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Active Epstein-Barr Virus Found in Myasthenia Gravis Thymus

ARTICLE IN BRIEF

Investigators report evidence of the Epstein-Barr virus (EBV) in the thymus of six patients with myasthenia gravis. None of the controls had EBV.

The Epstein-Barr virus is active in the thymus of myasthenia gravis patients, according to a new study in a small number of patients. If confirmed, this discovery could help explain the cause of the disease and, at least in theory, suggest new treatments.

A viral trigger has long been speculated to contribute to myasthenia gravis (MG) and other autoimmune diseases, lead researcher Renato Mantegazza, MD, professor of neurology at the Fondazione Istituto Neurologico “Carla Besta,” in Milan, Italy, wrote in the paper in the June Annals of Neurology. But, he said, the evidence has been sparse and equivocal.

Epstein-Barr virus (EBV) is a herpes virus that infects 90 percent of the world's population, but after an initial primary infection the virus becomes latent in virtually all individuals and can then periodically reactivate. It is a particularly intriguing candidate for triggering autoimmunity, because it infects and immortalizes B cells, the makers of antibodies, and the cause of MG is aberrant production of antibodies to the muscle acetylcholine receptor.

STUDY PROTOCOLS

In order to test whether EBV may be at work in MG, Dr. Mantegazza and colleagues studied thymus tissue from 17 MG patients who had undergone thymectomy to treat their disease: six with follicular hyperplasia, six with diffuse hyperplasia, and five with involuted thymus. Investigators compared them to thymus from six non-MG patients who had thymectomies in the course of heart surgery.

Since EBV infection is so widespread, it was not enough to determine whether viral DNA was present in the MG tissue; on the one hand, most people would be expected to have it, and on the other, the number of infected cells is generally so low that detection is unreliable. “DNA tells you the virus is integrated there,” Dr. Mantegazza said. “RNA tells you there is a persistence of viral replication, and protein tells you that replication is actually leading to functional proteins.”

Therefore, the researchers tested for EBV proteins and EBV RNAs, signs of an ongoing viral life cycle. No signs of active EBV infection were found in any of the control thymuses. In contrast, all MG patient thymuses showed multiple signs of EBV infection. Viral encoded small RNAs were seen in all six patients with follicular hyperplasia, three of six patients with diffuse hyperplasia, and three of five patients with involuted thymus. Protein markers for the lytic stage of the viral life cycle were found in all patients.

The results, Dr. Mantegazza said, provide the first evidence for an ongoing infection process in the thymus of patients with myasthenia gravis.

If EBV infection does help cause the disease, how would it do so? “I don't think this is really sorted out,” he said. One possibility is that the viral proteins themselves contain epitopes that mimic the acetylcholine receptor, but there is little evidence to support that. Instead, he said, the virus may activate B cells in the thymus, which then react to receptor-like proteins found in thymic tissue, creating antibodies that then leave the thymus and disable the muscle acetylcholine receptor.

Host genetic susceptibility factors are almost certainly part of the story as well, he said, since MG is so rare, while EBV infection is so common.

But whatever creates the conditions for autoimmunity, “chronic infection within the thymus probably explains why the reaction is ongoing,” he said. It is possible, he said, that the pattern or exacerbation and improvement seen in MG may be linked to the viral life cycle as well, though that speculation requires further exploration. “This is one of the clinical implications we have to address in the future,” Dr. Mantegazza said.

EXPERTS COMMENT

The study results are interesting, said Robert Lisak, MD, chairman of neurology at Wayne State University School of Medicine in Detroit, MI. But this study has “absolutely not” closed the case on EBV as a cause of MG, he said. The patient numbers are small, and there were no other autoimmune disease controls, he pointed out. In addition, the finding would need to be replicated by other groups, a problem Dr. Lisak identified with similar studies in multiple sclerosis.

DR. ROBERT LISAK

said this study has “absolutely not” closed the case on Epstein Barr virus as a cause of myasthenia gravis, adding the patient numbers are small, and there were no other autoimmune disease controls.

The proposed mechanism for explaining ongoing autoimmunity has scientific plausibility, “but that is speculation on ‘why,’ and first we have to know ‘if.’ There is a lot more work to be done, but it is definitely worth pursuing,” he said.

Henry Kaminski, MD, professor of neurology at Saint Louis University in MO, is more enthusiastic about the findings, although he also noted the small patient numbers. “This is really a new appreciation that EBV, or a viral infection of any kind, can be linked to myasthenia gravis,” he said, “but it is definitely only the first volley” in making the case for EBV. “It's a relatively small number of patients, and the data will have to be replicated in independent studies. But it is certainly highly suggestive that EBV could be a player in initiating an ongoing autoimmune process.”

“One vexing problem has been what sustains the autoimmune process in myasthenia,” he said. An acute autoimmune reaction to acetylcholine receptor can be induced in humans by penicillamine or passive transfer of antibodies from mother to child, but these are self-limiting.

“Something is going on to sustain the autoimmune reaction in MG, and this paper suggests it may be this chronic infection,” Dr. Kaminski said. The virus's ability to infect and transform B cells, allowing them to evade immune surveillance, “makes it a prime suspect for chronic infection,” and its concentration in the thymus, which contains proteins similar to the acetylcholine receptor, makes EBV infection “a strong possibility for the pathogenic insult that induces disease,” he added.

Developing therapy will be challenging, he said. One strategy might be vaccination, in which the immune system would be presented with much larger amounts of EBV antigen than it normally sees, in order to provoke a response. “But there are huge challenges to develop something like that,” he said, or to develop other types of therapies that target the small number of infected cells.

REFERENCES:

Cavalcante P, Serafini B, Mantegazza R. et al. Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol 2010;67:726–738.