High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection.
Cermelli C, Berti R, Soldan SS, Mayne M, D'ambrosia JM, Ludwin SK and Jacobson S;
Commented by , 19 Jun 2003
Background
The cause of MS is still unknown, although the pathophysiology of the disease have been extensively described. The general opinion is that MS is an autoimmune disease with a possible infectious etiology. Several infectious agents have been investigated and epidemiologic, immunologic and molecular studies have revealed a role for human herpes virus-6 (HHV-6).
Recently, evidence for an autoimmune hypothesis has been put forward, based on structural similarities between epitopes of HHV-6 and myelin basic protein, recognized by the T cell (Tejada-Simon et al., Ann Neurol 2003;53:189-97)
Aim
To assess the frequency of HHV-6 DNA in autopsy material from MS plaques.
Methods
Brain samples were obtained from autopsy and surgical specimen from 13 patients with MS, including 64 samples from plaque, and 44 samples from normal appearing white matter (NAWM). As controls, the authors used 46 white matter samples from 13 patients with neurologic disease other than MS (4 had inflammatory CNS disease), as well as 41 white matter samples from 12 patients with no neurologic disease.
The tissue samples were formalin-fixed, paraffin embedded, and selected areas were isolated by laser microdissection in a blinded manner. DNA was extracted and HHV-6 genomic sequences were amplified by nested polymerase chain reaction.
Results
Of the 64 samples from MS plaques, 57,8% were positive for HHV-6 DNA, compared with 15,9% in NAWM-MS samples (p<0,0005). HHV-6 DNA in NAWM-MS samples was comparable to non-MS disease controls samples (21,7%) (patients with inflammatory CNS disease (26,7%)), and healthy brain samples (26,8%).
There was an increase in HHV-6-specific sequences in MS plaques, compared with non-MS disease controls (p<0,003) and healthy brains (p<0,170). HHV-6 DNA was present in 92,3% of MS brains, compared with 61% of non-MS disease brains and 75% of normal brains. The porportion of HHV-6-positive samples in the MS plaques tended to be higher for active (65%) than for inactive (49%) lesions.
Discussion
First of all it should be emphasized that HHV-6 is normally a frequent habitant of the CNS in humans (20-70%). Furthermore, it has been suggested that the detection of HHV-6 may reflect inflammation as such, and the observed changes could therefore not be characteristic for MS. It is also possible that the HHV-6 DNA found in the MS plaques, is located in the T cells rather than CNS tissue, although a companion paper to some degree argues against this (Goodman et al., J Infect Dis 2003;187:1365-76).
Still it is interesting, that the authors find significantly more HHV-6 DNA in MS-plaques compared with NAWM of MS patients, as well as patients with other CNS inflammatory diseases and non-MS neurological patients. The HHV-6 DNA was present in CNS of nearly all MS patients, but a remarkably large fraction of the normal brains also contained viral DNA.
It is difficult to draw any firm conclusions from the study, since it cannot be ruled out that the observations are caused by an epiphenomenon. The study provides support for an association between HHV-6 and MS, but does not clarify if HHV-6 is a major pathogenic candidate.