Evaluation of Soluble Human Leukocyte Antigen-G (sHLA-G) Isoforms and Regulatory T Cells in Relapsing-Remitting Multiple Sclerosis
-
Fereshteh Alsahebfosoul
,
Ahmad Zavaran-Hosseini
,
Rasoul Salehi
,
Masood Etemadifar
,
Nafiseh Esmaeil
,
Azam Jamshidian
Abstract
Soluble forms of nonclassical human leukocyte antigen (HLA)-G have recently been suggested as immunomodulatory factors in multiple sclerosis (MS). HLA-G inhibits the effecter function of T cells and natural killer (NK) cells. Also regulatory T cells (Treg) are considered as pivotal players in MS pathogenesis. Thus, we aimed to evaluate the presence of HLA-G molecules and Treg cells in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and compare it to healthy controls.Patients with RRMS (n=205, mean age=31.32±8.53) and healthy subjects (n=205, mean age=32.2±7.48) were studied. The patients subgrouped to untreated and treated with Interferon beta. Then sHLA-G levels (sHLA-G1 and sHLA-G5) were measured using ELISA method. Treg (CD4+CD25+ Foxp3+) cells in patients who had sHLA-G>10 U/ml were characterized by using flow cytometry.Our data showed that there was no significant differences between RRMS patients and healthy controls in sHLA-G concentration (p>0.05). Treg cell frequencies were higher in the patients who had sHLA-G >10 U/ml compared to healthy subjects (p<0.05).Collectively, there was significant correlation between sHLA-G and frequency of Treg cells in treated RRMS patients and healthy individuals. It seems that high level sHLA-G has been instrumental in raising frequency of Treg cells in treated patients and could be associated with remission of MS disease.
1. Lin R, Taylor BV, Simpson S Jr, Charlesworth J, Ponsonby AL, Pittas F, et al. Association between multiple sclerosis risk-associated SNPs and relapse and disability - a prospective cohort study. Mult Scler 2013;20(3):313-21.
2. International Multiple Sclerosis Genetics Consortium.The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study. PLoS One 2011; 6(4):e18813.3. Reich D1, Patterson N, De Jager PL, McDonald GJ,
Waliszewska A, Tandon A, et al. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 2005; 37(10):1113-8.4. Martino G, Furlan R, Poliani PL. [The pathogenic role of inflammation in multiple sclerosis]. Rev Neurol 2000;30(12):1213-7.
5. Lukas C, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Bendfeldt K, et al. Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients. Radiology 2013; 269(2):542-52.
6. Poser CM, Brinar VV. Diagnostic criteria for multiple sclerosis. Clin Neurol Neurosurg 2001; 103(1):1-11.
7. Daria Bortolotti, V.G., Antonella Rotola, Enzo Cassai, Roberta Rizzo, Dario Di Luca, Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions. World Journal of W J M Methodology 2014;4(1):11-25.
8. Kirszenbaum M, Moreau P, Gluckman E, Dausset J, Carosella E. An alternatively spliced form of HLA-G mRNA in human trophoblasts and evidence for the presence of HLA-G transcript in adult lymphocytes. Proc Natl Acad Sci U S A 1994; 91(10):4209-13.
9. Fujii T, Ishitani A, Geraghty DE. A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol 1994; 153(12): p.5516-24.
10. Fujii T, Ishitani A, Geraghty DE. Geraghty, A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol 1994;153(12):5516-24.
11. Poláková K, Bandžuchová E, Russ G. Impact of blood processing on estimation of soluble HLA-G. Neoplasma 2011; 58(4):337-42.
12. Pistoia V, Morandi F, Wang X, Ferrone S. Soluble HLA- G: Are they clinically relevant? Semin Cancer Biol 2007;17(6):469-79.
13. Chen CH, Liao HT, Chen HA, Liu CH, Liang TH, Wang CT, et al. Human leukocyte antigen-G in ankylosing spondylitis and the response after tumour necrosis factor- alpha blocker therapy. Rheumatology (Oxford) 2010;49(2):264-70.
14. Bahri R, Hirsch F, Josse A, Rouas-Freiss N, Bidere N, Vasquez A, et al. Soluble HLA-G inhibits cell cycle progression in human alloreactive T lymphocytes. J Immunol 2006; 176(3):1331-9.
15. Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA- G. Proc Natl Acad Sci U S A 2003; 100(15):8856-61.
16. Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, et al. Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol 2003;33(1):125-34.
17. Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED. Soluble HLA-G protein secreted by allo- specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A 2001; 98(21):12150-5.
18. Riteau B, Rouas-Freiss N, Menier C, Paul P, Dausset J, Carosella ED. HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. J Immunol 2001;166(8):5018-26.
19. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci U S A 2004; 101(18):7064-9.
20. Waschbisch A, Sandbrink R, Hartung HP, Kappos L, Schwab S, Pohl C, et al. Evaluation of soluble HLA-G as a biomarker for multiple sclerosis. Neurology 2011;77(6):596-8.
21. Zozulya AL, Wiendl H. The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 2008; 4(7):384-98.
22. Fainardi E, Rizzo R, Melchiorri L, Stignani M, Castellazzi M, Caniatti ML, et al. Soluble HLA-G molecules are released as HLA-G5 and not as soluble HLA-G1 isoforms in CSF of patients with relapsing- remitting multiple sclerosis. J Neuroimmunol 2007;192(1-2):219-25.
23. Mitsdoerffer M, Schreiner B, Kieseier BC, Neuhaus O, Dichgans J, Hartung HP, et al. Monocyte-derived HLA-G acts as a strong inhibitor of autologous CD4 T cell activation and is upregulated by interferon-beta in vitro and in vivo: rationale for the therapy of multiple sclerosis. J Neuroimmunol 2005; 159(1-2):155-64.
24. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease- modulating drugs. J Clin Immunol 2004; 24(2):155-61.
25. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA.Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199(7):971-9.
26. Fritzsching B, Oberle N, Eberhardt N, Quick S, Haas J, Wildemann B, et al. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol 2005; 175(1):32-6.
27. Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 2007(147 ):412–8.
28. Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D'hooghe MB, et al. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 2006; 83(8):1432-46.
29. Kumar M, Putzki N, Limmroth V, Remus R, Lindemann M, Knop D, et al. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J Neuroimmunol 2006;180(1-2):178-84.
30. Khoury SJ, Guttmann CR, Orav EJ, Kikinis R, Jolesz FA, Weiner HL. CHanges in activated t cells in the blood correlate with disease activity in multiple sclerosis. Arch Neurol 2000; 57(8):1183-9.
31. Duszczyszyn DA, Beck JD, Antel J, Bar-Or A, Lapierre Y, Gadag V, et al. Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms. Clin Exp Immunol 2006; 143(2):305-13.
32. Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, et al. The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin Exp Immunol 2005; 140(3):540-6.
33. Rebmann V, Pfeiffer K, Pässler M, Ferrone S, Maier S, Weiss E, et al. Detection of soluble HLA-G molecules in plasma and amniotic fluid. Tissue Antigens 1999;53(1):14-22.
34. Abediankenari S, Farzad F, Rahmani Z, and Hashemi- soteh MB. HLA-G in pregnant women: HLA-G5 and G7 Isoforms in Pregnant Women, IJAAI, In press.
| Files | ||
| Issue | Vol 14, No 3 (2015) | |
| Section | Original Article(s) | |
| Keywords | ||
| Multiple sclerosis Regulatory T cells sHLA-G | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
