Skip to main content

Advertisement

SpringerLink
Log in

Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) and TIM-3 ligands in peripheral blood from patients with systemic lupus erythematosus

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease. The T cell immunoglobulin and mucin domain (TIM) family is associated with autoimmune diseases, but its level of expression in the immune cells of patients with SLE is still uncertain. The aim of this study was to examine whether TIM-3 and Galectin-9 (Gal-9) contribute to the pathogenesis of SLE. In total, 30 patients with SLE and 30 healthy controls were recruited, and their levels of TIM-3 expression in peripheral blood mononuclear cells (PBMCs) were examined via flow cytometry. Meanwhile, the levels of Gal-9 expression in serum and in PBMCs were measured via an enzyme-linked immunosorbent assay (ELISA) kit and immunofluorescence staining, respectively. The relation between the level of TIM-3 or Gal-9 expression and the SLE disease activity index (SLEDAI) was also studied. Finally, the function of the TIM-3 and Gal-9 pathway in the pathogenesis of SLE was explored. Our results showed that the levels of expression of TIM-3 and Gal-9 on CD4+ T cells, CD8+ T cells, CD56+ T cells and in serum in patients with SLE were significantly higher than those of healthy controls. We found that the level of Gal-9 expression was significantly higher in both serum and PMBCs of patients with SLE than in healthy controls. The up-regulation of TIM-3 and Gal-9 expression in patients with SLE was closely related to the SLEDAI scores. In addition, Gal-9 blocking antibody significantly inhibited CD3-stimulated PBMC proliferation and Th1-derived cytokines (IL-2, IFN-γ, and TNF-α), Th2-derived cytokines (IL-4, IL-10), a Th17-derived cytokine (IL-17A), and release of a pro-inflammatory factor (IL-6) in patients with SLE. The results suggest that increased expression of TIM-3 and Gal-9 may be a biomarker for SLE diagnosis and that the TIM-3 pathway may be a target for SLE treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Alunno A, Bartoloni E, Bistoni O, Nocentini G, Ronchetti S, Caterbi S, Valentini V, Riccardi C, Gerli R (2012) Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new. Clin Dev Immunol 2012:823085

    Article  PubMed  PubMed Central  Google Scholar 

  2. Anderson AC (2012) Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol 24(2):213–216

    Article  CAS  PubMed  Google Scholar 

  3. Arikawa T, Saita N, Oomizu S, Ueno M, Matsukawa A, Katoh S, Kojima K, Nagahara K, Miyake M, Yamauchi A, Kohrogi H, Hirashima M (2010) Galectin-9 expands immunosuppressive macrophages to ameliorate T-cell-mediated lung inflammation. Eur J Immunol 40(2):548–558

    Article  CAS  PubMed  Google Scholar 

  4. Bazso A, Szappanos A, Patocs A, Poor G, Shoenfeld Y, Kiss E (2015) The importance of glucocorticoid receptors in systemic lupus erythaematosus. A systematic review. Autoimmun Rev 14(4):349–351

    Article  CAS  PubMed  Google Scholar 

  5. Cai XZ, Huang WY, Qiao Y, Chen Y, Du SY, Chen D, Yu S, Liu N, Dou LY, Jiang Y (2015) Downregulation of TIM-3 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Braz J Med Biol Res 48(1):77–82

    Article  CAS  PubMed  Google Scholar 

  6. Chae SC, Park YR, Shim SC, Yoon KS, Chung HT (2004) The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Immunol Lett 95(1):91–95

    Article  CAS  PubMed  Google Scholar 

  7. de Kivit S, Lempsink LJ, Plants J, Martinson J, Keshavarzian A, Landay AL (2015) Modulation of TIM-3 expression on NK and T cell subsets in HIV immunological non-responders. Clin Immunol 156(1):28–35

    Article  PubMed  Google Scholar 

  8. Du WT, Zhao HF, Xu JH, Gu DS, Xue F, Ge J, Dong XW, Chen ZP, Zhou ZP, Yang RC (2009) The role of T-cell immunoglobulin- and mucin-domain-containing molecule-3 polymorphisms in idiopathic thrombocytopenic purpura. Hum Immunol 70(6):398–402

    Article  CAS  PubMed  Google Scholar 

  9. Ferris RL, Lu B, Kane LP (2014) Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. J Immunol 193(4):1525–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fujita T, Burwitz BJ, Chew GM, Reed JS, Pathak R, Seger E, Clayton KL, Rini JM, Ostrowski MA, Ishii N, Kuroda MJ, Hansen SG, Sacha JB, Ndhlovu LC (2014) Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. J Immunol 193(11):5576–5583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gleason MK, Lenvik TR, McCullar V, Felices M, O’Brien MS, Cooley SA, Verneris MR, Cichocki F, Holman CJ, Panoskaltsis-Mortari A, Niki T, Hirashima M, Blazar BR, Miller JS (2012) Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood 119(13):3064–3072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo L, Yang X, Xia Q, Zhen J, Zhuang X, Peng T (2014) Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) on kidney tissue from systemic lupus erythematosus (SLE) patients. Clin Exp Med 14(4):383–388

    Article  CAS  PubMed  Google Scholar 

  13. Hanly JG (2014) Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol 10(6):338–347

    Article  CAS  PubMed  Google Scholar 

  14. Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W, Liang X, Gao L, Ma C (2010) T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 52(3):322–329

    Article  CAS  PubMed  Google Scholar 

  15. Khaitan A, Unutmaz D (2011) Revisiting immune exhaustion during HIV infection. Curr HIV 8(1):4–11

    Article  Google Scholar 

  16. Koguchi K, Anderson DE, Yang L, O’Connor KC, Kuchroo VK, Hafler DA (2006) Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med 203(6):1413–1418

    Article  CAS  PubMed  Google Scholar 

  17. Konya C, Paz Z, Tsokos GC (2014) The role of T cells in systemic lupus erythematosus: an update. Curr Opin Rheumatol 26(5):493–501

    Article  CAS  PubMed  Google Scholar 

  18. Li S, Peng D, He Y, Zhang H, Sun H, Shan S, Song Y, Zhang S, Xiao H, Song H, Zhang M (2014) Expression of TIM-3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis. APMIS 122(10):899–904

    Article  CAS  PubMed  Google Scholar 

  19. Li WX, Chen GM, Yuan H, Yao YS, Li RJ, Pan HF, Li XP, Xu JH, Tao JH, Ye DQ (2011) Polymorphisms of the TIM-1 and TIM-3 genes are not associated with systemic lupus erythematosus in a Chinese population. Mutagenesis 26(4):507–511

    Article  CAS  PubMed  Google Scholar 

  20. Li Y, Feng J, Geng S, Geng S, Wei H, Chen G, Li X, Wang L, Wang R, Peng H, Han G, Shen B, Li Y (2011) The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity. Mol Immunol 48(4):670–677

    Article  CAS  PubMed  Google Scholar 

  21. Li Z, Ju Z, Frieri M (2013) The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity. Allergy Asthma Proc 34(1):e21–e26

    Article  CAS  PubMed  Google Scholar 

  22. Mak A, Kow NY (2014) The pathology of T cells in systemic lupus erythematosus. J Immunol Res 2014:419029

    Article  PubMed  PubMed Central  Google Scholar 

  23. Martin JC, Baeten DL, Josien R (2014) Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clin Immunol 154(1):1–12

    Article  CAS  PubMed  Google Scholar 

  24. Maurya N, Gujar R, Gupta M, Yadav V, Verma S, Sen P (2014) Immunoregulation of dendritic cells by the receptor T cell Ig and mucin protein-3 via Bruton’s tyrosine kinase and c-Src. J Immunol 193(7):3417–3425

    Article  CAS  PubMed  Google Scholar 

  25. Mikolajczyk TP, Skiba D, Batko B, Krezelok M, Wilk G, Osmenda G, Pryjma JR, Guzik TJ (2014) Characterization of the impairment of the uptake of apoptotic polymorphonuclear cells by monocyte subpopulations in systemic lupus erythematosus. Lupus 23(13):1358–1369

    Article  CAS  PubMed  Google Scholar 

  26. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541

    Article  CAS  PubMed  Google Scholar 

  27. Pan HF, Zhang N, Li WX, Tao JH, Ye DQ (2010) TIM-3 as a new therapeutic target in systemic lupus erythematosus. Mol Biol Rep 37(1):395–398

    Article  CAS  PubMed  Google Scholar 

  28. Pieterse E, van der Vlag J (2014) Breaking immunological tolerance in systemic lupus erythematosus. Front Immunol 5:164

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK (2011) Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol 32(8):345–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N, Nishi N, Yamauchi A, Katoh S, Matsukawa A, Kuchroo V, Hirashima M (2008) Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol 127(1):78–88

    Article  CAS  PubMed  Google Scholar 

  31. Seki M, Sakata KM, Oomizu S, Arikawa T, Sakata A, Ueno M, Nobumoto A, Niki T, Saita N, Ito K, Dai SY, Katoh S, Nishi N, Tsukano M, Ishikawa K, Yamauchi A, Kuchroo V, Hirashima M (2007) Beneficial effect of galectin 9 on rheumatoid arthritis by induction of apoptosis of synovial fibroblasts. Arthritis Rheum 56(12):3968–3976

    Article  CAS  PubMed  Google Scholar 

  32. Shin MS, Lee N, Kang I (2011) Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Curr Opin Rheumatol 23(5):444–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Song YW, Im CH, Park JH, Lee YJ, Lee EY, Lee EB, Park K (2011) T-cell immunoglobulin and mucin domain 3 genetic polymorphisms are associated with rheumatoid arthritis independent of a shared epitope status. Hum Immunol 72(8):652–655

    Article  CAS  PubMed  Google Scholar 

  34. Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C (2008) Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol 67(1):63–70

    Article  CAS  PubMed  Google Scholar 

  35. Xu J, Yang Y, Liu X, Wang Y (2012) Genetic variation and significant association of polymorphism rs7700944 G > A of TIM-4 gene with rheumatoid arthritis susceptibility in Chinese Han and Hui populations. Int J Immunogenet 39(5):409–413

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Q, Luan H, Wang L, He F, Zhou H, Xu X, Li X, Xu Q, Niki T, Hirashima M, Xu G, Lv Y, Yuan J (2014) Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice. Am J Physiol Renal Physiol 306(8):F822–F832

    Article  CAS  PubMed  Google Scholar 

  37. Zhang ZY, Schluesener HJ, Zhang Z (2011) Distinct expression of Tim-3 during different stages of rat experimental autoimmune neuritis. Brain Res Bull 86(3–4):229–234

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant Nos. 31170834 and 81402597) and the Science and Technology Project of Suzhou (Grant No. SYS201331). The authors express their appreciation to the enrolled patients.

Author information

Author notes

    Authors and Affiliations

    1. Clinical Immunology Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China

      Qingqing Jiao, Qihong Qian, Fumin Fang, Jian Wu & Cuiping Liu

    2. Department of Dermatology, The First Affiliated Hospital of Soochow University, Suzhou, China

      Qingqing Jiao, Qihong Qian & Fumin Fang

    3. Department of Dermatology, First Hospital, Peking University, Beijing, 100034, China

      Zuotao Zhao

    4. Institute of Medical Biotechnology, Medical College of Soochow University, Suzhou, China

      Xiaohan Hu & Jingnan An

    5. Department of Rheumatology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China

      Jian Wu

    Authors
    1. Qingqing Jiao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Qihong Qian
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Zuotao Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Fumin Fang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiaohan Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jingnan An
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jian Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Cuiping Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jian Wu or Cuiping Liu.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interests regarding the publication of this paper.

    Additional information

    Q. Jiao and Q. Qian contributed equally to this work

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 224 kb)

    Supplementary material 2 (PDF 155 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jiao, Q., Qian, Q., Zhao, Z. et al. Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) and TIM-3 ligands in peripheral blood from patients with systemic lupus erythematosus. Arch Dermatol Res 308, 553–561 (2016). https://doi.org/10.1007/s00403-016-1665-4

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00403-016-1665-4

    Keywords

    Search

    Navigation