T-cell immunoglobulin and mucin domain 3 is upregulated in rheumatoid arthritis, but insufficient in controlling inflammation
Caecilie Skejoe, Aida S Hansen, Kristian Stengaard-Pedersen, Peter Junker, Kim Hoerslev-Pedersen, Merete L Hetland, Mikkel Oestergaard, Stinne Greisen, Malene Hvid, Mette Deleuran, Bent Deleuran, Caecilie Skejoe, Aida S Hansen, Kristian Stengaard-Pedersen, Peter Junker, Kim Hoerslev-Pedersen, Merete L Hetland, Mikkel Oestergaard, Stinne Greisen, Malene Hvid, Mette Deleuran, Bent Deleuran
Abstract
Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease, that involves both pro- and anti-inflammatory mechanisms. The purpose of the present study is to investigate T-cell immunoglobulin and mucin domain 3 (Tim-3) in RA.
Methods: Plasma levels of soluble (s) Tim-3 in early RA (n=98), were followed, to evaluate association with treatment and disease activity, acquired from a prospective collected biobank (clinicaltrials.gov (NCT00660647)). We also investigate the influence of Tim-3 on spontaneous cytokine production in synovial fluid mononuclear cells (SFMC) from RA patients after addition of neutralizing anti-Tim-3's antibodies, either alone or in combination with neutralizing anti-Programmed Cell death protein 1 (PD-1) antibodies.
Results: Long-time stimulated CD4 T-cells expressed high levels of Tim-3, but tended to decrease their PD-1 expression. Tim-3 expression was exclusively seen co-expressed with PD-1 by CD3, CD4, CD45RO positive cells in the inflamed RA joint. Addition of neutralizing Tim-3 antibodies increased the secretion of IFNγ and MCP-1, in SFMC cultures from RA. Whereas neutralizing anti-PD-1 antibodies showed a broader impact on cytokine production. Finally, we observed that soluble Tim-3 is increased in plasma and is associated with disease activity in early RA.
Conclusion: Taken together, our findings indicate disease-suppressive functions of Tim-3 in RA.
Keywords: DAS28CRP; Rheumatoid arthritis; Tim-3; anti-TNF-alfa.
Conflict of interest statement
None.
AJCEI Copyright © 2022.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9301058/bin/ajcei0011-0034-f1.jpg)
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9301058/bin/ajcei0011-0034-f3.jpg)
Figure 4
Increased sTim-3 in synovial fluid…
Figure 4
Increased sTim-3 in synovial fluid (SF) and in plasma from RA patients (A,…
Figure 5
Plasma concentrations of soluble (s)…
Figure 5
Plasma concentrations of soluble (s) Tim-3 was examined in patients with early RA…
- Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28.Koohini Z, Hossein-Nataj H, Mobini M, Hosseinian-Amiri A, Rafiei A, Asgarian-Omran H. Koohini Z, et al. Clin Rheumatol. 2018 Aug;37(8):2063-2071. doi: 10.1007/s10067-018-4076-4. Epub 2018 Apr 7. Clin Rheumatol. 2018. PMID: 29626269
- High Interleukin-37 (IL-37) Expression and Increased Mucin-Domain Containing-3 (TIM-3) on Peripheral T Cells in Patients with Rheumatoid Arthritis.Song L, Wang Y, Sui Y, Sun J, Li D, Li G, Liu J, Li T, Shu Q. Song L, et al. Med Sci Monit. 2018 Aug 14;24:5660-5667. doi: 10.12659/MSM.909254. Med Sci Monit. 2018. PMID: 30106887 Free PMC article.
- Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis.Lee J, Oh JM, Hwang JW, Ahn JK, Bae EK, Won J, Koh EM, Cha HS. Lee J, et al. Scand J Rheumatol. 2011;40(5):334-40. doi: 10.3109/03009742.2010.547871. Epub 2011 Mar 30. Scand J Rheumatol. 2011. PMID: 21446887
- Novel insights into Tim-4 function in autoimmune diseases.Fang XY, Xu WD, Pan HF, Leng RX, Ye DQ. Fang XY, et al. Autoimmunity. 2015 Jun;48(4):189-95. doi: 10.3109/08916934.2014.983266. Epub 2014 Nov 19. Autoimmunity. 2015. PMID: 25470136 Review.
- Mechanisms of immune injury in rheumatoid arthritis: evidence for the involvement of T cells and heat-shock protein.Strober S, Holoshitz J. Strober S, et al. Immunol Rev. 1990 Dec;118:233-55. doi: 10.1111/j.1600-065x.1990.tb00818.x. Immunol Rev. 1990. PMID: 1967122 Review.
- The Variations' in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis.Andrzejczak A, Tupikowski K, Tomkiewicz A, Małkiewicz B, Ptaszkowski K, Domin A, Szydełko T, Karabon L. Andrzejczak A, et al. Int J Mol Sci. 2023 Jan 20;24(3):2042. doi: 10.3390/ijms24032042. Int J Mol Sci. 2023. PMID: 36768365 Free PMC article.
- ClinicalTrials.gov/NCT00660647
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![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9301058/bin/ajcei0011-0034-f4.jpg)
Figure 5
Plasma concentrations of soluble (s)…
Figure 5
Plasma concentrations of soluble (s) Tim-3 was examined in patients with early RA…
- Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28.Koohini Z, Hossein-Nataj H, Mobini M, Hosseinian-Amiri A, Rafiei A, Asgarian-Omran H. Koohini Z, et al. Clin Rheumatol. 2018 Aug;37(8):2063-2071. doi: 10.1007/s10067-018-4076-4. Epub 2018 Apr 7. Clin Rheumatol. 2018. PMID: 29626269
- High Interleukin-37 (IL-37) Expression and Increased Mucin-Domain Containing-3 (TIM-3) on Peripheral T Cells in Patients with Rheumatoid Arthritis.Song L, Wang Y, Sui Y, Sun J, Li D, Li G, Liu J, Li T, Shu Q. Song L, et al. Med Sci Monit. 2018 Aug 14;24:5660-5667. doi: 10.12659/MSM.909254. Med Sci Monit. 2018. PMID: 30106887 Free PMC article.
- Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis.Lee J, Oh JM, Hwang JW, Ahn JK, Bae EK, Won J, Koh EM, Cha HS. Lee J, et al. Scand J Rheumatol. 2011;40(5):334-40. doi: 10.3109/03009742.2010.547871. Epub 2011 Mar 30. Scand J Rheumatol. 2011. PMID: 21446887
- Novel insights into Tim-4 function in autoimmune diseases.Fang XY, Xu WD, Pan HF, Leng RX, Ye DQ. Fang XY, et al. Autoimmunity. 2015 Jun;48(4):189-95. doi: 10.3109/08916934.2014.983266. Epub 2014 Nov 19. Autoimmunity. 2015. PMID: 25470136 Review.
- Mechanisms of immune injury in rheumatoid arthritis: evidence for the involvement of T cells and heat-shock protein.Strober S, Holoshitz J. Strober S, et al. Immunol Rev. 1990 Dec;118:233-55. doi: 10.1111/j.1600-065x.1990.tb00818.x. Immunol Rev. 1990. PMID: 1967122 Review.
- The Variations' in Genes Encoding TIM-3 and Its Ligand, Galectin-9, Influence on ccRCC Risk and Prognosis.Andrzejczak A, Tupikowski K, Tomkiewicz A, Małkiewicz B, Ptaszkowski K, Domin A, Szydełko T, Karabon L. Andrzejczak A, et al. Int J Mol Sci. 2023 Jan 20;24(3):2042. doi: 10.3390/ijms24032042. Int J Mol Sci. 2023. PMID: 36768365 Free PMC article.
- ClinicalTrials.gov/NCT00660647
- Full Text Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9301058/bin/ajcei0011-0034-f5.jpg)
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