CHANGES IN CELLULAR GLYCOSYLATION AS A KEY FACTOR IN THE IMMUNOPATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS
- Inês Alves, Portugal
Abstract
Background and Aims
Systemic Lupus Erythematous (SLE) is one of the most challenging autoimmune disease for clinicians as it may be presented as a severe relapsing and disabling immune-mediated disorder, still remaining incurable. Protein glycosylation is an essential posttranslational modification that participates in the correct recognition of cells by the immune system. In this study we have investigated whether an incorrect protein glycosylation is associated with loss of tolerance in autoimmunity.
Methods
We have analysed the profile of the cellular glycosylation of a subset of biopsy-proven lupus nephritis from SLE patients and normal kidney tissue (from two Porto Centre Hospitals) and blood, through immunohistochemistry and flow-cytometry. MGAT5 null mice (with defects on glycosylation) were monitored for autoimmune signs by analysing proteinuria, weight loss and colonic and renal histologies were analysed.
Results
SLE patients revealed a significant decreased expression of complex N-glycans in the renal parenchyma, when compared to controls. Furthermore, we have identified in lupus patients a unique subset of circulatory CD3+T-cells with an abnormal glycosignature and an increased expression of specific glycan-binding receptors. Interestingly, the MGAT5 knock-out mice develop clinical signs compatible within autoimmune-like syndrome, particularly proteinuria and high levels of serum autoantibodies, together with a tissue infiltration of specific CD3+T-cells subsets identified in SLE patients.
Conclusions
These findings point towards the identification of a novel immune player with increased ability to sense abnormal N-glycans expression modulating the surrounding immune response. We propose glycosylation as a regulatory mechanism that tips the balance between homeostasis/self-tolerance and autoimmunity opening a potential novel targeted-specific mechanism in SLE pathogenesis.