Sclerosis associated Retrovirus) displays pro-inflammatory properties on antigen
E. JOUVIN-MARCHE1, M. SARESELLA2, P. FERRANTE2,
A. CREANGE3, H. PERRON4 and PN. MARCHE1*.
1 – Laboratoire
d’Immunochimie, INSERM U548/CEA, Grenoble, France. 2 – Don C. Gnocchi Foundation,
Milan, Italy. 3 – Hopital Henri Mondor, Créteil, France. 4 – BioMérieux, Marcy
*Presenting author [email protected].fr
The presence of MSRV, a retroviral
element defining a novel family of human endogenous retroviruses (HERV-W) has
now been confirmed in serum and CSF of patients with multiple sclerosis (MS) and
a correlation between circulating MSRV
virion load and MS evolution has been demonstrated.
potential of such retroviral expression in humans thus became critical. We have
recently found that MSRV and its envelope (MSRV-ENV) protein displayed
superantigen (Sag) properties associated with the production of pro-inflammatory
cytokines. The potent immunopathogenicity and the pro-inflammatory properties of
MSRV virions were later confirmed in vivo in SCID mice grafted with human
peripheral blood mononuclear cells
(PBMC). Given the extreme pro-inflammatory features observed in this animal
model, the objectives of the present study were to characterize the
pro-inflammatory effects of a recombinant MSRV protein (MSRVprot). The effects
of MSRVprot were first studied in vitro on human PBMC and were characterized by
the production of TNF-a,
and IL-6, three cytokines mainly produced by activated antigen presenting cells
a T cell cytokine was not or only slightly secreted in response to this protein,
thus demonstrating its ability to preferentially activate APCs rather than T
lymphocytes. The specificity of these
results was then demonstrated by the neutralization of the cytokine production
by monoclonal antibodies raised against MSRVprot.
In an attempt to link the potential effects of
this protein with MS disease, MSRVprot pro-inflammatory properties were then
further evaluated in PBMC of MS patients and compared with healthy controls. No
differences were found between both groups for the expression of the T cell
marker CD69 and the production of IFN-g.
However, when we looked at the secretion of APC derived cytokines, we observed
that MSRVprot mediated IL-6
production was increased in MS patients while
remained unchanged. Interestingly, this over IL-6 production was later found to
correlate with the clinical score (EDSS) of the patients.
levels of IL-6 in plasma, CSF and CNS tissue of MS patients have been reported
in several publications, and a role for this cytokine has been argued in
autoimmune diseases such as MS.
Altogether our data demonstrate
that a new MSRV protein preferentially targets and activates cells of the innate
immune system such as monocytes and macrophages rather than T lymphocytes and
induces the over secretion of IL-6 in MS.
These properties could thus further demonstrate
a role for MSRV in MS pathogenesis.