Pos1064 Abnormal Glycosignature of Host Tissue Triggers Pathogenic Recognition Through Gamma-Delta T Cells/Il-17a Axis in Autoimmunity

Background: Autoimmune diseases are life-threatening disorders with increasing disability. Systemic Lupus Erythematosus (SLE) as many other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Glycans are master regulators of the inflammatory response being important molecules for the discrimination between "self"/"non-self". Accumulating evidence demonstrate that protein glycosylation is significantly altered in disease development, but it is still largely unclear the mechanisms by which glycans trigger autoimmune responses¹,²,³. Objectives: We here explored whether lupus nephritis (LN) exhibit an altered cellular glycosylation aiming to identify a unique glycosignature that characterizes LN pathogenesis and disclosuring a novel immunopathogenesis mechanism. Methods: A comprehensive tissue glycomics characterization was performed in a cohort of human biopsy-proven LN clinical samples from SLE patients. A combination of advanced tissue mass spectrometry imaging (MSI); in situ glyco-characterization and ex vivo glycophenotyping of human kidney biopsies were performed to structurally map the N-glycans repertoire in LN samples. Mechanistically, in vitro primary cell cultures were used to teste the immunogenicity of glycobiomarker. Moreover, glycoengineered mice models as well as ex vivo glycoreprograming of SLE kidney fresh biopsies were performed and analyzed by flow cytometry and cytometric bead array. Results: LN revealed a unique glycan signature characterized by an increased abundance and spatial distribution of unusual mannose-enriched glycans that are typically found in lower microorganisms; this glycosignature was specific of LN as it was not observed in other kidney diseases⁴. Mechanistically, we originally showed that an abnormal exposure of these microbial-associated mannose structures at surface of kidney tissues triggers the recognition of DC-SIGN-expressing γδT-cells, inducing a pathogenic IL-17a-mediated autoimmune response. Glycoengineered mice with overexpression of mannose structures displayed increased γδT-cells infiltration in kidney associated with spontaneous development of lupus⁵. The metabolic glyco-reprogramming of kidney tissue, through the enhancement of the biosynthesis of tolerogenic branched N-glycans, was found to inhibit γδT-cells-producing IL-17a, controlling disease development. Conclusion: Taken together, this work revealed an unique immunological mechanism based in mannose-glycans/γδT-cells/IL-17a axis in SLE immunopathogenesis, proposing glycans as a strategy to reprogram the glyco-metabolic profile of tissues as a next-generation targeted-therapy for autoimmune diseases treatment and prevention. REFERENCES: [1] Alves & Fernandes et al. FEBS Letters 2023 [2] Kissel et al. Nat Rev Rheumatology 2023 [3] Pereira & Alves et al. Front Imm 2018 [4] Alves et al. Sci Tran Med 2023 [5] Alves et al. Arth Rheum 2021 Acknowledgements: This work was funded by 2022 Lupus Innovation Award (funded by Lupus Research Alliance), Basic Research in Autoimmunity prize (supported by National Medical Association in Autoimmunity (NEDAI) and National Society of Internal Medicine (SPMI)) and Pfizer prize (supported by Pfizer and Society of Medical Sciences of Lisbon). I.A. acknowledges Portuguese Foundation for Science and Technology (FCT) for funding (2022.00337.CEECIND). Disclosure of Interests: None declared.