The purpose
Systemic Lupus Erythematosus (SLE) is the most common systemic autoimmune disease. The
clinical manifestations are severe and affect multiple target organs such as the kidney,
central nervous system, skin, heart and joints. Despite the progress made in the therapeutic
approach with new immunosuppressive regimens, morbi-mortality is still high. Therefore, it's
important to identify new biomarkers to help clinicians to predict severity and evolution of
the disease for better adaptation of treatments and try to improve the prognosis.
RAGE (Receptor for Advanced Glycation Endproducts) :
RAGE (Receptor for Advanced Glycation Endproducts) is an ubiquitous membrane receptor,
involved in development of many diseases such as diabetes, chronic renal failure but also in
vascular remodelling, inflammatory, infectious deseases and cancer. RAGE regulates a number
of crucial cell processes like inflammation, and tissue and cellular homeostasis.
RAGE is able to bind not only the advanced glycation end products (AGEs) such as pentosidine,
carboxymethyllysine (CML), methyl-glyoxal-hydroimidazolone-1 (MG- H1), but also other ligands
such as HMGB1 (high mobility group box1), and S100A8/A9 proteins which have been correlated
in recent studies to the activity index of SLE. The activation of RAGE leads to a cascade of
intracellular signaling and activation of the transcription factor NF-ΚB . NF-ΚB enable the
traduction of proinflammatory cytokines such as IL-6, IL-1α ,IFN-γ. In SLE, these cytokines
involved in perpetuation of inflammation and tissue damages including lupus nephritis.
Moreover, the activation of RAGE induces the expression of adhesion molecule such as sICAM -1
and sVCAM -1 wich were recently involved in SLE vasculitis.
Soluble forms of RAGE, sRAGE and esRAGE :
RAGE is a proinflammatory membrane receptor. But RAGE also exists in soluble plasma forms,
esRAGE (secreted form) and sRAGE (a truncated form as cleaved by MMP9 and ADAM10 enzymes).
esRAGE and sRAGE have the same ligand-binding specificity as RAGE and may function as a
'decoy receptor' by binding pro-inflammatory ligands and preventing them from accessing cell
surface RAGE (Kierdorf and Fritz, 2013). Therefore, both soluble forms have an
anti-inflammatory action. Several studies have shown a decrease in circulating levels of
sRAGE in patients with Rheumatoid Arthritis, or Sjögren Syndrome compared with healthy
controls. However, the role of RAGE in SLE remains unknown.
RAGE and Systemic Lupus Erythematosus, recent advances :
Our team (Laboratory of Nephrology, CNRS UMR 7369, URCA) showed in a study in lupus RAGE
knockout mice (B6/ MRL-FAS lpr/J RAGE-/-) a strong involvement of RAGE in systemic
manifestations SLE. Recently, another report showed that sRAGE has an anti-inflammatory
effect on the lupus nephritis and could be a potent therapy in mice.
In humans, two studies show a correlation between the plasma level of sRAGE and lupus
phenotype ( Nienhuis et al. , 2008).
Working hypothesis :
Based on the results and those of the current studies, the investigators think that RAGE axis
and its soluble forms play a crucial role in the complex pathogenesis of SLE.
The investigators hypothesize that plasma levels sRAGE and esRAGE are a reflection of the
activity and the development of SLE in humans. Soluble forms of RAGE and ligands may be novel
biomarkers of SLE and sRAGE a potent therapeutic target.
