Epstein-Barr Virus and Systemic Lupus Erythematosus

The etiology of SLE is not fully established. SLE is a disease with periods of waning disease activity and intermittent flares. This fits well in theory to a latent virus infection, which occasionally switches to lytic cycle, and EBV infection has for long been suspected to be involved. This paper reviews EBV immunobiology and how this is related to SLE pathogenesis by illustrating uncontrolled reactivation of EBV as a disease mechanism for SLE. Studies on EBV in SLE patients show enlarged viral load, abnormal expression of viral lytic genes, impaired EBV-specific T-cell response, and increased levels of EBV-directed antibodies. These results suggest a role for reactivation of EBV infection in SLE. The increased level of EBV antibodies especially comprises an elevated titre of IgA antibodies, and the total number of EBV-reacting antibody isotypes is also enlarged. As EBV is known to be controlled by cell-mediated immunity, the reduced EBV-specific T-cell response in SLE patients may result in defective control of EBV causing frequent reactivation and expression of lytic cycle antigens. This gives rise to enhanced apoptosis and amplified cellular waste load resulting in activation of an immune response and development of EBV-directed antibodies and autoantibodies to cellular antigens

Justification of research using systematic reviews continues to be inconsistent in clinical health science:A systematic review and meta-analysis of meta-research studies

BACKGROUND: Redundancy is an unethical, unscientific, and costly challenge in clinical health research. There is a high risk of redundancy when existing evidence is not used to justify the research question when a new study is initiated. Therefore, the aim of this study was to synthesize meta-research studies evaluating if and how authors of clinical health research studies use systematic reviews when initiating a new study. METHODS: Seven electronic bibliographic databases were searched (final search June 2021). Meta-research studies assessing the use of systematic reviews when justifying new clinical health studies were included. Screening and data extraction were performed by two reviewers independently. The primary outcome was defined as the percentage of original studies within the included meta-research studies using systematic reviews of previous studies to justify a new study. Results were synthesized narratively and quantitatively using a random-effects meta-analysis. The protocol has been registered in Open Science Framework (https://osf.io/nw7ch/). RESULTS: Twenty-one meta-research studies were included, representing 3,621 original studies or protocols. Nineteen of the 21 studies were included in the meta-analysis. The included studies represented different disciplines and exhibited wide variability both in how the use of previous systematic reviews was assessed, and in how this was reported. The use of systematic reviews to justify new studies varied from 16% to 87%. The mean percentage of original studies using systematic reviews to justify their study was 42% (95% CI: 36% to 48%). CONCLUSION: Justification of new studies in clinical health research using systematic reviews is highly variable, and fewer than half of new clinical studies in health science were justified using a systematic review. Research redundancy is a challenge for clinical health researchers, as well as for funders, ethics committees, and journals

EBNA1 IgM-Based Discrimination Between Rheumatoid Arthritis Patients, Systemic Lupus Erythematosus Patients and Healthy Controls

Epstein–Barr Virus (EBV) has been associated with development of rheumatic connective tissue diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in genetically susceptible individuals. Diagnosis of RA and SLE relies on clinical criteria in combination with the presence of characteristic autoantibodies. In addition, antibodies to several EBV antigens have been shown to be elevated in patients with these diseases compared to healthy controls (HC). Here, we elaborated improved enzyme-linked immunosorbent assays for antibodies (IgM, IgA, IgG) to the EBV proteins Epstein-Barr Virus nuclear antigen (EBNA)1 and early antigen diffuse (EAD) in order to determine their potential diagnostic role. We showed that especially EBNA1 IgM distinguished RA from SLE and HCs and also distinguished SLE from HCs. EBNA1 IgA was almost as effective in differentiating RA from SLE and HC, while EAD IgG and IgA were able to discern SLE patients from RA patients and HCs. Collectively, these findings illustrate the potential diagnostic use of antibodies to EBV proteins to diagnose RA and to differentiate SLE from RA

Systematic reviews are rarely used to contextualise new results-a systematic review and meta-analysis of meta-research studies

BACKGROUND: Results of new studies should be interpreted in the context of what is already known to compare results and build the state of the science. This systematic review and meta-analysis aimed to identify and synthesise results from meta-research studies examining if original studies within health use systematic reviews to place their results in the context of earlier, similar studies. METHODS: We searched MEDLINE (OVID), EMBASE (OVID), and the Cochrane Methodology Register for meta-research studies reporting the use of systematic reviews to place results of original clinical studies in the context of existing studies. The primary outcome was the percentage of original studies included in the meta-research studies using systematic reviews or meta-analyses placing new results in the context of existing studies. Two reviewers independently performed screening and data extraction. Data were synthesised using narrative synthesis and a random-effects meta-analysis was performed to estimate the mean proportion of original studies placing their results in the context of earlier studies. The protocol was registered in Open Science Framework. RESULTS: We included 15 meta-research studies, representing 1724 original studies. The mean percentage of original studies within these meta-research studies placing their results in the context of existing studies was 30.7% (95% CI [23.8%, 37.6%], I(2)=87.4%). Only one of the meta-research studies integrated results in a meta-analysis, while four integrated their results within a systematic review; the remaining cited or referred to a systematic review. The results of this systematic review are characterised by a high degree of heterogeneity and should be interpreted cautiously. CONCLUSION: Our systematic review demonstrates a low rate of and great variability in using systematic reviews to place new results in the context of existing studies. On average, one third of the original studies contextualised their results. Improvement is still needed in researchers’ use of prior research systematically and transparently—also known as the use of an evidence-based research approach, to contribute to the accumulation of new evidence on which future studies should be based. SYSTEMATIC REVIEW REGISTRATION: Open Science registration number https://osf.io/8gkzu/ SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13643-022-02062-8

Mapping an epitope in EBNA-1 that is recognized by monoclonal antibodies to EBNA-1 that cross-react with dsDNA

Introduction: The Epstein Barr Virus (EBV) has been associated with the autoimmune disease, Systemic Lupus Erythematosus (SLE). EBV nuclear antigen-I (EBNA-1) is the major nuclear protein of EBV. We previously generated an IgG monoclonal antibody (MAb) to EBNA-1, 3D4, and demonstrated that it crossreacts with double stranded DNA (dsDNA) and binds the 148 amino acid viral binding site (VBS) in the carboxyl region of EBNA-1. The aim of the present study was to characterize another antibody to EBNA-1 that cross-reacts with dsDNA, compare its immunoglobulin genes to 3D4, and finely map the epitope in EBNA-1 that is recognized by these cross-reactive antibodies. Methods: We generated an IgM MAb to EBNA-1, 16D2, from EBNA-1 injected mice and demonstrated by ELISA that it cross-reacts with dsDNA and binds the 148 amino acid VBS. We sequenced the variable heavy and light chain genes of 3D4 and 16D2 and compared V gene usage. To more finely map the epitope in EBNA-1 recognized by these MAbs, we examined their binding by ELISA to 15 overlapping peptides spanning the 148 amino acid domain. Results: Sequence analysis revealed that 3D4 and 16D2 utilize different VH and VL genes but identical JH and Jk regions with minimal junctional diversity. This accounts for similarities in their CDR3 regions and may explain their similar dual binding specificity. Epitope mapping revealed 3D4 and 16D2 bind the same peptide in the VBS. Based on the crystal structure of EBNA-1, we observed that this peptide resides at the base of an exposed proline rich loop in EBNA-1. Conclusion: We have demonstrated that two MAbs that bind EBNA-1 and crossreact with dsDNA, recognize the same peptide in the VBS. This peptide may serve as a mimetope for dsDNA and may be of diagnostic and therapeutic value in SLE

Evidence-Based Research Series-Paper 2 : Using an Evidence-Based Research approach before a new study is conducted to ensure value

Background and Objectives There is considerable actual and potential waste in research. The aim of this article is to describe how using an evidence-based research approach before conducting a study helps to ensure that the new study truly adds value. Study Design and Setting Evidence-based research is the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient, and accessible manner. In this second article of the evidence-based research series, we describe how to apply an evidence-based research approach before starting a new study. Results Before a new study is performed, researchers need to provide a solid justification for it using the available scientific knowledge as well as the perspectives of end users. The key method for both is to conduct a systematic review of earlier relevant studies. Conclusion Describing the ideal process illuminates the challenges and opportunities offered through the suggested evidence-based research approach. A systematic and transparent approach is needed to provide justification for and to optimally design a relevant and necessary new study