RETROVIRAL ELEMENTS
ASSOCIATED WITH SUPERANTIGENS AND NEUROTOXINS:
LEARNING FROM OUR RESEARCH IN MULTIPLE SCLEROSIS
AND POSSIBLE AVENUE OF RESEARCH IN NEUROLOGICAL DISEASES
Herve Perron, Ph.D. bioMérieux S.A.
Lyon, France
A common point to a number of human
diseases in which no precise etiology has been identified despite
decades of research efforts, is outlined by epidemiological data
and experimental models suggesting the contribution of
“environmental factors” among which viruses might play
a major role. In parallel, another common point is the obvious
contribution of the human genotypes to an increased risk and/or
to disease severity. Several autoimmune, neurodegenerative and
psychiatric diseases are concerned by these observations. Among
them, multiple sclerosis (MS) may represent a prototypic example
in which viruses and hosts genetics have long been studied.
The recent identification of retroviral
RNA sequences (MSRV) associated with extracellular virions
detectable in the plasma, the CSF, and in some cell cultures from
patients with MS, as well as of a cytotoxic factor targeting
glial cells (gliotoxin) detected in parallel will be analysed. In
the light of the different aetiopathogenic hypotheses for the
disease and of our preliminary observations, a working hypothesis
could rely upon an initial co-expression of a gliotoxic molecule
and of a retroviral superantigen in, e.g., a perivascular
macrophage. Blood brain barrier (BBB) disruption would occur
after perivascular astrocyte death caused by the first molecule
and disproportionate inflammation, and dysregulation of
autoreactive lymphocytes would result from superantigenic
stimulation of T-cells entering the brain parenchyma through an
open BBB. Retroviral expression may itself result from
infection(s) by viral co-factors such as herpesviruses, which we
have shown to be transactivators of our first retroviral isolate
(LM7) in MS. Since MSRV is closely related to a family of human
endogenous retroviruses (HERV), its expression could result from
an endogenous haplotype present in MS-susceptible individuals and
be induced by co-factors, as well as from an eventual, exogenous
retroviral strain remaining latent in rare CNS cells. Though all
regions from a potential MSRV genome have been sequenced from
particle-associated RNA, the correct proviral clone at the origin
of these retroviral particles remains to be identified but is
strongly hampered by the presence of numerous homologous HERV
copies in DNA.
Similar data with other retroviruses which
were recently published concerning autoimmune diseases such as
diabetes 1, Sjögrens syndrome and systemic lupus, could
prefigurate a broader concept for the role of such retroviruses
in the aetiopathogenesis of autoimmune diseases. However, in
non-autoimmune diseases, existing models suggest that retroviral
expression in the CNS, though mostly defective and resulting from
complex interactions, can also generate cytotoxic molecules
which, either directly or indirectly through cytopathic effects
in glial cells, cause neurological diseases.
Therefore, the perspectives opened by the
concept of a retroviral aetiopathogenesis involving endogenous
and/or exogenous retroviruses encoding or inducing potent
cytopathogenic molecules in CNS diseases are considerable, but
require increased and concerted research in order to evaluate
their reliability.