Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Lymphocyte activation gene 3 (LAG3) resembles CD4 and is a key checkpoint molecule leading to downregulation of T cell proliferation and antigen presentation via interactions with CD3 and MHC-II respectively. LAG3 is primarily expressed by activated T cells, regulatory T cells, and exhausted T cells. LAG3 plays an important role in maintaining immunological unresponsiveness to self-antigens. However, little is known about its pathogenetic role in autoimmune diseases, like rheumatoid arthritis (RA).
Methods: The plasma level of soluble (s) LAG3 was measured in 120 treatment naïve patients with early RA, with symptoms for an average of 3 months. This was done at baseline and after 12 months of treatment with either methotrexate + placebo or methotrexate + adalimumab. Treatment response was evaluated by DAS28CRP, total sharp score (TSS), erosion score (ES) and joint space narrowing (JSN). IgM-RF and anti-CCP status were also measured. Further, we examined paired plasma and synovial fluid samples from 38 RA patients with long standing disease (> 8 years) and plasma from healthy donors (HD, n=35). Human peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMC)s were examined by flow cytometric analysis to characterize LAG3 and PD-1 expression on CD4+ T cells. Exhaustion status was assessed by IL-2 expression, after stimulation with CD3CD28 beads in a cell:bead ratio of 2:1 (suboptimal stimulation). Finally, SFMCs were stimulated with rhLAG3 for 48 hours.
Results: Plasma level of sLAG3 was increased in early RA patients (1725±2285pg/ml) vs HD (741±381pg/ml, p< 0.001). After 12 months of treatment, sLAG3 remains elevated compared with HD (1236 ±1326pg/ml, p < 0.05). The changes in sLAG3 were not affected by adding adalimumab to the methotrexate treatment. Baseline plasma levels of sLAG3 were strongly associated with autoantibody status, IgM-RF (ρ= 0.38, p=0.006) and anti-CCP (ρ= 0.38, p = 0.005), but not to DAS28CRP, and inversely with CRP (ρ= 0.38, p=0.04). Furthermore, baseline levels of sLAG3were associated with progression in TSS after two years (p<0.05) and changes in TSS (0-2 year) was also associated with change in sLAG3 (ρ= 0.25, p<0.05). Highest levels of sLAG3 were observed in the synovial fluid from patients with chronic RA (3615±2854 pg/ml), compared with plasma (p < 0.001). No correlation between sLAG3 in the two compartments was observed. Highest expression of LAG3 after suboptimal stimulation was observed in synovial IL-2–, FOXP3–,PD-1+, CD4+ T-cells. No biological effect was observed by addition of rhLAG3 to cultured PMBCs and SFMCs as assessed by production of TNFa, MCP-1 or IgM-RF.
Conclusion: sLAG3 in plasma is increased in early, untreated and longstanding RA despite a favorable response to intensive synovitis suppressive treatment. A high baseline sLAG3 level is associated autoantibody seropositivity and with radiographic progression at two years. These observations support that persistent CD4+ T cell activation is a key feature in the RA pathogenetic pathway.
To cite this abstract in AMA style:Pedersen JM, Hansen A, Hvid M, Hørslev-Petersen K, Hetland ML, Stengaard-Pedersen K, Østergaard M, Moeller BK, Hauge EM, Junker P, Deleuran B. Lymphocyte Activation Gene 3 Plasma Level Is Increased and Associated with Progression in Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/lymphocyte-activation-gene-3-plasma-level-is-increased-and-associated-with-progression-in-early-rheumatoid-arthritis/. Accessed April 13, 2021.
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