Background: Systemic Sclerosis (dcSSc) is an autoimmune disorder that affects the connective tissue. It is characterized by the thickening of the skin, which can lead to the fibrosis of internal organs. Although the overactivation of the immune system and increased proinflammatory cytokine production can explain the pathophysiology of this disease to a certain extent, the mechanisms leading to this are not well understood. Checkpoint inhibitory molecules function as physiological brakes in the immune system and help to maintain homeostasis. Aberrant checkpoint inhibitory pathways are often observed in patients with dcSSc. Lymphocyte activation gene-3 (LAG-3) is a late checkpoint inhibitory receptor that is mainly expressed by T cells and is involved in T cell inhibition. In this study, we focused on the role of LAG-3 in dcSSc and the effect of a LAG-3 agonist on immune cells from these patients.

Objectives: This study aims to analyse the role of LAG-3 dcSSc and the influence of a LAG-3 Agonistic antibody in influencing inflammation and fibrosis.

Methods: Plasma LAG-3 levels of 36 patients with dcSSc were compared to 20 healthy controls. PBMC’s from eight dcSSc patients and four Healthy Controls were analysed by flow cytometry for the surface expression of LAG-3 on CD4+ and CD8+T cells after stimulation with CD3/CD28 for 24 hours. Eight dcSSc PBMC’s were stimulated for 48 h with a LAG-3 Agonistic antibody and an isotype control. The harvested supernatants were analysed using a multiplex proinflammatory cytokine ELISA.

Results: Patients with dcSSc had decreased soluble levels of LAG-3 compared with healthy controls (p <0.0001). Increased surface expression of LAG-3 was observed in CD4+ T cells(p=<0.05) and CD8+ T cells(p=<0.005) in patients with dcSSc compared to healthy control PBMCs. When treated with a LAG-3 agonistic antibody (LAG-3 Ag), PBMC monocultures from dcSSc patients significantly downregulated the production of IFN gamma, IL-2, IL-4 and TNF alpha and upregulated the production of IL-10 as compared to non-treated controls(NT) (*=p<0.05,**=p<0.005). The Isotype control did not show a similar effect.

Conclusion: LAG-3 is immune-protective in Systemic Sclerosis and its agonistic antibody could be used as a potential treatment modality.

REFERENCES: NIL.

Figure 1.

Acknowledgements: NIL.

Disclosure of Interests: None declared.