Antibodies to an Epstein Barr Virus protein that cross-react with dsDNA have pathogenic potential

Singh, Divya; Oudit, Omar; Hajtovic, Sabastian; Sarbaugh, Dylan; Salis, Rafatu; Adebowale, Temitayo; James, Justin; Spatz, Linda

doi:10.1016/j.molimm.2021.01.013

Cited by 12 publications

(6 citation statements)

References 55 publications

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“…A strong candidate SLE autoantibody that begs testing is antidouble-stranded (ds) DNA. Linda Spatz has shown that immunizing animals with EBNA1 generates anti-dsDNA antibodies (39)(40)(41), but to our knowledge, no one has evaluated whether the anti-dsDNA autoantibodies, which are almost unique to SLE and powerfully support an SLE diagnosis when present, also cross-react with EBNA1. The fact that EBNA1 is a DNA-binding protein raises interesting idiotype and antiidiotype issues that await exploration.…”

Section: Discussionmentioning

confidence: 99%

A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies

et al. 2022

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BackgroundThat Epstein–Barr virus (EBV) infection is associated with systemic lupus erythematosus (SLE) is established. The challenge is to explain mechanistic roles EBV has in SLE pathogenesis. Previous studies identify four examples of autoantibody cross-reactions between SLE autoantigens and Epstein–Barr nuclear antigen 1 (EBNA1). For two of these examples, the earliest detected autoantibody specifically cross-reacts with EBNA1; thereby, defined EBNA1 epitopes induce a robust autoantibody response in animals. These results suggest that the autoantibodies initiating the process leading to SLE may emerge from the anti-EBNA1 heteroimmune response. If this hypothesis is true, then anti-EBNA1 responses would be more frequent in EBV-infected SLE patients than in EBV-infected controls. We tested this prediction.MethodsWe evaluated published East Asian data by selecting those with a positive anti-viral capsid antigen (VCA) antibody immunoglobulin G (IgG) test and determining whether anti-EBNA1 was more common among the EBV-infected SLE cases than among matched EBV-infected controls with conditional logistic regression analysis.ResultsAll the qualifying SLE patients (100%) in this dataset were EBV-infected compared to age- and sex-matched controls (92.2%) [odds ratio (OR) = 28.6, 95% CI 6.4–∞, p = 8.83 × 10-8], confirming the known close association of EBV infection with SLE. Furthermore, virtually all the SLE cases have both anti-VCA IgG and anti-EBNA1 IgG antibodies [124 of 125 (99.2%)], which are more frequently present than in age- and sex-matched EBV-infected controls [232 of 250 (93.2%)] (OR = 9.7, 95% CI 1.5–414, p = 0.0078) for an 89.7% SLE attributable risk from anti-EBNA1, which is in addition to the 100% SLE risk attributable to EBV infection in these data.ConclusionsThe association of EBV infection with SLE is reconfirmed. The prediction that anti-EBNA1 is more frequent in these SLE cases than in EBV-infected controls is true, consistent with the hypothesis that anti-EBNA1 contributes to SLE. This second EBV-dependent risk factor is consistent with a molecular mimicry model for the generation of SLE, starting with EBV infection, progressing to anti-EBNA1 response; then molecular mimicry leads to anti-EBNA1 antibodies cross-reacting with an SLE autoantigen, causing autoantibody epitope spreading, and culminating in clinical SLE. These results support the anti-EBNA1 heteroimmune response being a foundation from which pathogenic SLE autoimmunity emerges.

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Section: Discussionmentioning

confidence: 99%

A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies

et al. 2022

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“…16 Moreover, Singh et al, who have generated two monoclonal antibodies (mAbs) against Epstein Barr's viral nuclear antigen I (EBNA-1), demonstrated that these Abs cross-react with double-stranded DNA (dsDNA). 17 The seroprevalence of SARS-CoV-2 in HWs in this study was 0.58% (6/1036). This result is in line with previous studies which reported than the prevalence of IgG antibodies in HWs was between 0.5% and 7.6%.…”

Section: Discussionmentioning

confidence: 49%

Prevalence of anti-SARS-CoV-2 IgG antibodies in a group of patients, a control group, and healthcare workers of Thrace area in Greece, by the use of two distinct methods

Konstantinidis¹,

Zisaki²,

Mitroulis³

et al. 2021

Germs

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Introduction The aim of this study was to assess the clinical performance of different automated immunoassays available in Europe to detect anti-SARS-CoV-2 antibodies; an ELISA assay and a CLIA. The second goal was to estimate the seroprevalence of SARS-CoV-2 antibodies among healthcare workers in Evros area during the first pandemic wave of COVID-19. Methods The study included serum samples from 101 patients with confirmed COVID-19 by RT-PCR and 208 negative patients. Furthermore, it included 1036 healthcare workers (HWs) of the Evros Region, Northern Greece. The measurement of anti-SARS-CoV-2 antibodies was performed using the Abbott SARS-CoV-2 IgG and anti-SARS-CoV-2 ELISA IgG assay (Epitope Diagnostics, USA). Results Of 101 confirmed COVID-19 patients, 82 were hospitalized and 19 were outpatients. Hospitalized patients had higher IgG levels in comparison to outpatients (6.46±2.2 vs. 3.52±1.52, p<0.001). Of 208 non−COVID-19 patients only 1 was positive in both ELISA and CLIA assay. SARS-CoV-2-IgG antibodies were detected in 6 HWs out of 1036 (0.58%) with mean S/CO-value of anti-SARS-CoV-2 IgG 3.12±1.3 (confidence interval 0.95), which was lower than in COVID-19 patients (3.12 vs. 5.9; p=0.016). The clinical evaluation of two immunoassays showed remarkably high true positivity rates in the confirmed COVID-19 patients. Sensitivities obtained with CLIA and ELISA methods were 99.02% vs. 97.09% and specificities 99.52% vs 99.05% respectively.Conclusions We found an acceptable accordance between CLIA and ELISA assays in the confirmed COVID-19 patients. In all subjects included in this study in the past medical history, the information that was obtained included details about the presence of autoimmune diseases.

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“…These findings are in agreement with some studies addressing the presence of EBV in renal tissue from patients with lupus nephritis 16 . EBV antigens are able to generate pathogenic antinuclear antibodies that cross-react with double-stranded DNA, causing glomerular immune deposition, proteinuria, and histopathological lesions of glomerulonephritis in experimental lupus nephritis 17 , as well as in small kidney biopsy using PCR for EBV, and in immunohistochemistry study for the severity of nephropathy 16 , 18 . However, despite no significant association with serum EBV antibodies, 100% positivity for anti-VCA-IgG-EBV was seen in SLE patients with renal manifestations 19 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of herpesvirus members on hospital admission in patients with systemic lupus erythematous shows higher frequency of Epstein-Barr virus and its associated renal dysfunction

et al. 2022

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Introduction: Members of the Herpesviridae family have been described in patients with systemic lupus erythematous (SLE), but the clinical impact on renal function is not well known. Methods: HSV1, HSV2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8 were evaluated by molecular biology on admission in blood samples from 40 consecutive SLE patients hospitalized for lupus activity. Results: Patients were 90.0% female, 77.5% non-white, with average age of 32.7 ± 13.6 years. We found positivity for EBV (65.0%), CMV (30.0%), HSV-1 (30.0%), HHV-6 (12.5%), and HHV-7 (7.5%). For all viruses, age, SLEDAI, hematological tests, ferritin, LDH, C-reactive protein, and erythrocyte sedimentation rate (ESR) were not significant. However, EBV positivity was a significant factor for higher serum creatinine (3.0 ± 2.8 vs. 0.9 ± 0.8; P = 0.001) and urea (86 ± 51 vs. 50 ± 46; P = 0.03). Moreover, positive cases for EBV only or with combined co-infections (66.7%-CMV; 58.3%-HSV-1) or negative for EBV only were evaluated by Kruskal-Wallis test again showed statistical significance for serum creatinine and urea (both P ≤ 0.01), with posttest also showing statistical differences for renal dysfunction and EBV presence (alone or in combined co-infections). The presence of EBV viral load was also significant for nephrotic-range proteinuria, renal flare, and the need for hemodialysis. Conclusion: Members of the Herpeviridae family (mainly EBV, HSV-1 and CMV) are common on hospital admission of SLE patients, reaching 65% for EBV, which seems to be associated with renal dysfunction and could reflect a previous association or overlapping disease, which is not well understood.

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Antibodies to an Epstein Barr Virus protein that cross-react with dsDNA have pathogenic potential

Cited by 12 publications

References 55 publications

A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies

A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies

Prevalence of anti-SARS-CoV-2 IgG antibodies in a group of patients, a control group, and healthcare workers of Thrace area in Greece, by the use of two distinct methods

Evaluation of herpesvirus members on hospital admission in patients with systemic lupus erythematous shows higher frequency of Epstein-Barr virus and its associated renal dysfunction

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