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      Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at risk individuals

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          Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown etiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition.


          SLE patient relatives (n=436) who did not have SLE at baseline were re-contacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative ACR criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information, and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3, and CD40 genes were typed by ImmunoChip™. Generalized estimating equations were used to test associations between viral antibody levels and transitioning to SLE.


          Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared to autoantibody negative non-transition relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95%CI 1.07–1.53 p=0.007, OR 1.43 95%CI 1.06–1.93 p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels, and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE.


          Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

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          Most cited references 32

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          Seroprevalence of cytomegalovirus infection in the United States, 1988-1994.

          Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and <1% for Mexican Americans. On the basis of these results, we estimate that each year in the United States approximately 340,000 non-Hispanic white persons, 130,000 non-Hispanic black persons, and 50,000 Mexican American women of childbearing age experience a primary CMV infection. Given the number of women at risk and the significance of congenital disease, development of programs for the prevention of CMV infection, such as vaccination or education, is of considerable public health importance.
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            Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2.

            Identity of the Epstein-Barr virus (EBV) receptor with the complement receptor type 2 (CR2) was established in three sets of experiments using the monoclonal antibodies, HB-5 and anti-B2, which recognize a Mr 145,000 B-lymphocyte membrane protein that is CR2. First, the rank order for binding of fluoresceinated EBV to four lymphoblastoid cell lines (SB, JY, Raji, and Molt-4) was identical to the rank order for binding of HB-5 and anti-B2 by analytical flow cytometry. Second, pretreatment of cells with HB-5 followed by treatment with goat F(ab')2 fragments to mouse IgG blocked binding of fluoresceinated EBV on SB, a B-lymphoblastoid cell line. Virus attachment was not inhibited by HB-5 alone, second antibody alone, rabbit anti-C3b receptor, or UPC10 (an irrelevant monoclonal antibody). Third, transfer of CR2 from SB to protein A-bearing Staphylococcus aureus particles, to which HB-5 had been absorbed, conferred on them the specific ability to bind 125I-labeled EBV. We conclude that CR2 is the EBV receptor of human B lymphocytes.
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              A revised estimate of twin concordance in systemic lupus erythematosus.

              Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage. We established a registry of twins with SLE, based upon self-reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins. Of 107 twin pairs meeting the American College of Rheumatology 1982 revised criteria for the diagnosis of SLE, 24% of 45 MZ pairs and 2% of 62 dizygous (DZ) pairs were concordant. The frequency distributions of diagnostic criteria and disease symptoms in the SLE patients were similar to those in other published reports of SLE patients. Zygosity was confirmed by DNA fingerprinting in a subsample of 15 self-described MZ twins and 7 self-described DZ twins. All individuals had correctly predicted their zygosity. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.

                Author and article information

                Ann Rheum Dis
                Ann. Rheum. Dis.
                Annals of the rheumatic diseases
                31 July 2019
                19 June 2019
                September 2019
                01 September 2019
                : 78
                : 9
                : 1235-1241
                [1 ]Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
                [2 ]Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
                [3 ]Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
                [4 ]Division of Rheumatology, Cedar-Sinai Medical Center, Los Angeles, CA, USA
                [5 ]Division of Rheumatic Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
                [6 ]Center of Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
                [7 ]Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
                [8 ]US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
                [9 ]Departments of Medicine and Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
                Author notes

                Author contributions. All authors contributed to drafting or critically revising the article for intellectual content and approved the final version of the article. JAJ had access to all data and analyses.

                Study conception and design: NRJ, KAY, MEM, JMG, DLK, MW, DJW, GG, DRK, JBH, JMN, JAJ.

                Acquisition of data. NRJ, MTH, JMG, DLK, MW, DJW, GG, DRK, PMG, JBH, JAJ.

                Analysis and interpretation of data. NRJ, KAY, MEM, MTH, JMG, DLK, MW, DJW, GG, DRK, JAK, JBH, JMN, JAJ.

                Correspondence: Judith A. James, MD, PhD, Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, 825 NE 13 th Street, Oklahoma City, OK 73104, Phone: 405-271-4987, Fax: (405) 271-7063, judith-james@

                License Statement. I, the Submitting Author, have the right to grant and do grant on behalf of all authors of the Work (as defined in the below author license), an exclusive license and/or a non-exclusive license for contributions from authors who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY license shall apply, and/or iii) in accordance with the terms applicable for US Federal Government officers or employees acting as part of their official duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its licensees and, where the relevant Journal is co-owned by BMJ, to the co-owners of the Journal, to publish the Work in Annals of the Rheumatic Diseases and any other BMJ products and to exploit all rights, as set out in our license.The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to the Submitting Author unless you are acting as an employee on behalf of your employer or a postgraduate student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative Commons license – details of these licenses and which Creative Commons license will apply to this Work are set out in our license referred to above.



                autoimmunity, epstein-barr virus, systemic lupus erythematosus


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