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Epstein-Barr virus Trigger for autoimmunity.

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EDITORIAL
Epstein-Barr Virus
Trigger for Autoimmunity?
M
yasthenia gravis (MG) is perhaps the best understood autoimmune disease and among the few that
fulfills strict criteria for its antibody-mediated basis.1,2
• Antibodies are identified at the neuromuscular junction, the site of physiological defect.
• Immunoglobulin from patients with MG or antibody
directed against the acetylcholine receptor (AChR),
when injected into animals, produces manifestations
of MG.
• Administration of purified AChR to animals reproduces the disease.
• Plasma exchange that removes antibodies reduces MG
manifestations.
Despite our knowledge of the disease, the mechanisms that induce and sustain the autoimmune reaction
toward the AChR are not known3–5; however, a chronic
stimulus to drive the pathology, such as an infection, appears necessary. Why? Injury isolated to the neuromuscular junction alone is not sufficient to sustain the disease.
Three situations support this proposition. Placental transfer of AChR antibodies from mother to infant produces
transient injury to the neuromuscular junction, but the
disorder resolves after clearance of maternal antibodies,
and the child does not develop a persistent autoimmune
disorder. Next, the AChR may react with thiol groups on
penicillamine to form a hapten, which stimulates autoantibody formation and clinical pathology typical of spontaneous MG. However, discontinuation of the offending
agent leads to resolution of MG. Finally, experimental autoimmune MG may be produced in animals by either infusion of pathogenic AChR antibodies or administration
of purified AChR. A monophasic illness occurs, and if
animals survive, then weakness resolves. In each of these
situations, the neuromuscular junctions have been injured
profoundly by a brisk autoimmune reaction, but a sustained autoimmune disease does not result.
The thymus, rather than the muscle, is a likely candidate for the site where MG is initiated. The thymus
expresses AChR-like proteins and contains antigenpresenting cells. The majority of patients with MG have
lymphoid follicular hyperplasia of the thymus. The
perivascular spaces are swollen with lymphoid tissue that
resembles peripheral immune organs; active germinal centers are present, similar to the secondary lymph follicles of
peripheral lymph nodes. Hyperplastic MG thymus contains significant numbers of mature immune cells, and
they include anti-AChR T and B cells, which are capable
of mounting a pathogenic AChR antibody response. An
inflammatory response resulting from infection in the
thymus could cause professional antigen-presenting cells
to present epitopes derived from the thymus AChR-like
proteins. This would activate potentially autoreactive antiAChR T cells and initiate the autoimmune reaction of
MG.1–3,5
In this issue of Annals of Neurology, Cavalcante and
colleagues6 offer a potential answer to the vexing question
of how the immune response to the AChR may be maintained and provide further support that thymus is the site
of initiation of the autoimmune reaction. They identify
Epstein-Barr virus (EBV)-infected B cells only in the thymus of patients with MG regardless of the thymic pathology. EBV is unique in its ability to latently infect and
immortalize B cells, which may provide an explanation
for why EBV has been suggested as having a pathogenic
role in several autoimmune disorders with diverse effector
arms, such as systemic lupus erythematosus (immune
complex deposition), multiple sclerosis (autoreactive T
cells and others), and rheumatoid arthritis (immune complex, cellular immune injury).7 With the Cavalcante et al,
study the prototypic antibody-mediated disease, MG, is
added to this list.
EBV infects 90% of the world’s population, with
the majority of individuals demonstrating seroconversion
prior to age 10 years. Therefore, the simple detection of
viral DNA would not necessarily indicate a pathogenic
role; however, expression of latent and lytic genes and
proteins is consistent with an active infection. The expression pattern of latent EBV genes observed in intrathymic
B cells of patients resembles the pattern characteristic for
B lymphoblastoid cell lines (LCL) immortalized by EBV
© 2010 American Neurological Association
697
ANNALS
of Neurology
in vitro; both the nuclear antigen EBNA2 and the latent
membrane proteins LMP1 and LMP2A are present (EBV
latency type III). This is in agreement with early reports
demonstrating the direct outgrowth of B-like LCL from
explants of human myasthenic thymus in tissue culture.8,9
Although the antibodies produced by these B cell lines
did not react with the AChR, peripheral B cells of other
patients with MG stimulated by EBV or pokeweed mitogen in vitro did secrete AChR antibodies.10 EBV is capable of establishing persistent infection without detriment
to the host.11 Switching on lytic, productive EBV replication may result, however, in new infection events and
EBV-associated cell transformation/immortalization events,
even at ectopic sites like the thymus. One could speculate
that an increased EBV load or altered presentation of certain EBV proteins that cross-react with, or mimic, the
AChR may trigger the development of MG. In addition,
EBV-infected latency type III B cells may bypass B-cell
tolerance checkpoints.
Assuming EBV infection of the thymus proves to be
common among patients with MG, including those with
muscle-specific kinase antibodies, the obvious question is
what can be done? The viral rate of replication is likely
extremely low, and the presently available antivirals are
poorly effective at eradicating acute infections and therefore
unlikely to be worthwhile treatments for chronic autoimmune disorders induced by EBV.7 Would a vaccination be
an effective treatment for chronic EBV-related MG?
Henry J. Kaminski, MD
Department of Neurology & Psychiatry
Saint Louis University School of Medicine
Saint Louis, MO
Janos Minarovits, MD, PhD
Microbiological Research Group
National Center for Epidemiology
Budapest, Hungary
References
1. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past,
present, and future. J Clin Invest 2006;116:2843–2854.
2.
Lang B, Vincent A. Autoimmune disorders of the neuromuscular
junction. Curr Opin Pharmacol 2009;9:336 –340.
3.
Willcox N, Leite MI, Kadota Y, et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci 2008;1132:
163–173.
4.
Lindstrom J. Acetylcholine receptors and myasthenia. Muscle
Nerve 2000;23:453– 477.
5.
Conti-Fine BM, Diethelm-Okita B, Ostlie N, et al. Immunopathogenesis of myasthenia gravis. In: Kaminski HJ, ed. Myasthenia
and related disorders. New York, NY: Humana Press, 2009:
43–70.
6.
Cavalcante P, Serafini B, Rosicarelli B, et al. Epstein-Barr virus
persistence and reactivation in myasthenia gravis thymus. Ann
Neurol 2010;67:726 –738.
7.
Niller HH, Wolf H, Minarovits J. Regulation and dysregulation of
Epstein-Barr virus latency: implications for the development of
autoimmune diseases. Autoimmunity 2008;41:298 –328.
8.
Williams CL, Lennon VA. Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin. J Exp
Med 1986;164:1043–1059.
9.
Vilquin JT, Braun S, Labouret P, et al. Establishment and characterization of B-like lymphoblastoid cell lines by long-term culture of primary explants from human myasthenic thymus. Thymus
1993;21:25– 42.
10.
Brenner T, Timore Y, Wirguin I, et al. In vitro synthesis of antibodies to acetylcholine receptor by Epstein-Barr virus-stimulated
B-lymphocytes derived from patients with myasthenia gravis.
J Neuroimmunol 1989;24:217–222.
11.
Thorley-Lawson DA, Duca KA, Shapiro M. Epstein-Barr virus: a
paradigm for persistent infection—for real and in virtual reality.
Trends Immunol 2008;29:195–201.
Acknowledgment
This editorial was supported by the NIH NEI
(R24EY014837, H.J.K.).
Potential Conflicts of Interest
H.J.K. serves as a consultant for Varleigh Limited in the
development of therapeutics for myasthenia gravis.
DOI: 10.1002/ana.22031
698
Volume 67, No. 6
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