Iranian Journal of Allergy, Asthma and Immunology 2017. 16(1):21-27.

Inverse Relation between MxA Gene Expression and Age in Multiple Sclerosis Patients Reveals a Gender Difference in Response to Interferon Therapy
Mohammad Taheri, Mohammadreza Mirinezhad, Mir Davood Omrani, Elham Sajjadi, Hidetoshi Inoko, Arezou Sayad

Abstract


Multiple sclerosis (MS) is an inflammatory, multifocal, immune-mediated disease of the central nervous system that women are at a higher risk to acquire than men. Myxovirus resistance protein A (MxA) is used as a predictive marker of bioactivity of interferon-beta (IFN-β) therapy in MS patients. This study was undertaken in west of Iran to investigate gender differences in the expression level of MxA in relapsing-remitting MS (RRMS) patients receiving IFN-β therapy, compared with untreated normal individuals. The expression level of the MxA gene in RRMS samples were compared to untreated normal individuals using the extracted RNA from whole blood of 50 RRMS patients (31 females and 19 males) and 50 normal controls (29 females and 21 males). All patients were HLA-DRB1*15 negative and responded to IFN-β with a normal vitamin D level. The level of MxA gene expression was measured by quantitative RT-PCR. The levels of gene expression were decreased in RRMS patients compared with normal counterparts (p=0.025). This decrease was significant in females (p=0.009) compared to males (p>0.05). The level of expression varied across different female age-groups with no significant difference in women younger than 30 years, but a significant decrease in expression in women between 30 to 40 years or above 40 years of age was seen. There was neither linear correlation between the MxA expression level and risk of expanded disability status scale of Kurtzke (EDSS); nor were there any significant correlation between expression status of MxA and duration of the disease. In conclusion, the decrease in the level of MxA expression in MS patients treated with IFN-β when compared to normal individuals was significantly lower in females than males.  This demonstrated a gender bias in the response to IFN-β therapy that will need to be confirmed and further investigated in more detail.


Keywords


Gene expression; Interferon-beta; Multiple sclerosis; Mx1

Full Text:

PDF

References


1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis results of an international survey. Neurology 1996; 46(4):907-11.

2. Berer  K, Krishnamoorthy G. Microbial  view of central nervous    system    autoimmunity.    FEBS    lett    2014;588(22):4207-13.

3. Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med 1994; 96(5):457-62.

4.   Oksenberg   JR,   Barcellos   LF.   The   complex   genetic aetiology  of   multiple   sclerosis.   J   Neurovirol   2000;6(2):S10-4.

5. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics  and  the  environment.  Autoimmun  Rev  31;9(5):A387-94.

6. Taheri M, Nemati S, Movafagh A, Eftekharian MM, Mirfakhraie R, Saberi M, et al. TRAIL gene expression analysis in multiple sclerosis patients. Hum Antibodies2016; 24(1-2):338.

7.  Eftekharian MM, Ghannad MS, Taheri M, Roshanaei G, Mazdeh M, Musavi M, et al. Frequency of viral infections and environmental factors in multiple sclerosis. Hum Antibodies 2015; 24(1-2):17-23.

8.  Izadi S, Nikseresht A, Sharifian M, Sahraian MA, Jahromi AH, Aghighi M, et al. Significant increase in the prevalence of multiple sclerosis in iran in 2011. Iran J Med Sci 2014; 39(2):152-3.

9.   Eftekharian,  Mohammad  Mahdi,  et  al.  "RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis. Journal of the Neurological Sciences 2016; 369:259-62.

10. Eftekharian MM, Sayad A, Omrani MD, Ghannad MS, Noroozi R, Mazdeh M, Mirfakhraie R, Movafagh A, Roshanaei G, Azimi T, Inoko H. Single nucleotide polymorphisms in the FOXP3 gene are associated with increased  risk of relapsing-remitting multiple sclerosis. Human Antibodies. 2016 21(Preprint):1-6.

11. Nazdik MK, Taheri M, Omrani MD, Sajjadi E, Arsang- Jang S, Koohpar ZK, Inoko H, Sayad A. Increased expression ratio of matrix metalloproteinase-9 (MMP9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) RNA levels in Iranian multiple sclerosis patients. Human Antibodiesh 2016 22(Preprint):1-5.

12. Bertolotto A, Granieri L, Marnetto F, Valentino P, Sala A, Capobianco M, et al. Biological monitoring of IFN-β therapy in  Multiple Sclerosis.  Cytokine Growth  Factor Rev 2015; 26(2):241-8.

13. Stone LA, Frank JA, Albert PS, Bash CN, Calabresi PA, Maloni H, McFarland HF. Characterization of MRI response to treatment with interferon beta-1b: contrast- enhancing MRI lesion frequency as a primary outcome measure. Neurology 1997; 49(3):862-9.

14. Arababadi MK, Mosavi R, Khorramdelazad H, Yaghini N, Zarandi ER, Araste M, et al. Cytokine patterns after therapy with Avonex®, Rebif®, Betaferon® and CinnoVex™ in relapsing-remitting multiple sclerosis in Iranian patients. Biomark Med 2010; 4(5):755-9.

15. Mekky RY, Abdelaziz AI. Sex hormones and HCV: an unresolved  mystery.  Expert  Rev  Gastroenterol  Hepatol 2013; 7(1):69-75.

16. Panchanathan R, Shen H, Zhang X, Ho SM, Choubey D.Mutually positive regulatory feedback loop between interferons and estrogen receptor-α in mice: implications for   sex   bias   in   autoimmunity.   PLoS   One   2010;5(5):e10868

17. Ahmed SA, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex MxA Gene Expression in MShormone action. Am J Patho 1985; 121(3):531-51.

18. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004; 13(9):635-8.

19. Nakaya M, Tachibana H, Yamada K. Effect of estrogens on the interferon-γ producing cell population of mouse splenocytes. Biosci Biotechnol Biochem 2006; 70(1):47-53.

20. Cunningham S, Graham C, Hutchinson M, Droogan A, O'Rourke K, Patterson  C,  et al. Pharmacogenomics  of responsiveness   to   interferon   IFN-beta   treatment   in multiple sclerosis: a genetic screen of 100 type I interferon-inducible  genes.  Clin  Pharmacol  Ther  2005;78(6):635-46.

21. Vallittu AM, Salmi AA, Erälinna JP. MxA protein induction  in  MS  patients  treated  with  intramuscular IFNβ-1a. Neurol Sci 2006; 26(6):438-43.

22. Hesse D, Sellebjerg F, Sorensen PS. Absence of MxA induction  by interferon  β  in  patients with  MS  reflects complete loss of bioactivity. Neurology 2009; 73(5):372-7.

23. Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, et al. Biological markers of interferon- beta therapy: comparison among interferon-stimulated genes  MxA,  TRAIL  and  XAF-1.  Mult  Scler  2006;12(1):47-57.

24. Matas E, Bau L, Martínez-Iniesta M, Romero-Pinel L, Mañé MA, Cobo-Calvo Á, et al. Baseline MxA mRNA expression predicts interferon beta response in multiple sclerosis patients. PloS one 2014; 9(11):e112758.

25. Ronni T, Melen K, Malygin A, Julkunen I. Control of IFN-inducible MxA gene expression in human cells.  J Immunol 1993; 150(5):1715-26.

26. Mibayashi M, Nakade K, Nagata K. Promoted cell death of cells expressing human MxA by influenza virus infection. Microbiol Immunol 2002; 46(1):29-36.

27.  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.

28. 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.

29. Mazdeh M, Taheri M, Sayad A, Bahram S, Omrani MD, Movafagh A, et al. HLA genes as modifiers of response to IFN-beta-1a therapy in relapsing-remitting multiple sclerosis. Pharmacogenomics 2016; 17(5):489-98.

30.     Al‐Masri     AN,     Heidenreich     F,     Walter     GF.Interferon‐induced Mx proteins in brain tissue of multiple sclerosis   patients. Eur J Neurol 2009; 16(6):721-6.

31. Van der Voort LF, Vennegoor A, Visser A, Knol DL, Uitdehaag BM, Barkhof F, et al. Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurology 2010; 75(14):1228-33.

32. Furuyama H, Chiba S, Okabayashi T, Yokota SI, Nonaka M, Imai T, et al. Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis. J Neurol Sci 2006; 249(2):153-7.

33. Chieux V, Chehadeh W, Hautecoeur P, Harvey J, Wattré P, Hober D. Increased levels of antiviral MxA protein in peripheral blood of patients with A chronic disease of unknown etiology*. J Med Virol 2001; 65(2):301-8.

34.  Hughes  GC,  Thomas  S,  Li  C,  Kaja  MK,  Clark  EA.Cutting edge: progesterone regulates IFN-α production by

plasmacytoid    dendritic    cells.    J    Immunol    2008;180(4):2029-33.

35. Mekky RY, Hamdi N, El-Akel W, Esmat G, Abdelaziz AI. Estrogen-related MxA transcriptional variation in hepatitis  C  virus-infected  patients.  Transl  Res  2012;159(3):190-6.

36. Smith-Bouvier DL, Divekar AA, Sasidhar M, Du S, Tiwari-Woodruff SK, King JK, et al. A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 2008; 205(5):1099-108.

37. Hayashi J, Kishihara Y, Ueno K, Yamaji K, Kawakami Y, Furusyo N, et al. Age-related response to interferon alfa treatment in women vs men with chronic hepatitis C virus infection. Arch Intern Med 1998; 158(2):177-81.

38. Villa E, Karampatou A, Cammà C, Di Leo A, Luongo M, Ferrari A, et al. Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology 2011; 140(3):818-29.


Refbacks

  • There are currently no refbacks.


Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.