AB0123 CHANGES IN CELLULAR GLYCOSYLATION AS A KEY FACTOR IN THE IMMUNOPATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract

Background:Systemic Lupus Erythematous (SLE) is one of the most challenging autoimmune diseases as it may be presented as a severe, relapsing and disabling immune-mediated disorder still remaining incurable (1,2).Protein glycosylation is an essential post translational modification that participate in the correct recognition of cells by the immune system (3–5). Moreover, glycosylation changes in T cells (specifically loss of branchedN-glycans mediated by GnTV, encoded byMGAT5gene) have been shown to impact its intrinsic function and activity in a diverse panel of autoimmune diseases (3,4,6)Objectives:To evaluate the impact of glycans in the cellular and molecular mechanisms underlying the loss of immune-tolerance, envisioning the identification of a new targeted-specific mechanism.Methods:We have analysed the profile of cellular glycosylation of a subset of biopsy-proven lupus nephritis from SLE patients and normal kidney tissue (from two Porto Centre Hospitals), through immunohistochemistry (IHC) as well as by real time PCR using RNA extracted from paraffin tissues. Blood samples were collected and were analysed by flow cytometry.Mgat5null mice with 15-months old were monitored for autoimmune signs by evaluating proteinuria, weight loss and colon and kidney tissues were analysed by IHC and FACS.Results:SLE patients revealed a significant decreased expression of complexN-glycans in the renal parenchyma, when compared to healthy kidney. In addition, we have identified in lupus nephritis patients a unique subset of circulatory CD3+T cells with an abnormal glycosignature and displaying an increased expression of specific glycan-binding receptors. Interestingly,Mgat5null mice develop clinical signs compatible within autoimmune-like syndrome together with an increased infiltration of specific CD3+T cells subset identified in SLE patients.Conclusion:These findings point towards the identification of a novel immune player with increased ability to sense abnormalN-glycans, 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.