Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis

Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, Md, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 06/2005; 293(20):2496-500. DOI: 10.1001/jama.293.20.2496
Source: PubMed


Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear.
To determine whether antibodies to EBV are elevated before the onset of MS.
Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. Serial samples collected before the onset of symptoms were available for 69 matched case-control sets.
Antibodies including IgA against EBV viral capsid antigen (VCA), and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus.
The average time between blood collection and MS onset was 4 years (range, <1-11 years). The strongest predictors of MS were serum levels of IgG antibodies to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody titers to EBNA complex were similar to those of controls before the age of 20 years (geometric mean titers: cases = 245, controls = 265), but 2- to 3-fold higher at age 25 years and older (cases = 684, controls = 282; P<.001). The risk of MS increased with these antibody titers; the relative risk (RR) in persons with EBNA complex titers of at least 1280 compared with those with titers less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase in anti-EBNA complex or anti-EBNA-1 titers during the follow-up was associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0; 95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was found between cytomegalovirus antibodies and MS.
These results suggest an age-dependent relationship between EBV infection and development of MS.

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Available from: Lynn I. Levin, Oct 13, 2015
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    • "Numerous evidences strongly suggest that it is an autoimmune disease in which activated T cells enter the CNS and trigger an inflammatory cascade resulting in demyelination and axonal loss. Different genetic and environmental factors have shown to play a role in MS susceptibility, being class II alleles of the major histocompatibility complex (MHC), the more closely associated genes [1], and infectious agents such as Epstein-Barr virus, the environmental factors that have been more clearly associated with MS susceptibility [2]. Conversely, high serum levels of vitamin D have a protective role, delaying the appearance of a second demyelinating event after a clinically isolated syndrome [3]. "
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    ABSTRACT: Background and objectives: Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods: For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35-55 peptide of myelin oligodendrocyte glycoprotein (MOG35-55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results: Upon immunization with MOG35-55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35-55. Accordingly, resistant mice experienced a rise in regulatory B cells (P=0.001) and, to a lower extent, in regulatory T cells (P=0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35-55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P=0.02) and IL-17 (P=0.009) and higher serum levels of IL-17 (P=0.04) than resistant mice. Conclusions: Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.
    Research Journal of Immunology 04/2014; 2014(5966):156380. DOI:10.1155/2014/156380
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    • "Krone and collegues [104] postulate that these findings reflect a dysregulation of immune function as a consequence of the development of the disease. They assert that immune dysregulation in MS is likely to be an early event preceding the onset of MS disease by many years or even decades [14,105,106]. It is likely that the elevated antibody concentrations do not directly cause MS but rather reflect a shift in patterns of immune reactivity away from protection towards enhancement of the risk of disease. "
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    ABSTRACT: Background Although the precise etiology of multiple sclerosis is largely unknown, there is some speculation that a prior history of surgery may be associated with the subsequent risk for developing the disease. Therefore, we aimed to examine surgery as a risk factor for the diagnosis of multiple sclerosis. Methods We searched for observational studies that evaluated the risk for developing multiple sclerosis after surgery that occurred in childhood (≤ 20 years of age) or “premorbid” (> 20 years of age). We specifically included surgeries classified as: tonsillectomy, appendectomy, adenoidectomy, or “surgery”. We performed a systematic review and meta-analyses and calculated odds ratios (OR) and their 95% confidence intervals (CIs) using a random effects model. Results We identified 33 case–control studies, involving 27,373 multiple sclerosis cases and 211,756 controls. There was a statistically significant association between tonsillectomy (OR = 1.32, 95% CI 1.08-1.61; 12 studies, I2 = 44%) and appendectomy (OR = 1.16, 95% CI 1.01-1.34; 7 studies, I2 = 0%) in individual’s ≤ 20 years of age and the subsequent risk for developing multiple sclerosis. There was no statistically significant association between risk for multiple sclerosis and tonsillectomy occurring after age 20 (OR = 1.20, 95% CI 0.94-1.53; 9 studies, I2 = 32%), in those with appendectomy at > 20 years (OR = 1.26, 95% CI 0.92-1.72; 5 studies, I2 = 46%), and in those with adenoidectomy at ≤ 20 years of age (OR = 1.06, 95% CI 0.68-1.68; 3 studies, I2 = 35%). The combined OR of 15 studies (N = 2,380) looking at “surgery” before multiple sclerosis diagnosis was not statistically significant (OR = 1.19, 95% CI 0.83-1.70; I2 = 71%). Conclusions We found a small but statistically significant and clinically important increased risk for developing multiple sclerosis, in those with tonsillectomy and appendectomy at ≤ 20 years of age. There was no convincing evidence to support the association of other surgeries and the risk for multiple sclerosis. Well-designed prospective etiological studies, pertaining to the risk for developing multiple sclerosis, ought to be conducted and should include the examination of various surgeries as risk factors.
    BMC Neurology 05/2013; 13(1):41. DOI:10.1186/1471-2377-13-41 · 2.04 Impact Factor
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    • "An increased EBV antibody seroprevalence has been found to occur in MS patients compared to controls [11] [12]. While current evidence is not sufficiently robust to confirm an increased risk of developing MS in patients with prior EBV infection, research of the association remains plausible [11] [13] [14] [15]. More recently Chlamydia pneumonia and viruses such as herpes simplex and retroviruseshave drawn attention as potential candidates for increasing the risk of developing MS but conclusive data are lacking [10] [16] [17] [18]. "
    International Journal of Clinical Medicine 01/2013; 04(10):459-471. DOI:10.4236/ijcm.2013.410082
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