ArticleArthritis research & therapy2023
Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis.
Article in Arthritis research & therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 13 citations in OpenAlex.
- The Complexity of Soluble Checkpoint Molecules in Modulating Immune-Mediated Diseases and Autoimmunity.International journal of molecular sciences · 2026Review
- Matrix Type Influences the Levels of Soluble Immune Checkpoints.Journal of clinical laboratory analysis · 2026Article
- PD-1, BTLA and TIGIT as therapeutic targets for rheumatic disease.Nature reviews. Rheumatology · 2026Review
- Galectin-3 exacerbates autoimmune diabetes by limiting regulatory T cell differentiation and function.Science advances · 2026Article
- Lymphocyte activation gene 3 in autoimmune disease: from molecular mechanisms to clinical applications.Frontiers in immunology · 2026Review
- Frequencies of PD-1 and LAG-3 positive T cells in asthmatic children and their relationship with inflammatory cytokines.Open medicine (Warsaw, Poland) · 2026Article
- Advanced Immunomodulation in Rheumatoid Arthritis: Immune Checkpoints, microRNAs, and Cell-Based Therapies.Biomedicines · 2025Review
- SLAM receptors regulate immune checkpoints via SAP and EAT- 2 in rheumatoid arthritis: association with disease activity.Clinical rheumatology · 2025Article
- Plasma inflammatory and angiogenic protein profiling of patients with sickle cell disease.British journal of haematology · 2025Article
- Baseline sLAG-3 levels in Caucasian and African-American breast cancer patients.Breast cancer research and treatment · 2024Article
- Immune checkpoints in rheumatoid arthritis: progress and promise.Frontiers in immunology · 2023Review
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Authors and funding
15 authors at 7 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
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.
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