Association of New Putative Epitopes of Myelin Proteolipid Protein (58-74) with Pathogenesis of Multiple Sclerosis
Abstract
Multiple sclerosis (MS) is an autoimmune disease in which auto-reactive T cells react with self-antigens expressed in the central nervous system (CNS). The main cause of MS is unknown. Nonetheless, the most probable theory is based on molecular mimicry, which suggests that some infections can activate T cells against brain auto-antigens like myelin proteolipid protein (PLP) and initiate the disease cascade. This study is conducted to evaluate the activatory effects of PLP58-74 on T lymphocytes and humoral immunity. PLP58-74 was considered as an immunodominant epitope candidate of PLP using bioinformatics tools. Patients and healthy individuals’ peripheral blood mononuclear cells (PBMCs) were treated with PLP58-74 and its proliferative effects were evaluated through assessing proliferating cell nuclear antigen (PCNA) gene expression changes by real time PCR and immunocytochemistry assay. Finally, the rate of CD4+ and CD8+ T cells were assessed by flowcytometry. ELISA was also performed to measure anti PLP58-74 antibody in patients’ serum. PLP58-74 induced proliferation in patients’ PBMCs while it did not influence PBMCs of healthy individuals. CD4+ T cells were the main activated cells in reaction to PLP58-74 which increased from 22% to 39.91%. In addition, immune assay showed threefold increase in specific anti PLP58-74 IgG in patients compared to healthy controls. Results showed that PLP58-74 can stimulate CD4+ T cells and humoral immunity. Therefore it seems that the epitopes of some microorganisms mimicking PLP such as PLP58-74 might have a potential role in the initiation of MS.
1. Wootla B, Eriguchi M, Rodriguez M. Is Multiple Sclerosis an Autoimmune Disease? Autoimmune Dis 2012; 2012:969657.
2. Schmitt N. Role of T Follicular Helper cells in Multiple Sclerosis. J Nat Sci 2015; 1(7):e139.
3. Bitarafan S, Saboor-Yaraghi A, Sahraian M-A, Soltani D, Nafissi S, Togha M, et al. Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A Double-Blind Placebo-Controlled Clinical Trial. Iran J Allergy Asthma Immunol 2015;15(1):13-9.
4. Houshmand M, Sanati M, Babrzadeh F, Ardalan A, Teimori M, Vakilian M, et al. Population screening for association of mitochondrial haplogroups BM, J, K and M with multiple sclerosis: interrelation between haplogroup J and MS in Persian patients. Mult Scler 2005; 11(6):728-30.
5. Goldenberg MM. Pharmaceutical approval update. PT 2009; 34(10):569-74.
6. Tafreshi AP, Mostafavi H, Zeynali B. Induction of experimental allergic encephalomyelitis in C57/BL6 Mice: an animal model for multiple sclerosis. Iran J Allergy Asthma Immunol 2005; 4(3):113-7.
7. Rivers TM, Sprunt D, Berry G. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 1933; 58(1):39-53.
8. Chintha R. Role of proteolipid protein (PLP/Dm20) and polyunsaturated fatty acids in normal and pathological central nervous system: Universität zu Köln; 2012.
9. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 2012; 42(1):102-11.
10. Elong-Ngono A, Pettré S, Salou M, Bahbouhi B, Soulillou J-P, Brouard S, et al. Frequency of circulating autoreactive T cells committed to myelin determinants in relapsing–remitting multiple sclerosis patients. Clin Immunol 2012; 144(2):117-26.
11. Massilamany C, Steffen D, Reddy J. An epitope from Acanthamoeba castellanii that cross-react with proteolipid protein 139-151-reactive T cells induces autoimmune encephalomyelitis in SJL mice. J Neuroimmunol 2010; 219(1-2):17-24.
12. Greer JM, Pender MP. Myelin proteolipid protein: an effective autoantigen and target of autoimmunity in multiple sclerosis. J Autoimmun 2008; 31(3):281-7.
13. Yamaguchi Y, Ikenaka K, Niinobe M, Yamada H, Mikoshiba K. Myelin proteolipid protein (PLP), but not DM-20, is an inositol hexakisphosphate-binding protein. J Biol Chem 1996; 271(44):27838-46.
14. Popot J-L, Dinh DP, Dautigny A. Major myelin proteolipid: the 4-α-helix topology. J Membr Biol 1991;120(3):233-46.
15. Stecca B, Southwood CM, Gragerov A, Kelley KA, Friedrich VL, Gow A. The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin. J Neurosci 2000;20(11):4002-10.
16. Taube JR, Sperle K, Banser L, Seeman P, Cavan BCV, Garbern JY, et al. PMD patient mutations reveal a long- distance intronic interaction that regulates PLP1/DM20 alternative splicing. Hum Mol Genet 2014; 23(20):5464-78.
17. Mecha M, Carrillo-Salinas FJ, Mestre L, Feliú A, Guaza C. Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theilers virus. Prog Neurobiol 2012.
18. Göbel K, Bittner S, Ruck T, Budde T, Wischmeyer E, Döring F, et al. Active immunization with proteolipid protein (190-209) induces ascending paralysing experimental autoimmune encephalomyelitis in C3H/HeJ mice. J Immunol Methods 2011; 367(1-2):27-32.
19. Tuohy V, Lu Z, Sobel R, Laursen R, Lees M.Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J Immunol 1989;142(5):1523-7.
20. Greer JM, Kuchroo VK, Sobel RA, Lees M.Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178-191) for SJL mice. J Immunol 1992; 149(3):783-8.
21. Tuohy VK, Thomas DM. Sequence 104–117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. J Neuroimmunol 1995;56(2):161-70.
22. Greer JM, Sobel RA, Sette A, Southwood S, Lees MB, Kuchroo VK. Immunogenic and encephalitogenic epitope clusters of myelin proteolipid protein. J Immunol 1996;156(1):371-9.
23. Whitham R, Jones R, Hashim G, Hoy C, Wang R, Vandenbark A, et al. Location of a new encephalitogenic epitope (residues 43 to 64) in proteolipid protein that induces relapsing experimental autoimmune encephalomyelitis in PL/J and (SJL x PL) F1 mice. J Immunol 1991; 147(11):3803-8.
24. Pelfrey CM, Trotter JL, Tranquill LR, McFarland HF.Identification of a novel T cell epitope of humanproteolipid protein (residues 40–60) recognized by proliferative and cytolytic CD4 T cells from multiple sclerosis patients. J Neuroimmunol 1993; 46(1):33-42.
25. Pelfrey CM, Trotter JL, Tranquill LR, McFarland HF.Identification of a second T cell epitore of human proteolipid protein (residues 89–106) recognized by proliferative and cytolytic CD4 T cells from multiple sclerosis patients. J Neuroimmunol 1994; 53(2):153-61.
26. Markovic-Plese S, Fukaura H, Zhang J, Al-Sabbagh A, Southwood S, Sette A, et al. T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans. J Immunol 1995; 155(2):982-92.
27. Greer JM, Csurhes PA, Cameron KD, McCombe PA, Good MF, Pender MP. Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain 1997; 120(8):1447-60.
28. Zamanzadeh Z. Ahangari Gh. Ataei M. Pouragahi S.Nabavi SM. Sadeghi M. Sanati MH. In Silico Perspectives on the Prediction of the PLP's Epitopes involved in Multiple Sclerosis. Iranian J of Biotechnol 2016 (in press).
29. Kaushansky N, Altmann DM, David CS, Lassmann H, Ben-Nun A. DQB1* 0602 rather than DRB1* 1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP). J Neuroinflammation 2012; 9:29.
30. Alcina A, Abad-Grau Mdel M, Fedetz M, Izquierdo G, Lucas M, Fernández Ó, et al. Multiple sclerosis risk variant HLA-DRB1* 1501 associates with high expression of DRB1 gene in different human populations. PloS one 2012; 7(1):e29819.
31. 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.
32. Pornour M, Ahangari G, H Hejazi S, Deezagi A. New perspective therapy of breast cancer based on selective dopamine receptor D2 agonist and antagonist effects on MCF-7 cell line. Recent Pat Anticancer Drug Discov 2015; 10(2):214-23.
33. Lunardi C, Tinazzi E, Bason C, Dolcino M, Corrocher R, Puccetti A. Human parvovirus B19 infection and autoimmunity. Autoimmun Rev 2008; 8(2):116-20.
34. Schloot N, Willemen S, Duinkerken G, Drijfhout J, De Vries R, Roep B. Molecular mimicry in type 1 diabetes mellitus revisited: T-cell clones to GAD65 peptides with sequence homology to Coxsackie or proinsulin peptides do not crossreact with homologous counterpart. Hum Immunol 2001; 62(4):299-309.
35. Poole BD, Scofield RH, Harley JB, James JA. Epstein- Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity 2006; 39(1):63-70.
36. Greene MT, Ercolini AM, DeGutes M, Miller SD.Differential induction of experimental autoimmune encephalomyelitis by myelin basic protein molecular mimics in mice humanized for HLA-DR2 and an MBP 85–99-specific T cell receptor. J Autoimmun 2008;31(4):399-407.
37. Westall FC. Molecular mimicry revisited: gut bacteria and multiple sclerosis. J Clin Microbiol 2006;44(6):2099-104.
38. Marín N, Eixarch H, Mansilla M, Rodríguez‐Martín E, Mecha M, Guaza C, et al. Anti‐myelin antibodies play an important role in the susceptibility to develop proteolipid protein‐induced experimental autoimmune encephalomyelitis. Clin Exp Immunol 2014; 175(2):202-7.
39. Munger K, Levin L, O’Reilly E, Falk K, Ascherio A.Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 2011; 17(10):1185-93.
40. Wegmann KW, Bouwer HA, Whitham RH, Hinrichs DJ.
Eluding anaphylaxis allows peptide-specific prevention of the relapsing stage of experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 274(1-2):46-52.
41. Badawi AH, Siahaan TJ. Suppression of MOG-and PLP- induced experimental autoimmune encephalomyelitis using a novel multivalent bifunctional peptide inhibitor. J Neuroimmunol 2013; 263(1-2):20-7.
42. Kasarello K, Kwiatkowska-Patzer B, Lipkowski AW, Bardowski JK, Szczepankowska AK. Oral Administration of Lactococcus lactis Expressing Synthetic Genes of Myelin Antigens in Decreasing Experimental Autoimmune Encephalomyelitis in Rats. Med Sci Monit 2015; 21:1587-97.
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Issue | Vol 15, No 5 (2016) | |
Section | Original Article(s) | |
Keywords | ||
Autoimmune disease Experimental autoimmune encephalomyelitis Myelin proteolipid protein Molecular mimicry Multiple sclerosis |
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