systematic search was conducted in commonly used databases. Meta-analysis was performed by STATA12.0. A total of 43 studies were included. In the overall population, the TNF-α-238A allele was observed to be a protective factor for RA (A vs G: OR=0.75, 95%CI=0.57-0.99, P=0.040) and the TNF-α-308A allele was found to be a risk factor for SLE (A vs G: OR=1.78, 95%CI=1.45-2.19, P<0.001). However, no evidence of association was found between TNF-α-238 G/A polymorphism and SLE nor between -308G/A and RA. In the subgroup analysis, TNF-α-308A allele played a pathogenic role for RA in Latin Americans (A vs G: OR=1.46, 95%CI=1.15-1.84, P=0.002) and for SLE in Latin Americans (A vs G: OR=2.12, 95%CI=1.32-3.41, P=0.002) and Europeans (A vs G: OR=2.03, 95%CI=1.56-2.63, P<0.001), while it played a protective role for RA in Asians (A vs G: OR=0.54, 95%CI=0.32-0.90, P=0.017). No significant association was found between TNF-α-308G/A and SLE susceptibility in Africans and Asians. This meta-analysis demonstrated that TNF-α-238A was associated with decreased risk of RA rather than SLE, while -308G/A polymorphism was associated with SLE rather than RA. Stratification analysis indicated that different ethnicities would have different risk alleles.
| S-EPMC6437938 | biostudies-literature