Nature Medicine
3, 1394 - 1397 (1997)
doi:10.1038/nm1297-1394
Association of human herpes virus 6 (HHV-6) with multiple sclerosis: Increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNASamantha S. Soldan1, Rossana Berti1, Nazi Salem2, Paola Secchiero3, Louis Flamand3, Peter A. Calabresi1, Meghan B. Brennan1, Heidi W. Maloni1, Henry F. Mcfarland1, Hun-Chi Lin2, Madhumita Patnaik2
& Steven Jacobson1, 4
1Viral Immunology Section, National Institute of Neurological Disorders and Stroke, Building 10, Room 5B-16, 9000 Rockville Pike, Bethesda, Maryland 20892, USA
2Specialty Laboratories, Inc., Santa Monica, California, 90404-3900 USA
3Institute of Human Virology, University of Maryland Medical School, 725 West Lombard Street, Room S307, Baltimore, Maryland, 21201 USA
4Correspondence should be addressed to S.J. Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS)1. This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection1,2; (2) geographic association of disease susceptibility with evidence of MS clustering3−4; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS (refs. 2, 5); (4) abnormal immune responses to a variety of viruses6,7; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination1,2. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV)8, has been reported to be present in active MS plaques9. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association10, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.
REFERENCES
- Johnson R.T. The virology of demyelinating diseases. Ann. Neurol. 36, S54−S60 (1994).
- Weinshenker, B.G. Epidemiology of multiple sclerosis. Neuro. Clin. 14 (2), 291−308 (1996). [AUTHOR, Journal name? YEAR?]
- Haahr, S., Munch, M., Christensen, T., Meller-Larson, A. & Hvas, J. Cluster of multiple sclerosis patients from Danish community. Lancet 349, 9056 (1997).
- Kurtzke J.F., Hyllested K. & Heltberg A. A Multiple sclerosis in the Faroe Islands: Transmission across four epidemics. Acta Neurol. Scand. 91 (5), 321−325 (1995).
- Alter, M., Leibowitz, U. & Speer, J. Risk of Multiple sclerosis related to age at immigration to Israel. Arch. Neurol. 15 (3), 234−237 (1966).
- Neighbour, P.A., Miller, A.E. & Bloom, B.R. Interferon responses of leukocytes in multiple sclerosis. Neurology 31, 561−566 (1981).
- Jacobson, S., Flerlage, M.L. & McFarland, H.F. Impaired measles virus specific cytotoxic-T Cell responses in multiple sclerosis. J. Exp. Med. 162, 839−850 (1985).
- Efstathiou, S., Gomples, U.A., Craxton, M.A., Honess, R.W. & Ward, K. DNA homology between a novel human herpesvirus (HHV-6) and human cytomegalovirus. Lancet 1, 63−64 (1988).
- Challoner, P.B., Smith, K.T., Parker, J.D. et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc. Natl. Acad. Sci. USA 92, 7440−7444 (1995).
- Secchiero, P., Carigan, D.R. et al. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. J. Infect. Dis. 171 (2), 273−280 (1995).
- Patnaik, M. & Komaroff, A.L. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J. Infect. Dis. 172 (5), 1364−1367 (1995).
- Yoshikawa, T., Suga, S., Asano, Y. et al. Neutralizing antibodies to human herpesvirus-6 in healthy individuals. Pediatr. Infect. Dis. J. 9, 589−590 (1990).
- Yamanishi, K., Okuno, T., Shiraki, K. et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1, 1065−1067 (1988).
- Nagasato, K., Nakamura, T. et al. Active production of anti-human T-lymphotropic virus type I (HTLV-I) IgM antibody in HTLV-l-associated myelopathy. J. Neuroimmunol. 32, 105−109 (1991).
- Koike, K., Lino S., Kurai K., et al. IgM anti-HBc in anti-HBe positive chronic type B hepatitis with acute exacerbations. Hepatology 7 (3), 573−576 (1987).
- Paniton, H. Influence of infection on exacerbations of multiple sclerosis. Ann. Neurol. 36, S25−S28 (1994).
- Lusso P., Markham P.D., Tschachler E. et al. In vitro cellular tropism of human Blymphotropic virus (human herpesvirus-6). J. Exp. Med. 167, 1659−1670 (1988).
- Luppi, M., Barozzi, P., Maiorana, A. et al. Human herpesvirus 6 infection in normal brain tissue. J. Infect. Dis. 169, 943−944 (1994).
- Pearson, G.R. ELISA tests and monoclonal antibodies for EBV. J. Virol. Methods 21, 97−104 (1987).
- Boom, R., Sol, C.J.A., Salimans, M.M.M. et al. Rapid and simple method for purification of nucleic acids. J. Clin. Microbiol. 28, 495−503 (1990).
|
