AB1368 UNRAVELLING THE (T)REGULATORY POWER OF GLYCANS IN MYASTHENIA GRAVIS: MECHANISM AND POTENTIAL CLINICAL APPLICATIONS
Authors: Â. Fernandes, M. M. Vicente, P. Carneiro, M. I. Leite, M. E. Santos, S. Pinho
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Regulatory T-cells (Tregs) have been highlighted as key players in the immunopathogenesis of several autoimmune disorders, presenting a fundamental role on the maintenance of peripheral tolerance [1]. However, the precise mechanism associated with Treg dysfunction and the consequent development of autoimmunity remains largely unknown. This major unanswered question combined with the lack of efficient and targeted treatment options for autoimmune diseases emphasizes an urgent clinical need to identify the mechanism underlying Tregs dysfunction. Autoimmune disorders comprise several complex diseases, being myasthenia gravis (MG) a well-defined pathology that targets neuromuscular junctions, resulting in generalized skeletal muscle weakness and fatigability, with consequent restriction of patients' daily functions and, in the most severe cases, leading to death [2]. This autoimmune disorder represents the perfect disease model to study the dynamics between Treg (dys)function and autoimmunity, since MG mainly develops at a central level (thymus) with the Treg axis having a main role in its pathogenesis [3,4]. In fact, several studies have reported that Tregs are dysregulated in MG patients, losing their effective capacity to suppress conventional T cells [3,4]. In accordance, the inoculation of functional autologous Tregs in experimental autoimmune MG rat models was shown to effectively ameliorate clinical symptoms of MG, highlighting the key role of Tregs in this disorder [5]. Glycosylation, a major post-translational mechanism characterized by the addition of glycans to proteins/lipids of all cells, has been demonstrated by others and us to be fundamental regulators of T cells activity and function, both in homeostasis and disease [6-9]. These evidences led us to hypothesize that the Tregs glycans play a key role in MG immunopathogenesis, suggesting the glycoreprogramming of these cells as a potential novel therapy to reach MG control. <h3>Objectives:</h3> Therefore, in this project we are exploring how Tregs glycosylation is a novel disease factor in autoimmunity/MG, using human clinical samples. <h3>Methods:</h3> Using a cohort of 16 blood samples from MG patients (versus healthy controls), the Tregs glyco-profile was detailed characterized, using markers for Tregs' discrimination combined with a panel of lectins (glycan-specific binding proteins). These analyses were performed by flow cytometry. <h3>Results:</h3> Our results demonstrated that Tregs from MG patients exhibit a different glycosylation signature characterized by high levels of high-mannose/less complex <i>N</i>-glycans, when compared to Tregs from healthy subjects. Furthermore, MG patients with active disease display higher levels of high-mannose/less complex <i>N</i>-glycans on the surface of Tregs, when compared with the Treg <i>N</i>-glycome from MG patients in remission. <h3>Conclusion:</h3> These evidences led us to postulate that Treg dysregulation in MG might be controlled by glycans, that might contribute to the impairment of its suppressive functions associated with autoimmunity. The data of this project unraveled novel pathogenic mechanisms in MG and open new avenues for new therapeutic applications in several autoimmune disorders. <h3>REFERENCES:</h3> [1] Dominguez-Villar M, Hafler DA. <i>Nat Immunol</i>. 2018;19(7):665–73. [2] Vincent A. <i>Nat Rev Immunol</i>. 2002;2(10):797–804. [3] Balandina A, et al. <i>Blood</i>. 2005;105(2):735–41. [4] Gradolatto A, et al. <i>J Autoimmun</i>. 2014;52:53–63. [5] Aricha R, et al. <i>J Autoimmun</i>. 2016;67:57–64. [6] Pereira MS, et al. <i>Front Immunol</i>. 2018;9(2754):1–13. [7] Fernandes Â, et al. <i>Immunology</i>. 2023;168:217–232 [8] Dias AM, et al. <i>PNAS</i>. 2018;115(20):E4651–60. [9] Pinho SS, Reis CA. <i>Nat Rev Cancer</i>. 2015;15(9):540–55. <h3>Acknowledgements:</h3> The authors acknowledge FCT (Portuguese Foundation for Science and Technology) for funding (Grant: 2022.01422.PTDC). <h3>Disclosure of Interests:</h3> <b>None declared.</b>