Published: Jan 14, 2014
By Nancy Walsh, Staff Writer, MedPage Today

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Full Story:  http://www.medpagetoday.com/Rheumatology/GeneralRheumatology/43797

Action Points

A common viral infection and its subsequent immunologic machinations and manifestations may help explain why, in some individuals, the immune system turns against itself in the potentially devastating process of autoimmunity.

It’s long been suspected that viral infections may serve as the trigger for autoimmune disease, and a potential link between autoimmunity and Epstein-Barr virus (EBV) was first proposed in The Lancet in 1971, following the observation that patients with systemic lupus erythematosus had increased levels of antibodies to this virus.

But EBV, also known as human herpesvirus 4, is near-ubiquitous, being present in some 90% to 95% of adults following initial infection via the oral and nasal epithelial tissues and residing in a lifelong latent state in B cells.

The strongest evidence has been for MS and lupus, where positive serology for EBV has been detected in more than 99% of patients. But the fact that patients are seropositive suggests only that prior infection is required for the development of disease.

Other factors also must be in play, and researchers from around the globe have been piecing together this complicated epidemiologic and molecular puzzle….

B Cells and Friendly Fire

A decade ago, Michael P. Pender, MD, PhD, of the University of Queensland in Australia published a paper in which he hypothesized that chronic autoimmune diseases result from the infection of autoreactive B lymphocytes by EBV.

“Here, I propose a novel hypothesis that is based primarily on the unique ability of EBV to infect, activate, and latently persist in B lymphocytes, including autoreactive B cells, and that incorporates the known association of different autoimmune diseases in individuals and among family members,” he wrote in Trends in Immunology.

He noted that a sizable body of epidemiologic evidence existed suggesting that EBV infection was a prerequisite for the development of both lupus and multiple sclerosis — two quite different autoimmune diseases.

“Most people who were interested in this concept thought the connection was through molecular mimicry, whereby a person would mount an immunologic response to components of EBV that resembled structures in the brain in MS or anti-double stranded DNA or other lupus antigens for lupus. This immune response intended to control EBV then by ‘friendly fire’ could lead to organ damage,” Pender told MedPage Today.

However, he believed there was more to it, because if molecular mimicry were the sole mechanism, other infections should be able to lead to this process — and EBV was the only pathogen that was universally associated with both MS and lupus, he explained.

“So there’s something unique about EBV’s role as a microbial agent,” he said. And that, it turned out, was that EBV is the only human virus that can activate and survive in B cells, inducing clonal expansion and inhibiting apoptosis. Moreover, those B lymphocytes are precursors of the plasma cells that make antibodies characteristic and pathogenic in autoimmune disease.

A Viral Strategy

Humans and EBV have evolved together for thousands of years, according to Marc S. Horwitz, PhD, of the University of British Columbia in Vancouver.

“The way the virus has learned to survive is to infect us and stay hidden inside a subset of cells for the remainder of our lives,” Horwitz said in an interview.

But the cells this virus adapted to live in, B cells, are a poor host in some ways, he said. This is because B cells turn over rapidly and often, unlike many other tissues in the body.

“So the strategy EBV has developed to keep its host B cell alive but latent and hidden from attack by the immune system is by constantly poking the immune system’s low level interferon response, which is akin to keeping the immune system on the edge of its seat and ready to pounce,” said Horwitz, who is co-leader of the university’s infection, inflammation, and immunity program.

In that hyperalert state, when the immune system detects a new threat its response could be excessive, which could push the individual over the edge into autoimmunity, he explained.

The T-Cell Connection

Many epidemiologic studies have found a strong familial component in autoimmune diseases. In a healthy host, EBV infection is tightly controlled by a subset of cytotoxic CD8+ cells, which destroy the infected cells. As Pender continued his research, he then suggested that this genetic component could be an inherited deficiency of CD8+ cells.

“Since 1980 it has been recognized that the proportion and number of CD8+ T cells in the peripheral blood are decreased and that the CD4/CD8 ratio is increased,” factors that are under genetic control, he noted.

When an individual with that genetic background is infected with EBV, a greater number of B cells harboring the virus will remain in the circulation, he said. And because 20% of B cells are autoreactive, those cells could begin making potentially pathogenic antibodies that then traffic throughout the body, lodging in target organs and, in turn, producing target-specific antibodies.

His expanded hypothesis, published in 2012 in Autoimmune Diseases, proposed “that, in genetically susceptible individuals, EBV-infected autoreactive B cells seed the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis.”

Age Matters

In the developing world, EBV infection is almost universal by 3 years of age, and is largely asymptomatic and lacking in clinical consequences. However, in the developed world early life exposure is less common because of improved hygiene, and in Denmark, for example, at least half of children haven’t been infected by age 10, according to Pender.

And when infection doesn’t occur until adolescence, it’s typically much more severe, manifesting as infectious mononucleosis. The reason for this, he explained, is that healthy people have three times as many CD8+ T cells at age 2 years than at 15. Therefore, when a person already has a genetically determined deficiency in these cells and exposure occurs after the age-related CD8+ T cell decline, the autoimmune cascade can ensue.

Another contributory factor is location. “It has long been known that the further people live from the equator the more likely they are to get MS, and it seems the same may apply to rheumatoid arthritis and type 1 diabetes,” Pender said.

“And we now know that if you give an extra hour of sunlight a day to a person for 2 weeks, you can increase their number of CD8+ T cells by about 35%, at least some of which occurs through the action of vitamin D,” he said.

Sex also matters. Females tend to have lower numbers of CD8 T cells than CD4 T cells, which is thought to be hormonally regulated, and females are predominantly affected in the majority of autoimmune diseases, he pointed out.

Assessing the Evidence

Even in the latent state in B cells, EBV continues to express a limited number of virus-specific proteins, and a number of studies have sought to confirm a virus-autoimmunity link by quantifying those proteins, but the findings have been unclear because of small numbers.

Therefore, a group of researchers from the University of Aberdeen in Scotland led by Mark A. Vickers, MBChB, performed a systematic literature review and meta-analysis in which they combined the results from 25 case-control studies to provide a larger body of evidence, specifically for lupus.

In 15 of the studies included in the analysis, data were available on the frequency of seropositivity to antibodies to EBV viral capsid antigens (anti-VCA).

The overall prevalence of these antibodies in patients with lupus was 95% compared with 88.7% among controls, which gave an statistically significant odds ratio of 2.08 (95% CI 1.15-3.76, P=0.02), Vickers and colleagues recently reported online in Arthritis Research & Therapy.

Data on early antigen (EA) IgG antibodies were included in seven studies. In these, there was a significant association between EA antibodies and lupus, with an odds ratio of 5.76 (95% CI 3-11.6, P<0.00001).

In addition, four studies included assays of anti-VCA IgA, which showed an odds ratio of 5.05 (95% CI 1.95-13.13, P=0.0009).

The authors noted that there was considerable heterogeneity and variation in quality in the studies they analyzed, and advised that the results be interpreted with caution.

Nonetheless, they concluded, “These findings support the hypothesis that prior infection with EBV is important in the development of SLE, as indicated by a higher seroprevalence of anti-VCA IgG.”

Further evidence also was recently demonstrated by a group of European researchers who found active infection of autoreactive plasma B cells in the synovium of patients with rheumatoid arthritis.

In experiments using immunohistochemistry, indirect immunofluorescence, and real-time PCR analysis of tissue samples from 43 patients with rheumatoid arthritis, researchers led byCostantino Pitzalis, MD, from the William Harvey Research Institute in London found abnormal EBV infection in ectopic lymphoid structures (ELS) of the joints.

“Our study supports a complex role for EBV in [rheumatoid arthritis] pathogenesis through its ability to establish a persistent infection in autoreactive B cells that expand and differentiate in synovial ELS, stimulate production of antibodies to citrullinated and unmodified EBV antigens and, possibly, induce an immunopathological response,” they observed in Annals of the Rheumatic Diseases.

But none of this means that EBV causes lupus, MS, or rheumatoid arthritis. “No specific infectious agent directly causes immunity,” Horwitz cautioned. “It’s not like influenza where we can track it, or like every newly emerging virus such as HIV or SARS that we’ve been able to track.”

“Rather, we see EBV as a co-factor, a common virus that promotes us to be in the condition where the disease can develop,” he said.