Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis

Arthritis Research & Therapy

Research

Lene Dreyer¹  Merete Lund Hetland²  Mikkel Østergaard²  Kim Hørslev-Petersen³  Ellen-Margrethe Hauge⁴  Cæcilie Skejø⁵  Kristian Juul-Madsen⁵  Aida Solhøj Hansen⁵  Janni Maria Pedersen⁶  Malene Hvid⁷  Stinne Greisen⁸  Bent Deleuran⁸  Bjarne Kuno Møller⁹  Peter Junker^1,10  Kristian Stengaard-Pedersen^1,11 

[1] Center for Rheumatic Research Aalborg, Department of Rheumatology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark;DANBIO and Copenhagen Centre for Arthritis Research (COPECARE), Centre for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet Glostrup, Glostrup, Denmark;Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark;Danish Hospital for the Rheumatic Diseases, University of Southern Denmark, Odense, Denmark;Department of Acute Medicine and Trauma Care, Aalborg University Hospital, Aalborg, Denmark;Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark;Department of Biomedicine, Aarhus University, C.F. Møllers Alle 6, 8000, Aarhus C, Denmark;Department of Biomedicine, Aarhus University, C.F. Møllers Alle 6, 8000, Aarhus C, Denmark;Department of Acute Medicine and Trauma Care, Aalborg University Hospital, Aalborg, Denmark;Department of Biomedicine, Aarhus University, C.F. Møllers Alle 6, 8000, Aarhus C, Denmark;Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark;Department of Biomedicine, Aarhus University, C.F. Møllers Alle 6, 8000, Aarhus C, Denmark;Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark;Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark;Department of Rheumatology C, Odense University Hospital & Institute for Clinical Research, University of Southern Denmark, Odense, Denmark;Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark;

关键词: Rheumatoid arthritis;    LAG-3;    Inflammation;    Galectin-3;    Co-inhibitory receptors;   

DOI  :  10.1186/s13075-023-03073-z

 received in 2022-12-21, accepted in 2023-05-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLymphocyte activation gene-3 (LAG-3) inhibits T cell activation and interferes with the immune response by binding to MHC-II. As antigen presentation is central in rheumatoid arthritis (RA) pathogenesis, we studied aspects of LAG-3 as a serological marker and mediator in the pathogenesis of RA. Since Galectin-3 (Gal-3) is described as an additional binding partner for LAG-3, we also aimed to study the functional importance of this interaction.MethodsPlasma levels of soluble (s) LAG-3 were measured in early RA patients (eRA, n = 99) at baseline and after 12 months on a treat-to-target protocol, in self-reportedly healthy controls (HC, n = 32), and in paired plasma and synovial fluid (SF) from chronic RA patients (cRA, n = 38). Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were examined for LAG-3 expression by flow cytometry. The binding and functional outcomes of LAG-3 and Gal-3 interaction were assessed with surface plasmon resonance (SPR) and in cell cultures using rh-LAG3, an antagonistic LAG-3 antibody and a Gal-3 inhibitor.ResultsBaseline sLAG-3 in the plasma was increased in eRA compared to HC and remained significantly elevated throughout 12 months of treatment. A high level of sLAG-3 at baseline was associated with the presence of IgM-RF and anti-CCP as well as radiographic progression. In cRA, sLAG-3 was significantly increased in SF compared with plasma, and LAG-3 was primarily expressed by activated T cells in SFMCs compared to PBMCs. Adding recombinant human LAG-3 to RA cell cultures resulted in decreased cytokine secretion, whereas blocking LAG-3 with an antagonistic antibody resulted in increased cytokine secretion. By SPR, we found a dose-dependent binding between LAG-3 and Gal-3. However, inhibiting Gal-3 in cultures did not further change cytokine production.ConclusionssLAG-3 in the plasma and synovial fluid is increased in both early and chronic RA patients, particularly in the inflamed joint. High levels of sLAG-3 are associated with autoantibody seropositivity and radiographic progression in eRA, and LAG-3 plays a biologically active role in cRA by decreasing inflammatory cytokine production. This functional outcome is not affected by Gal-3 interference. Our results suggest that LAG-3 is a faceted regulator of inflammation in early and chronic RA.

【 授权许可】

CC BY   
© The Author(s) 2023

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