Original Article
 

Downregulation of Immunosuppressive Molecules, PD-1 and PD-L1 but not PD-L2, in the Patients with Multiple Sclerosis

Abstract

Programmed cell death-1 (PD-1) and its ligands, PD-L1 and PD-L2, have been regarded as important immune system regulatory molecules. The aberrant expression of the molecules has been related to several autoimmune disorders. This study is aimed to assess the mRNA expression level of PD-1, PD-L1, and PD-L2 molecules in the peripheral blood mononuclear mells (PBMCs) from multiple sclerosis (MS) patients. PBMCs were isolated from the whole blood of 50 MS and 50 healthy individuals. Total RNA content of the leukocytes was extracted. Then, cDNA was synthesized from the extracted RNA. Afterwards, quantitative analysis of PD-1, PD-L1 and PD-L2 was carried out through Real Time PCR using the TaqMan gene expression assays. Relative expression of PD-1 and PD-L1 in PBMCs from MS patients was significantly lower compared with the healthy control group (p=0.003 and 0.012, respectively). However, no significant difference was observed in the expression level of PD-L2 between patients and healthy individuals. Relative expression of PD-1 correlated with expanded disability status scale score (EDSS) of the patients (r=-0.763, p=0.008). Downregulation of the immunosuppressive molecules, PD-1 and PD-L1, may imply that over-activation of immune cells in multiple sclerosis occurs through signaling dysfunction of these molecules and PD-L2 plays no important role in this context.

Tobón GJ, Pers J-O, Cañas CA, Rojas-Villarraga A, Youinou P, Anaya J-M. Are autoimmune diseases predictable? Autoimmun Rev 2012; 11(4):259-66.
2. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7):1027-34.
3. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for
PD-1 and inhibits T cell activation. Nat Immunol 2001;2(3):261-8.
4. Chen L, Flies DB. Molecular mechanisms of T cell co- stimulation and co-inhibition. Nat Rev Immunol 2013;
13(4):227-42.
5. Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev 2013; 12(11):1091-100.
6. Goldenberg MM. Multiple sclerosis review. P T 2012;37(3):175-84.
7. Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 2011; 82(10):1132-41.
8. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. The Lancet Neurol 2005;4(5):281-8.
9. Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol 2015; 14(4):406-19.
10. Khondkarian O, Zavalishin I, Nevskaia O. [Classification of multiple sclerosis]. Zh Nevropatol Psikhiatr Im S S Korsakova 1983; 83(2):164-6.
11. Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature 1999; 399 (6738 Suppl):A40-7.
12. Compston, A. and A. Coles, Multiple sclerosis. Lancet 2002; 359 (9313):1221-31.
13. Anaya J-M. The autoimmune tautology. Arthritis Res Ther 2010; 12(6):147.
14. Jafari N, Shaghaghi H, Mahmoodi D, Shirzad Z, Alibeiki F, Bohlooli S, et al. Overexpression of microRNA biogenesis machinery: Drosha, DGCR8 and Dicer in multiple sclerosis patients. J Clin Neurosci 2015;22(1):200-3.
15. Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Mäurer M, et al. A PD‐1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 2005; 58(1):50-7.
16. Ortler S, Leder C, Mittelbronn M, Zozulya AL, Knolle PA, Chen L, et al. B7‐H1 restricts neuroantigen‐specific T cell responses and confines inflammatory CNS damage: Implications for the lesion pathogenesis of multiple sclerosis. Eur J Immunol 2008; 38(6):1734-44.
17. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50(1):121-7.
18. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2):292-302.
19. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc 2008;3(6):1101-8.
20. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004; 4(5):336-47.
21. Carter LL, Leach MW, Azoitei ML, Cui J, Pelker JW, Jussif J, et al. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 2007;
182(1-2):124-34.
22. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8(3):239-45.
23. Zamani MR, Asbagh FA, Massoud AH, Salmaninejad A, Massoud A, Rezaei N. Association between a PD-1 gene polymorphism and antisperm antibody-related infertility in Iranian men. J Assist Reprod Genet 2015; 32(1):103-6.
24. Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, Zhu G, et al. Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 2003; 111(3):363-70.
25. Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, Weller M, et al. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD- L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004; 155(1-2):172-82.

Files
IssueVol 15, No 4 (2016) QRcode
SectionOriginal Article(s)
Keywords
Gene expression Multiple sclerosis Programmed cell death 1 receptor Programmed cell death 1 ligand 1 protein Programmed cell death 1 ligand 2 protein

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Javan MR, Aslani S, Zamani MR, Rostamnejad J, Asadi M, Farhoodi M, Nicknam MH. Downregulation of Immunosuppressive Molecules, PD-1 and PD-L1 but not PD-L2, in the Patients with Multiple Sclerosis. Iran J Allergy Asthma Immunol. 2016;15(4):296-302.