(Abstract) Epstein-Barr virus & MS

 
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agate
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PostPosted: Mon Jun 12, 2006 6:04 pm    Post subject: (Abstract) Epstein-Barr virus & MS Reply with quote

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Vol. 63 No. 6, June 2006




Epstein-Barr Virus and Multiple Sclerosis
Evidence of Association From a Prospective Study With Long-term Follow-up


Gerald N. DeLorenze, PhD; Kassandra L. Munger, MSc; Evelyn T. Lennette, PhD; Norman Orentreich, MD; Joseph H. Vogelman, DEE; Alberto Ascherio, MD, DrPH


Arch Neurol. 2006;63:839-844.

Objective To determine whether serum titers of anti–Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS).

Methods Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls.

Results
The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter.

Conclusion
The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.


Author Affiliations:
Kaiser Permanente Division of Research, Oakland, Calif (Dr DeLorenze); Departments of Nutrition (Dr Ascherio and Ms Munger) and Epidemiology (Dr Ascherio), Harvard School of Public Health, and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School (Dr Ascherio), Boston, Mass; Virolab Inc, Berkeley, Calif (Dr Lennette); Orentreich Foundation for the Advancement of Science Inc, New York, NY (Drs Orentreich and Vogelman).
















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PostPosted: Wed Jul 12, 2006 2:04 pm    Post subject: Reply with quote

From Web MD/Medscape Today:

Quote:




Anti-EBV Titers May Increase Early in Pathogenesis of Multiple Sclerosis




NEW YORK (Reuters Health) Jul 04 - Elevation of serum antibody titers to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 appears to be an early event in the pathogenesis of multiple sclerosis (MS), according to results of a study published in the June issue of the Archives of Neurology.

"Epidemiologic evidence of changes in risk among migrants clearly implicates exogenous factors in the etiology of MS, but the nature of these factors remains uncertain," Dr. Alberto Ascherio, of Harvard School of Public Health, Boston, and colleagues write. "During the past two decades, results of numerous studies have suggested a possible role for the Epstein-Barr virus."

The researchers examined whether serum titers of anti-EBV antibodies are elevated in blood specimens collected up to 30 years before MS onset. Patients with MS were identified among members of the Kaiser Permanente Northern California health plan who took part in a multiphasic examination between 1965 and 1974. The team used stored serum samples to compare anti-EBV antibody titers in 42 patients who developed MS and matched controls.

The median age at MS onset was 45 years. The median time between baseline blood collection and MS onset was 15 years. Compared to controls, patients with MS had significantly higher geometric means titers of antibodies to the EBNA complex and its component EBNA1.

The relative risks of developing MS associated with a 4-fold increase in antibody titers were 2.1 and 1.8 for the EBNA complex and EBNA-1, respectively. Elevations of antibody titers to the EBNA complex and EBNA-1 among patients with MS first occurred between 15 and 20 years prior to the onset of symptoms. These elevations persisted thereafter.

EBV may "persist in the central nervous system and become reactivated at times of disease activity," write Drs. Amy E. Lovett-Racke and Michael K. Racke, of the University of Texas Southwestern Medical Center, Dallas, in an accompanying editorial. "Glia cells express the EBV entry receptor and can be infected with the virus; however, EBV messenger RNA has not been detected in MS lesions."

"Another possibility is that infected B cells could spread the virus to the central nervous system and that a local antiviral immune response could contribute to establishing inflammation in the central nervous system," they write.

Arch Neurol 2006;63:839-844.





This article summarizes the findings in the article that was abstracted in the earlier post above.
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LoLo



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PostPosted: Wed Jul 12, 2006 4:03 pm    Post subject: Reply with quote

I know I had it, when I was...13? I was sick as a dog for weeks. I lost 20 lbs., and I looked like a scarecrow by the time I recovered. Took me a LONG time to get my strength back.
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PostPosted: Sat Jul 15, 2006 10:40 am    Post subject: Reply with quote

My last neuro ran these tests and told me I had chronic active Epstein Barr. My hemo dr disagrees with that, but I can't get anyone to run the full panel and get this settled once and for all, they say it's not necessary, I disagree, I want to know.

I feel I do have it, why else would my husband and 2 daughters and my daughters friend come down with mono?

My husband died due to complications of mono. Well in my beleif he was killed, because his doctor wouldn't listen to me or test him. He had CLL and had been in remission for over 2 years, we both got sick with the same symptoms.

She thought the CLL had taken a turn for the worst, I showed her my test results, she blew me off time after time and refused to check him. She kept pouring chemo into him round the clock for day after day each month in the hospital.
She totally distroyed his immune system and his ability to fight the mono.

He was admitted to the hospital last labor day and tested for mono, guess what he had it. She stepped aside as his doctor and he died on October 11th at 2:26 am at home with me curled up next to him.

The staff doctors at the hospital asked why he was never tested for mono, as this is standard proceedure. I told them I had tried for for 6 months to get her to test him, she refused. They said giving chemo to a patient with mono is the worst thing you could do. He died from hemolitic anemia, which is a side effect of mono. This wouldn't happen to an uncomprimized patient, but the chemo took away his ability to fight it.

I have an attorney. Which in my opinion is why I cannot get decient care. Doctors don't want a patient that might possibly sue, no matter how justified it may be.

So I live in limbo, unable to see a neuro. I am awaiting to here from my councilor on the 20th as to who's decision this is, my PCP or the insurance.
Pat
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agate
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PostPosted: Sat Jul 15, 2006 11:28 am    Post subject: Reply with quote

What a terrible trauma you must have had, and recently too!

You must have been overwhelmed. Maybe by now you'll have gathered the strength to fight for your right to decent medical care.

I've heard that doctors back off from new patients if they think they might sue--and having a lawyer and being involved in a medically related lawsuit, you just might have raised some red flags.

I suppose you could just keep trying doctors until you find one who isn't such a scaredycat.
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PostPosted: Sat Jul 15, 2006 12:55 pm    Post subject: Reply with quote

Agate, my husbands records were in the legal department at the hospital before I even contacted a attorney. It took him 7 months to get them released, and still we don't have them all.

I am denied to see a neuro, I'll just have to wait. Maybe if I get bad enough they might listen.

I have been going through this fight so long, it is tireing. I have many things documented by testing, but no one will look at them and figure out what is going on. I am going to switch my insurance next March when new enrollment comes up. I'll just have to chill for now.

It was rough. I started in an ?attack shortly before things started happening with him, it was bad, and lasted 5 1/2 months. I was falling, pissing and craping on myself, didn't know my own phone # that I had for 30 years. I kept getting lost driving got in an accident, was robbed. Lost part of my vision, it still hasn't all returned, and I've had double vision for over a year now. ( it took 7 months to convince them to let me see an ophtho)
My head rings 24/7, 3 types of tremors, lesions showing progression of a demyelinating brain disease, MBP of 21, Barium swallow test show dsyphasia to liquids and solids, I go back to the gastro Monday. I've lost the ability to swallow 7 times now. Awh geeze I can't even remember everything. And with that a MS specialist that just looked at my MRI's tells me I am perfectly healthy, I don't have any problems and probably never will. (asshole) He wouldn't read my reports either.

Red flagged YOU BET! nothing I can do about it though. I just want to get that bitch of a doctor and send her back to India. I know many of her patients, you get to know them when you live at a hospital round the clock for a month. The stories I could tell, and they aren't good.

Thankfully I got a bit better when he got his worst and died, it was an intervention as far as I'm conserned, by a higher power.
I am just waiting to find out from that higher power why this all happened, and what good can come from it. I'll know some day.
Thanks girl,
Pat
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PostPosted: Thu Aug 24, 2006 2:15 pm    Post subject: Abstract from PubMed: Reply with quote

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Rev Med Virol. 2006 Jul 11

Multiple sclerosis is linked to Epstein-Barr virus infection.

Haahr S, Hollsberg P.
Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark.

The aetiology and pathogenesis of MS are unknown, but environmental agents, genetic susceptibility and stochastic events are likely to be involved.

In order to evaluate the possibility that MS is linked to EBV infection, we here evaluate studies on MS- and EBV-epidemiology, prospective and retrospective analysis of EBV-serology, investigations of EBV DNA sequences in blood and tissues, specificity of antibodies in oligoclonal bands in MS patients and results from antiviral chemotherapy of MS patients. It could be demonstrated that EBV is complying with the epidemiological observations in MS and that all MS patients are seropositive to EBV in contrast to healthy controls. Importantly, despite difficulties in diagnosing child-MS, the vast majority of these patients are also EBV seropositive. In contrast to control groups, recent EBV infections have never been observed in children or adults with MS.

Further prospective studies indicate a 2.8 times higher tendency for development of MS after infectious mononucleosis. In MS patients, unbiased analyses pull out EBV antigens as high-affinity targets for the antibodies in the oligoclonal bands.

Humans are the exclusive natural host for EBV, a finding that may explain why MS is unique to humans.

Together these unique observations strongly suggest a linkage between MS and EBV infection. Infection by EBV offers numerable mechanisms to perturb the immune system, including mimicry and superantigen induction, which may potentially participate in the disease mechanisms.

In contrast, studies demonstrating higher IgG titres and occurrence of viral DNA in serum/plasma are likely to reflect a consequence of the disease. An explanation for a potential role of respiratory diseases in MS is discussed.

It is concluded that the ultimate test to the hypothesis of MS and EBV is the development and application of an EBV vaccine, which is predicted to eradicate the disease.


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Matt



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PostPosted: Thu Aug 24, 2006 3:32 pm    Post subject: Reply with quote

Pat, you have been through the hardest stuff ever. OMG. I suspect I would never recover from that experience, but I sure hope you do. It's amazing how many incompetent doctors there are out there.
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Matt



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PostPosted: Thu Aug 24, 2006 3:33 pm    Post subject: Re: Abstract from PubMed: Reply with quote

agate wrote:

It is concluded that the ultimate test to the hypothesis of MS and EBV is the development and application of an EBV vaccine, which is predicted to eradicate the disease.

bounce bounce bounce bounce
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Matt



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PostPosted: Sat Aug 26, 2006 5:52 pm    Post subject: Reply with quote

Archives of neurology 2006

Quote:

Epstein-Barr Virus and Multiple Sclerosis
[Editorial]
Lovett-Racke, Amy E. PhD; Racke, Michael K. MD

Correspondence: Dr Racke, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 (michael.racke@utsouthwestern.edu).
Funding/Support: The authors are supported by grants NS37513 and NS44250 from the National Institutes of Health and by grant RG-3490-A-9 from the National Multiple Sclerosis Society. Dr Lovett-Racke is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society.
ALTHOUGH THE CAUSE OF MULTIPLE SCLErosis (MS) is unknown, clinical and pathologic evidence strongly suggest a link between an infectious agent and an autoimmune response directed against myelin. 1–3 Epidemiologic studies also have implicated an environmental factor, most likely an infectious agent, as a necessary element in the development of MS. 2 One possibility is that antigens from infectious pathogens may activate autoreactive T cells, causing them to expand and leading to clinical autoimmune disease. 4,5 However, molecular mimicry (as this process is termed) has found limited empirical support as a general mechanism to explain the origin and course of a broad range of autoimmune diseases. Another possibility is that rather than there being a specific pathogen causing MS, infections in and of themselves may be able to aggravate autoimmune processes. For example, infectious processes such as Chlamydia pneumoniae can activate antigen-presenting cells and consequently activate autoreactive T cells that do not cross-react with chlamydial antigens. 6 The diversity of infectious agents associated with onset or exacerbation of clinical MS, the difficulty in identifying pathogen-associated antigens that activate autoreactive T cells, and the demonstration that antigen-presenting cell activation by infection can trigger an autoimmune response all suggest that the role of infection in autoimmunity may not be specific to a particular pathogen.

Epstein-Barr virus (EBV) is a pathogen that has been associated with the pathogenesis of MS. The titer of antibodies directed against EBV are higher in patients with MS than in control subjects. 7 While almost all patients with MS are seropositive for EBV, about 10% of the general population is seronegative for the virus. Patients with MS are more likely to have had a history of mononucleosis than people who do not develop the disease. In addition, children who develop MS can be distinguished from control subjects by higher immunoreactivity to EBV but not to other common viral pathogens. 8 A similar observation was made in donors who later went on to develop MS. 9 Another possible indicator of EBV in the pathogenesis of MS is the observation that there is an increase in EBV DNA levels in the blood of patients with MS during relapse. 10

Recent studies have used sophisticated molecular techniques to implicate EBV in the pathogenesis of MS. One common observation in MS is the development of oligoclonal antibodies in the cerebrospinal fluid. One such study screened the oligoclonal antibodies from patients with MS on protein expression arrays and demonstrated that the most frequent MS-specific reactivities were identified as EBV proteins, including the Epstein-Barr nuclear antigen (EBNA-1). 11 Interestingly, CD8+ T cell responses were also examined to the latent EBV proteins and were found to be higher in patients with MS than in controls.

In this issue of the ARCHIVES, DeLorenze and colleagues 12 studied the levels of anti-EBV antibodies in blood specimens collected up to 30 years prior to the onset of MS. The antibody titers to both the Epstein-Barr nuclear antigen complex and EBNA-1 were significantly higher in patients with MS compared with matched controls. A 4-fold increase in antibody titers for the EBNA complex increased the relative risk for MS by 2.1 and for EBNA-1 by 1.8. This prospective study with a 30-year follow-up period suggests that elevation of EBV antibody titer could be a very early event in MS.

Keeping the previously mentioned results in mind, how can EBV participate in MS pathogenesis? One possibility is that the virus could persist in the central nervous system and become reactivated at times of disease activity. Glia cells can express the EBV entry receptor and can be infected with the virus; however, EBV messenger RNA has not been detected in MS lesions. 13 Another possibility is that infected B cells could spread the virus to the central nervous system and that a local antiviral immune response could contribute to establishing inflammation in the central nervous system.

Another potential scenario hypothesizes that EBV-infected peripheral B cells may trigger an immune response against the virus that may trigger a cross-reactive autoimmune response against central nervous system antigens (molecular mimicry). Reactivation of the virus could expand both the T-cell and antibody response against the virus. Because of the life-long persistence of EBV in infected individuals and its potential for several rounds of reactivation, we can envision a scenario where this cross-reactive autoimmune response can be stimulated for decades before eventually eliciting the clinical signs of MS. The present study gives credence to this hypothesis by demonstrating the presence of high anti-EBV titers decades before the clinical appearance of MS. Interestingly, decades are not always required as noted by the observation that even pediatric patients with MS can have elevated titers of EBV. 8

As researchers solidify the link between EBV and MS, important questions still remain. If many individuals can harbor EBV and make an immune response against the virus, what are the mechanisms that result in disease initiation and progression? Furthermore, would patients with MS who make an immune response against EBV that cross-reacts with myelin antigens benefit from strategies that alter the latency of EBV or the immune response against the virus? These are questions that remain to be answered and could address the fundamental role of infections in autoimmunity. Until that time, the current data suggest that EBV is one of many pathogens that has the potential to increase an individual's susceptibility to developing MS.

Amy E. Lovett-Racke, PhD

Michael K. Racke, MD

REFERENCES
1. Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature. 1999;399:40–47. [Context Link]

2. Kurtzke JF. Epidemiologic evidence for MS as an infection. Clin Microbiol Rev. 1993;6:382–427. Bibliographic Links [Context Link]

3. Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR. From infection to autoimmunity. J Autoimmun. 2001;16:175–186. Bibliographic Links [Context Link]

4. Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987;50:819–820. Bibliographic Links [Context Link]

5. Hausmann S, Wucherpfennig KW. Activation of autoreactive T cells by peptides from human pathogens. Curr Opin Immunol. 1997;9:831–838. Full Text Bibliographic Links [Context Link]

6. Sriram S, Stratton CW, Yao S, et al. C. pneumoniae infection of the CNS in MS. Ann Neurol. 1999;46:6–14. Bibliographic Links [Context Link]

7. Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology. 2000;11:220–224. Ovid Full Text Bibliographic Links [Context Link]

8. Alotaibi S, Kennedy J, Tellier R, et al. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004;291:1875–1879. Ovid Full Text Bibliographic Links [Context Link]

9. Hernan MA, Zhang SM, Lipworth L, et al. Multiple sclerosis and age at infection with common viruses. Epidemiology. 2001;12:301–306. Ovid Full Text Bibliographic Links [Context Link]

10. Ferrante P, Omodeo-Zorini E, Zuffolato MR, et al. Human T-cell lymphotropic virus tax and Epstein-Barr virus DNA in peripheral blood of multiple sclerosis patients during acute attack. Acta Neurol Scand Suppl. 1997;169:79–85. Bibliographic Links [Context Link]

11. Cepok S, Zhou D, Srivastava R, et al. Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest. 2005;115:1352–1360. Ovid Full Text Bibliographic Links [Context Link]

12. DeLorenze GN, Munger KL, Lennette ET, et al. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol. 2006;63:839–844. Ovid Full Text Bibliographic Links [Context Link]

13. Menet A, Speth C, Larcher C, et al. Epstein-Barr virus infection of human astrocyte cell lines. J Virol. 1999;73:7722–7733. Bibliographic Links [Context Link]

Epstein-Barr Virus see Herpesvirus 4, Human; Herpesvirus 4, Human; Multiple Sclerosis


Last edited by Matt on Sat Aug 26, 2006 5:59 pm; edited 1 time in total
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Matt



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PostPosted: Sat Aug 26, 2006 5:54 pm    Post subject: Reply with quote

Archives of Neurology 2006

Quote:

Epstein-Barr Virus and Multiple Sclerosis: Evidence of Association From a Prospective Study With Long-term Follow-up
[Original Contribution]
DeLorenze, Gerald N. PhD; Munger, Kassandra L. MSc; Lennette, Evelyn T. PhD; Orentreich, Norman MD; Vogelman, Joseph H. DEE; Ascherio, Alberto MD, DrPH

Kaiser Permanente Division of Research, Oakland, Calif (Dr DeLorenze); Departments of Nutrition (Dr Ascherio and Ms Munger) and Epidemiology (Dr Ascherio), Harvard School of Public Health, and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School (Dr Ascherio), Boston, Mass; Virolab Inc, Berkeley, Calif (Dr Lennette); Orentreich Foundation for the Advancement of Science Inc, New York, NY (Drs Orentreich and Vogelman).
Correspondence: Alberto Ascherio, MD, DrPH, 665 Huntington Ave, Boston, MA 02115 (aascheri@hsph.harvard.edu).
Author Contributions: Study concept and design: DeLorenze, Orentreich, Vogelman, and Ascherio. Acquisition of data: DeLorenze, Munger, Lennette, Orentreich, Vogelman, and Ascherio. Analysis and interpretation of data: DeLorenze, Munger, and Ascherio. Drafting of the manu1: DeLorenze, Munger, and Ascherio. Critical revision of the manuscript for important intellectual content: DeLorenze, Munger, Lennette, Orentreich, Vogelman, and Ascherio. Statistical analysis: DeLorenze and Ascherio. Obtained funding: Ascherio. Administrative, technical, and material support: Munger, Lennette, Orentreich, Vogelman, and Ascherio. Study supervision: DeLorenze and Ascherio.
Funding/Support: This study was supported by grant NS43604 from the National Institute of Neurological Disorders and Stroke and by a pilot grant from the National Multiple Sclerosis Society.
Acknowledgment: We thank Allen Bernstein, MD, chief of neurology at Kaiser Permanente Santa Rosa Medical Center, Santa Rosa, Calif, for providing consultation and advice during the initial MS case confirmation reviews. We also thank Steven Black, MD, for providing the MS chart abstraction forms, and Alice Jacobson (Kaiser Permanente Division of Research) for her data processing efforts in matching OFAS serum treasury specimens to Kaiser Permanente patients and in the selection of study controls. We thank Elsa Jiménez and Eilis O'Reilly for their technical assistance and Nancy P. Durr at OFAS for her editorial critique.
Published Online: April 10, 2006 (doi:10.1001/archneur.63.6.noc50328).
Accepted for Publication: October 7, 2005.
Abstract
Objective: To determine whether serum titers of anti–Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS).

Methods: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls.

Results: The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1–3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1–2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter.

Conclusion: The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.


--------------------------------------------------------------------------------


EPIDEMIOLOGIC EVIDENCE OF changes in risk among migrants clearly implicates exogenous factors in the etiology of multiple sclerosis (MS), 1 but the nature of these factors remains uncertain. During the past 2 decades, results of numerous studies have suggested a possible role for the Epstein-Barr virus (EBV). In a meta-analysis, EBV-infected individuals were found to have greater than a 10-fold higher risk of developing MS than EBV-seronegative individuals. 2 A similar result has recently been found in children, which virtually rules out genetic susceptibility to EBV infection as a sufficient explanation of these serologic findings. 3 Further, increased anti-EBV antibody titers have been reported as long as 10 years prior to the first symptoms of MS. 4,5 To confirm and extend these findings, we undertook a prospective serologic study of EBV infection from serum samples collected up to 30 years before the clinical diagnosis of MS among patients and matched controls in a large integrated health plan. This is the first MS-EBV investigation to use a prospective study design with a very long period of follow-up.

METHODS
This study has been approved by the Human Subjects Committees of the Harvard School of Public Health, Boston, Mass, and the Kaiser Foundation Research Institute, Oakland, Calif. The sponsors of the study had no role in the study design, in the collection, analysis, and interpretation of the data, or in the writing of the article and the decision to submit it for publication.

STUDY POPULATION
The study population was composed of patients who were members of the Kaiser Permanente Northern California (KPNC) health plan and participated in the multiphasic examinations administered between 1965 and 1974. As a fully integrated health plan, KPNC currently provides inpatient and outpatient medical care to more than 3 million members in northern California. During the multiphasic examinations, new members were asked to provide a blood specimen and answer a questionnaire on health background and medical risk behaviors. More than 100 000 new KPNC members provided blood specimens that were processed and stored as sera frozen at - 20°C. These sera were retained by KPNC until 1979, when they were transferred to the serum treasury of the Orentreich Foundation for the Advancement of Science (OFAS) in Cold Spring-on-Hudson, NY, for cataloging and indefinite frozen storage at - 40°C.

Kaiser Permanente Northern California has maintained medical records of all members who provided serum specimens and who were KPNC members for all or some of the time between the administration of the multiphasic examination and 1999 (maximum time period, 1965–1999). Kaiser Permanente Northern California began computerizing inpatient hospitalization data in 1984 with the establishment of an admission, discharge, and transfer (ADT) hospitalization database. All outpatient encounters at KPNC hospitals, medical centers, and medical offices are stored electronically in a database called the outpatient summary clinical record (OSCR). The database, which was created in 1993 and implemented in all facilities by December 1994, uses more than 40 different optically scannable medical specialty-specific forms. The appropriate OSCR form is generated at the time of registration and contains a check-off list for the most commonly used diagnoses and procedures. The data in the OSCR contains, but is not limited to, medical record number, registration information, and procedure/diagnosis codes for each outpatient encounter. International Classification of Diseases, Ninth Revision, Clinical Modification and Current Procedural Terminology, Fourth Revision codes were used for diagnoses and procedures.

CASE ASCERTAINMENT AND CONTROL SELECTION
In the current study, during the years between 1995 and 1999, both the ADT and OSCR were searched for evidence of medical coding that would indicate a potential diagnosis of MS among active KPNC members. More than 2000 potential MS cases were identified and then linked to the OFAS serum treasury specimen database. The results of this linkage indicated that 93 potential MS cases had stored serum specimens. Manual review of medical records using an abstraction instrument designed for the Centers for Disease Control and Prevention's Demyelinating Diseases Study 6 was undertaken to confirm the MS diagnosis for the 93 potential cases. A medical records analyst recorded dates of MS diagnosis (including optic neuritis or transverse myelitis), dates and duration of neurologic symptoms (eg, transient scanning speech, Bell palsy, Lhermitte sign, tic douloureux, tonic seizures), dates and interpretation of brain magnetic resonance images, cerebrospinal fluid IgG concentrations, cerebrospinal fluid oligoclonal bands, and other criteria used to make a diagnosis. Of the 93 potential MS cases, 72 received diagnostic confirmation of MS made by a neurologist and were considered eligible for the study. Onset date was set as the earliest date of any symptom attributable to MS as described by Poser, 7 or a diagnosis of optic neuritis. Onset date was determined for 58 cases, 46 of whom had a serum sample collected before onset. Cases with unknown date of MS onset were excluded from all analyses. The clinical course of MS at the time of the latest clinical assessment was progressive for 26 members (57%), relapsing-remitting for 7 (15%), and other or unknown for 13 (28%). Most individuals with progressive MS were probably in the secondary progressive phase of relapsing-remitting MS, but the information on the medical records was often insufficient to distinguish a primary (typically accounting for only 10% of all cases) from secondary progressive course, and therefore this distinction was not made in the analyses.

For each case, 3 controls were selected from the serum treasury database and matched by age at the time of blood collection (± 1 year), by sex, and by date of blood collection. All controls were active members of KPNC on the date of onset of their matched case and between 1995 and 1999, and showed no evidence of receiving an MS diagnosis in the ADT and OSCR databases between 1995 and 1999. For laboratory analyses, 2 of 3 control specimens matched to an MS case were randomly selected. If 1 of 2 control specimens proved to be inadequate (ie, insufficient or desiccated sample), the third specimen was substituted.

Demographic data for cases and controls (age, sex, race/ethnicity) were obtained from the KPNC patient demographics computerized database, the ADT, and the multiphasic examination. During the multiphasic examination, clinicians classified individuals based on their perception of a new member's race; this classification was related to the subgroups white, black, Asian, and other race. Although some new members may have mentioned their race/ethnicity during the examination, KPNC routine practice during 1965 to 1974 did not include asking new patients to identify their race/ethnicity. However, this classification has high concordance among a subgroup of individuals in our study who were asked to self-report their race/ethnicity at a later visit, usually at the time of a hospital admission (whites, 93%; blacks, 83%; Asians, 100%). Although clinicians may have misclassified some members based on personal perception, we felt that the information was preferable to having no race/ethnicity information for a given patient.

LABORATORY ANALYSES
Serum samples for cases and controls were aliquotted into cryovials at OFAS for overnight shipment to Virolab Inc (Berkeley, Calif) in triplets of 1 case and 2 matched controls in random order. Staff at OFAS and Virolab were blinded to case-control status and unidentified triplets were included as assay quality controls.

Immunoglobulin G and IgA antibodies to EBV viral capsid antigen (VCA) and IgG to anti–early antigen complex (diffuse and restricted) were determined by indirect immunofluorescence. 8 The IgG antibodies against the Epstein-Barr nuclear antigen (EBNA) complex and 2 of its individual components, EBNA-1 and EBNA-2, were determined using anticomplement immunofluorescence. 9 Immunoglobulin G antibody titers against cytomegalovirus (CMV) were also determined to assess the specificity of any association found between MS and EBV serology. 10 The intra-assay coefficients of variation were less than 5% for VCA IgG and IgA, diffuse early antigen, restricted early antigen, and EBNA-1; the coefficients of variation were 17.8% for the EBNA complex, 8.3% for EBNA-2, and 12% for CMV.

STATISTICAL ANALYSIS
Geometric mean antibody titers (reciprocal of the dilution) in cases and controls were compared using generalized linear models. 11 Subjects with missing values for any of the covariables were excluded from the analyses.

To account for matching, we used conditional logistic regression to estimate the relative risk of MS associated with a 4-fold increase in antibody titers. 4 Under the design of our study, these relative risks estimate the corresponding incidence rate ratios. Unconditional logistic regression was also used in analyses including all controls (matched and unmatched) to increase power. These analyses also included controls originally matched to cases excluded from the analyses because of missing serum samples before baseline (n = 132). All statistical tests were 2-sided, and P values of less than .05 were considered statistically significant. Point estimation was via maximum likelihood; statistical tests were based on the likelihood ratio statistic and Wald confidence intervals. 12 Statistical analyses were conducted using SAS statistical software (version 8.0; SAS Institute Inc, Cary, NC).

RESULTS
We excluded from analyses 4 seronegative (VCA <10) cases, 8 controls matched to these cases, and all seronegative controls. Table 1 lists the demographic characteristics of the remaining 42 MS cases and 79 controls. The median age at onset of MS was 45 years (mean ± SD, 46 ± 11 years; range, 24–69 years) and the median time between baseline blood collection and onset of MS was 15 years (mean ± SD, 15 ± 8.9 years; range, <1-32 years).



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[Email Jumpstart To Image] Table 1. Selected Demographic and Clinical Characteristics of MS Cases and Controls*

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Geometric mean titers of EBV and CMV antibodies in cases and controls are presented in Table 2. Geometric mean titers to the EBNA complex and to EBNA-1 were significantly higher among MS cases when compared with matched controls (P = .007 and P = .01, respectively) and when compared with all controls (P = .001 and P = .004, respectively). Geometric mean titers to EBNA-2 were not significantly higher among MS cases when compared with matched controls, but were significantly elevated when compared with all controls. Geometric mean titers for IgG to EBV VCA, IgA to EBV VCA, IgG to anti–early antigen (diffuse and restricted), and CMV were not significantly elevated in MS cases. The relative risks of developing MS associated with a 4-fold increase in EBV and CMV antibody titers are presented in Table 3. Significantly elevated relative risks were observed for the EBNA complex and EBNA-1 antibodies in analyses including only matched controls or all controls. Excluding cases with onset at age 60 years or later (n = 4) did not materially change these results.



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[Email Jumpstart To Image] Table 2. Geometric Mean Titers of EBV/CMV Antibodies for MS Cases With Blood Collected Before Onset and Matched/All Controls*

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[Email Jumpstart To Image] Table 3. Relative Risk Associated With a 4-fold Increase in Titers of Antibodies to EBV and CMV in MS Cases With Blood Collected Before Onset and Matched/All Controls*

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To examine temporal relationships between antibody responses to EBV and MS onset, we plotted the mean of anti-EBNA titers in MS cases as a percent of their matched controls' means by the time between blood collection and MS onset. Elevations in both the anti-EBNA complex and anti–EBNA-1 titers among the cases became evident between 15 and 20 years before the first onset of neurological symptoms of MS and remained constant thereafter (Figure).



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[Email Jumpstart To Image] Figure. Mean Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 IgG titers among multiple sclerosis (MS) cases as percentage of mean control titers by time of blood collection in years, excluding Epstein-Barr virus–negative cases and controls. Asterisks indicate that P value is less than or equal to .05 (paired t test comparing mean levels of EBNA-1 in cases and matched controls). Daggers indicate that 2 cases and 1 control were excluded because EBNA titers could not be determined (an aspecific reaction in indirect immunofluorescence assay). Controls matched to the 2 cases with missing EBNA titers were also excluded.

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COMMENT
The main finding of our study is that serum antibody titers to the EBNA complex and EBNA-1 in individuals with MS were increased up to 20 years before the first symptoms of the disease and then remained constant over time. It is important to note that this finding was obtained in a population with an unusually late age at MS onset, and as discussed in the following section, may not apply to individuals with MS onset at younger ages. The temporal relationship between changes in anti-EBV antibody titers and the onset of MS can be better understood by considering jointly the results of our study and those of the following 3 previous prospective investigations: the Nurses' Health Study, the study conducted among US Army personnel, 5 and the study in Vasterbotten County, northern Sweden.

In each cohort, significant elevations in antibodies to the EBNA complex or EBNA-1 were found in serum or plasma collected several years before the onset of MS symptoms. Changes in antibody titers to other EBV antigens (VCA, EBNA-2, and early antigens) were more variable across the studies. The consistency of results for the EBNA complex and EBNA-1 is quite striking considering the markedly different age and ethnic composition of the study populations. Similar to our study, the Nurses' Health Study mostly included individuals with late age at MS onset (median, 52 years; range, 39–66 years) and EBV antibody titers were measured in samples collected between several months before the onset of MS up to several years after MS onset; the mean age at blood collection was 49 years (range, 34–65 years). The anti-EBNA complex and anti–EBNA-1 titers were significantly elevated in plasma collected before the onset of MS and did not change significantly after MS onset. 4 In the study of US Army personnel, which included a much younger population (mean age at MS onset, 27 years; range, 18–41 years; mean age at baseline blood collection, 24 years; range, 17–39 years), repeated samples (up to 3 per subject) were collected between 1 and 11 years before MS onset. 5 Serum titers of antibody to the EBNA complex and EBNA-1 in individuals who later developed MS increased sharply in early adulthood—from means similar to those of controls at younger than 20 years to means 2- to 3-fold higher at age 25 years—and remained constant thereafter. 5 Finally, in the Vasterbotten study, blood samples were collected at a median of 7 years before MS onset. The median age at blood collection was 28 years (range, 17–59 years) and the median age at MS onset was 34 years (range, 22–65 years). 13 A significant association between anti–EBNA-1 titers and risk of MS was already present in samples collected more than 5 years before MS onset, but became more pronounced in the 5-year period preceding MS onset. This strengthening of the association could be explained by an increase in antibody titers in early adulthood, as seen in the US Army study, because individuals with MS with blood collected more than 5 years before onset were presumably younger than those with blood collected soon before onset. Although an increase in EBV antibody titers is observed in other EBV-related conditions, a specific increase in anti–EBNA-1 and the anti-EBNA complex without a concomitant increase in anti-VCA is unique to MS and is consistent with the hypothesis of T-cell hyperreactivity because anti–EBNA-1 titers are positively correlated with T-cell function. 14

Overall, the results of these studies are consistent with the hypothesis that elevations in the anti-EBNA complex and anti–EBNA-1 titers in individuals who develop MS occur in the late teenage years or early 20s and may precede the time of onset of MS symptoms by 10 years or more. This hypothesis needs to be tested in further studies including teenagers and young adults. In the current study, only 2 individuals with MS had blood drawn before the age of 20 years; therefore, we could not examine changes in antibody titers in this age range. If confirmed, this finding would indirectly support the concept of an age of vulnerability for the acquisition of MS, which according to Kurtzke, 15 would start at puberty and end in early adulthood.

A critical question is what causes the increase in the anti-EBNA complex and anti–EBNA-1 titers in early adulthood? Two possibilities deserve careful consideration. One possibility is that the triggering event is an infection with a separate microorganism that alters the host-EBV balance, perhaps by activating EBV-specific memory T-cells (heterologous T-cell immunity). 16 The other possibility is reinfection with a strain of EBV different from that originally carried by the host. Two types of EBV circulate in human populations and they are identified as type 1 (or type A) and type 2 (or type B). 17 Type 1 EBV predominates in the United States and Europe, 18 but infection with type 2 is not uncommon. Other substantial variations exist in the EBV genotype, which are probably caused by genetic evolution influenced by HLA-restricted EBV-specific cellular immunity. 19 Munch et al 20 have recently reported that individuals with MS in a small Danish cluster (n = 8) were infected with a single subtype of EBV. No other investigations have addressed the possible role of EBV genetic variations in MS. Several variations may influence functions that are critical for the viral life cycle and hence are likely to be relevant for the pathogenesis of EBV-associated diseases, or they may result in mutations in highly immunogenic peptide epitopes and thus influence the T-cell mediated immune response to EBV infection. There is growing evidence that coinfection with multiple EBV strains, either acquired sequentially or simultaneously, is common even in healthy subjects, 21 but little is known about the serologic response or other consequences of reinfection/coinfection.

Although the epidemiologic evidence indicating that people with elevated titers of antibodies directed against the EBNA complex and EBNA-1 are at greater risk of developing MS is compelling, the mechanisms underlying this association are uncertain. 4 A hypothesis that is gaining increasing support is that EBV infection in genetically susceptible individuals activates T-lymphocytes that cross-react with myelin antigens, 22–24 but other mechanisms have been proposed, such as cross-reacting antibodies, 25 infection of autoreactive B lymphocytes, 26 the activation of superantigens, and an increased expression of [alpha]B-crystallin. 27 Recently, 2 EBV peptides, one of which is from EBNA-1, have been identified as targets of the immune response in the cerebrospinal fluid of patients with MS. 28 The mounting evidence that relates EBV infection to other autoimmune diseases, particularly systemic lupus erythematosus, 29 suggests that EBV may have a broad role in predisposing to autoimmunity. A comparative investigation of individuals with systemic lupus erythematosus and MS may provide new clues to their possible commonalities. A fine understanding of the mechanisms that connect EBV infection to MS is important because it will provide the basis for the translation of this epidemiologic finding into new ways to treat and prevent MS.

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Epstein-Barr Virus see Herpesvirus 4, Human; Herpesvirus 4, Human; Multiple Sclerosis
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