Association of Epstein‐Barr virus with systemic lupus erythematosus: Effect modification by race, age, and cytotoxic T lymphocyte–associated antigen 4 genotype

Abstract

Objective. Epstein-Barr virus (EBV) is hypothesized to play a role in the development of systemic lupus erythematosus (SLE). Cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) is important in regulating T cell-mediated immunity, encompassing the first line of response to viral infections, and genetic variation in CTLA-4 has been associated with SLE. This study examined the seroprevalence of EBV in a populationbased study of SLE patients from the southeastern United States, and potential interactions with CTLA-4 polymorphisms were assessed.Methods. Cases comprised 230 subjects recently diagnosed as having SLE (144 African American and 86 white) from university and community-based clinics, and controls comprised 276 age-, sex-, and statematched subjects (72 African American and 204 white) recruited from driver's license registries. Antibodies to EBV capsid antigen were determined by enzyme-linked immunosorbent assay, with results expressed as positive or negative using the international standardized ratio (ISR) (a ratio of the sample absorbance to a known standard). CTLA-4 genotypes were identified by polymerase chain reaction-based methods.Results. In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0-10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6-10.4). The seroprevalence of EBV-IgM and that of EBV-IgG were not associated with SLE. Higher EBV-IgG absorbance ratios were observed in SLE patients, with a significant dose response across units of the ISR in African Americans (P < 0.0001). Allelic variation in the CTLA-4 gene promoter (؊1661A/G) significantly modified the association between SLE and EBV-IgA (P ‫؍‬ 0.03), with a stronger association among those with the ؊1661AA genotype.Conclusion. These findings suggest that repeated or reactivated EBV infection, which results in increased EBV-IgA seroprevalence and higher IgG antibody titers, may be associated with SLE, and that the CTLA-4 genotype influences immune responsiveness to EBV in SLE patients. The observed patterns of effect modification by race, age, and CTLA-4 genotype should be examined in other studies and may help frame new hypotheses regarding the role of EBV in SLE etiology.

Systemic autoimmune disease mortality and occupational exposures

“…A possible hypothesis for the development of autoimmunity as a result of contact with the public is that exposure to multiple infectious agents leads to an autoimmune response. This theory is supported by evidence that several infectious agents have been linked to autoimmunity (6,7,42,43), but the inconsistency of our results indicates that further studies are needed before firm conclusions can be drawn.…”

“…Twin studies suggest a genetic component to the epidemiology of these diseases but have also revealed that environmental risk factors are important (3,4). Several risk factors have been proposed, including smoking (5) and infectious agents such as the EpsteinBarr virus (6,7).…”

The Herpes Simplex Virus Gene Pol Expressed in Herpes-Associated Erythema Multiforme Lesions Upregulates/Activates SP1 and Inflammatory Cytokines

“…While molecular mimicry was not yet documented for Pol, it was previously reported for members of the herpesvirus family and associated with disease pathogenesis. Thus the HSV protein VP16 causes increased viral gene expression through molecular mimicry of the cellular protein LZIP [33] and the Epstein-Barr virus nuclear antigen-1 protein mimics the cellular proteins Ro and SM, that are involved in the pathogenesis of systemic lupus erythematosus [34,35,36,37]. Alternative interpretations for the ability of Pol to cause overload of SP1-regulated genes include: (i) Pol binds and sequesters SP1 in the nucleus, which is analogous to the previously reported function of the Epstein-Barr virus Pol protein, thereby interfering with its proteosomal degradation and (ii) Pol stimulates the SP1 transactivating function through binding of Hsp90 [38,39,40,41].…”

FcαRI (CD89) Alleles Determine the Proinflammatory Potential of Serum IgA

“…Although the mean IgA1 and total IgA in samples from SLE patients are significantly higher than those from the normal population (50), IgA Abs have received little attention in SLE. IgA anti-Ro/SSA, anti-La/SSB, anti-cardiolipin, and anti-␤ 2 -glycoprotein-I autoantibodies are present in the serum of patients with SLE, Sjogren's syndrome, and anti-cardiolipin syndrome (45,51,52) and, very recently, reports indicate that not only EBV seropositivity but also a specific IgA Ab against EBV are associated with SLE patients (46,53). The reports of IgA autoantibodies and IgA anti-EBV seropositivity suggest a provocative and perhaps underappreciated link in which a more activating host response to IgA might influence an autoimmune and inflammatory response.…”