The following proposal concerns the study of a putative advantageous role of a
peptide derived from an endogenous retroviral envelope protein in inflammatory
bowel disease (IBD). The Envelope 59 is a HERV-H derived envelope protein and is
one of only three to constitute a complete open reading frame among over 100
HERV-H derived sequences in the human genome. Genetics, functional expression,
and immunological lines of evidence suggest a role for this protein in controlling the
adverse effects associated with Systemic Lupus Erythematous (SLE).
that finding an anti-inflammatory peptide was synthesized and shown to have a
protective effect in a murine rheumatoid arthritis (RA) model. Furthermore, the
peptide can modulate the inflammatory state of cells isolated from blood samples
from SLE and RA patients.
We now want to investigate if a similar effect can be
exerted on cells isolated from blood samples obtained from IBD patients.
Retroviruses have been repeatedly discussed as etiological factors of autoimmune
rheumatic diseases including SLE and RA and antibodies to gag and env regions of
retroviruses, including Human Endogenous Retroviruses (HERVs), have been
reported in patients with autoimmune disease, but the role of retroviruses in these
diseases remains unclear.
Patients with rheumatoid arthritis (RA) are positive
for HTLV-1 p19 and p24 antigens but, intriguingly, no antibodies to HTLV-1 are
detected in the sera.
Other studies revealed that SLE patients make antibodies to
p24 gag of HIV-1 and anti-SM (anti-smith) antibody can cross-react with p24 gag.
Moreover, HRES-1 (Human T-cell lymphotropic virus-related endogenous sequence)
is a HERV sequence expressed in higher quantities in patients with varying
autoimmune disease than healthy controls (8,9).
Given the autoimmune nature of
the diseases and of IBD, we hypothesize that HERVs could also be involved in IBD
pathogenesis - thus the interest in this study to evaluate findings in patients with
In our studies with SLE patients we have found that there is a significant
upregulation of an endogenous HERV derived envelope gene in patients with SLE
compared to healthy controls. This gene encodes a protein that is transported to the
cell surface and thus is available for interaction with the cells of the immune system.
Those results corroborate the possibility that HERVs could be potentially assembled
into infectious virions through pseudotyping with virion proteins encoded by
different HERVs or exogenous counterparts.
In our studies, we found a negative correlation between the expression levels of
Env59 and IL-6 and TLR7 molecules. IL-6 is believed to be a critical modulator in various
inflammatory diseases with a broad range of activities on diverse target cells.
the early phase of infectious inflammation, IL-6 is produced by monocytes and
macrophages immediately after stimulation of Toll-like receptors e.g. TLR-7 with
distinct pathogen-associated molecular patterns (PAMPs). Elevated levels of IL6 have been found in patients with various inflammatory and autoimmune diseases
and blocking the IL-6 receptor has been shown to have beneficial effect in all models
of lupus tested to date.
Furthermore, anti-IL6-receptormAb treatment has
been reported to be effective in clinical trials including RA and juvenile idiopathic
arthritis and is now used as a standard treatment regimen. IL-6 signaling has
also been suggested to be of importance in the immunopathogenesis of IBD,
however, no effect of anti-IL6-receptor treatment has been documented in these
We have further shown that a peptide derived from the Env59 protein exhibited an
anti-inflammatory effect. We have shown in vitro that a peptide derived from the
immune suppressive domain of an endogenous retrovirus diminishes production of IL-6 in stimulated human PBMCs obtained from patients with SLE and RA.
Furthermore, the peptide had a beneficial effect on the development of disease in a
murine animal model of RA and multiple sclerosis.
The immunosuppressive peptide derived
from HERV-H env59 is capable of lowering ex-vivo IL-6 expression in immune
cells isolated in blood samples from Crohn's disease patients ex vivo.