Evaluation of viral antibodies in Iranian multiple sclerosis patients

Evaluation of viral antibodies in Iranian multiple sclerosis patients


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نویسندگان: محسن خاکی , محمد رفیعی , احسان اله غزنوی راد , کیوان قسامی , علی قضاوی , قاسم مسیبی , محمد علی پایانی

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نشریه: Neurosciences, 16,, - ,

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کد مقاله 1799
عنوان فارسی مقاله Evaluation of viral antibodies in Iranian multiple sclerosis patients
عنوان لاتین مقاله Evaluation of viral antibodies in Iranian multiple sclerosis patients
نوع مقاله بر حسب نگارش پژوهشی اصیل
مقاله برحسب نمایه ISI
IF 0.708
عنوان نشریه Neurosciences
نوع نشریه علمی پژوهشی
شماره نشریه 16
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صفحه شروع و پایان در نشریه -
سال انتشار/ ارائه شمسی 1390
سال انتشار/ارائه میلادی
آدرس لینک مقاله/ همایش در شبکه اینترنت
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آدرس علمی (Affiliation) نویسنده متقاضی

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چکیده انگلیسیAbstract Objectives: Multiple sclerosis (MS) is a multifactorial disease. Many viruses have been reported to be associated with MS, though none of the associations has proved to be a definitive causative agent. The aim of present study is to evaluate the viral antibodies in Iranian new MS patients. Methods: In a cross sectional study sera from 61 MS patients and 60 healthy individuals were collected from January 2009 to March 2010 in Immunology Department of Arak University of Medical Sciences and examined for the presence of the anti-Epstein-Barr virus , human herpesvirus 6, measles, mumps, and para-influenza viruses IgG and IgM using an enzyme-linked immunosorbent assay or immunofluorescence. Results: Results showed that there were significant differences between the MS patients and the healthy individuals (control) in seroprevalence of anti-HHV-6 IgM (OR=4.3, 95% CI=2-9.3, p=0.001); anti-HHV-6 IgG (OR=2, 95% CI=1-4, p=0.04); anti-measles IgM (OR=3.2, 95% CI=1.5-6.9, p=0.002); and the anti-mumps IgM (OR=4.1, 95% CI=1.9-8.8, p=0.0001) and IgG (OR=9.5, 95% CI=3-29.6, p=0.0001). Almost all MS patients and the control individuals were negative to EBV and parainfluenza IgM. Conclusion: These results confirm an association between the incidence of MS and the antibodies to HHV-6 and the measles and mumps viruses, and show induction of a primary immune response (IgM), or virus reactivation, in MS patients. These viruses may have important role in development of MS as initial trigger in this geographical area. Key words: Multiple Sclerosis, Epstein-Barr virus, human herpesvirus 6, measles virus, mumps virus, para-influenza virus demonstration of increased antibody titer in response to presence of a particular virus, whereas some described isolation of viruses from MS patients [7, 8]. Several studies compared the seroprevalence of common Epstein-Barr virus (EBV) antibodies between MS patients and healthy individuals[7, 9]. Ascherio et al. [10] showed that the risk of MS in an EBV-negative individual was very low and that it increased in the same individual after seroconversion. On the other hand, a positive association was observed between other viral infections, such as human herpesvirus 6 (HHV-6), and the risk of developing MS[11]. The HHV-6 DNA was also found in over 70% of the brains of both MS patients and controls, however, HHV-6 protein expression was only identified in plaques and non-plaques of MS patients[11]. In contrast, several studies reported a lack of evidence on viral infections in MS patients[12, 13]. Within this context, no virus to date has been conclusively shown to be the sole agent responsible for causing MS . MS is a multifactorial disease that is influenced by geographical location, ethnic background and environmental factors[2]. Recently, epidemiological and clinical observations have shown that incidence and prevalence of MS is increasing in Iran, particularly in the middle and north east of Iran[14, 15]. In the present study, we evaluate the antibodies to EBV, HHV-6, measles, mumps and parainfluenza viruses in Iranian new MS patients. Materials and Methods Patients The present study was carried out from January 2009 to March 2010. The study sample comprised patients diagnosed with MS according to the McDonald criteria [16]. Selection of MS patients in this study was based on a number of inclusion criteria such that the individuals with at least one relapse in the past two years; more than three lesions on spinal or brain-MRI scans, or both; a score on the baseline Expanded Disability Status Scale (EDSS) within the range of 0 to 3.5; and age between 15 and 60 years. Additionally, special consideration was paid to select MS patients who had not previously received any immunosuppressive or corticosteroid treatment. On the other side, the following main exclusion criteria were adopted: clinically isolated syndrome (CIS), drug abuse, and previous therapy with immunomodulatory agents or vaccination for one year before commencement of this study . The Control group Normal individuals were selected to serve as a control group from the same geographical area and ethnic background. These subjects have no signs of MS and were matched for age, sex and socioeconomic status. Ethics approval This study was approved by the Arak University of Medical Sciences Ethics Committee (AUMSEC-86-22/4), all the patients and healthy controls were agree and filled up relevant consent form. Clinical samples and antibodies detection Serum samples of 61 new MS patients and 60 normal individuals were collected at the section of Immunology, Arak University of Medical Sciences, and stored at -80°C awaiting further investigation. Anti-EBV, measles, mumps and Para-influenza (PI) IgG and IgM and anti-HHV-6 IgG have been analyzed by enzyme-linked immunosorbent assay (ELISA) using commercial kits (IBL, Hamburg, Germany) according to instruction. The levels of the anti-HHV-6 IgM were determined by indirect fluorescence immunoassay (Biotrin, Dublin, Ireland). Patients were considered virus-positive when the serum anti-virus specific antibodies IgG and IgM were detected at levels higher than the corresponding cut-off levels specified by the kits. Statistical analysis Non-parametric tests were employed since the study variables were non-normally distributed. The Kruskal–Wallis test was used to test for significant differences between group medians in the variables studied. The logistic regression was used to investigate relations between the various study variables and to predict the probability that the incidence of MS will occur as a linear function of one (or more) of the independent variables and to estimate the risk (odd ratio) of the disease. A probability value of less than .05 (p < 0.05) was considered as indicative of statistical significance. On the other hand, the descriptive variables are reported here as mean ± standard deviation. (Mean is measurement of each variable in all of patients and compared with control group) Results There is no difference between patients with multiple sclerosis and control group in demographic characteristics (Table-1). None of the MS patients, nor the controls were positive for anti- EBV IgM. The anti-EBV IgG was positive in 82% (50 of the 61 cases) of the MS patients and in 67% of the control group. Furthermore, no significant difference was found in the anti-EBV IgG concentrations between the MS patients (166±114 U/mL) and the control group (156±146 U/mL). On the other hand, neither the MS patients, nor the controls were positive for anti-EBV IgM. The anti-EBV IgG was positive in 82% (50 of the 61 cases) of the MS patients and in 67% of the control group. The prevalence of anti-HHV-6 IgM in the sera of the MS patients was significantly higher than that in the sera of the control group (75.4% versus 41.6%, OR= 4.3, 95% CI=2-9.3, p=0.001). The IgG antibody to HHV-6 was found in 37 out of the 61 MS patients and in 26 out of the 61 controls (OR=2, 95% CI=1-4, p=0.04). As shown in Table 2, almost all the MS patients, except two, and all of control individuals were negative to parainfluenza IgM. The IgG against parainfluenza was found in all of the MS patients and controls (Table 2). The prevalence of anti-measles IgM was significantly higher in the MS patients than in the control group (OR=3.2, 95% CI=1.5-6.9, p=0.002). Anti-measles IgG was detectable in 51 of the 61 MS patients and in 53 of the 60 controls. Although there was no significance difference in seroprevalence of anti-measles IgG between the two groups, but the serum anti-measles IgG titers were higher in the MS patients than in the controls. The levels of the anti-mumps IgM were significantly higher (p=0.0001) in the sera of the MS patients (64%) than in those of the controls (30%); OR=4.1, 95% CI=1.9-8.8, and p=0.0001. Moreover, the seroprevalence of anti-mumps IgG were significantly higher in the MS patients than the controls (OR=9.5, 95% CI=3-29.6, p=0.0001) ( Table 2). Discussion The genesis and pathogenesis of MS remain under debate. It has been proposed that antigenic cross-reactivity or molecular mimicry between infectious agents and some myelin proteins in the CNS plays a role in the development of MS [4, 17]. Several studies advocated a correlation between association of the risk for MS and viral infections such as EBV, HHV-6, and the mumps and measles viruses [5, 7, 18]. Epidemiological and clinical evidences demonstrate a strong association between EBV infection and MS [19, 20]. Elevated IgG reactivity to EBV nuclear antigen 1 (EBNA1) has been found in MS patients and correlated with the number of T2 lesions on brain MRI scans and with change in EDSS [8, 21]. Serological evidences showed that the risk of acquiring MS is associated with increased levels of EBV antibody titers [22, 23]. Banwell et al. [24] showed that 86% of the pediatric MS patients were seropositive for EBV compared to 64% of matched controls . Our results showed that anti-EBV IgG levels were positive in 82% MS patients and in 67% of the control individuals (40 out of the 60). Almost all the MS patients and controls were negative for anti-EBV IgM. These results suggest that there is no temporal coincidence between EBV reactivation (production of IgM antibody to EBV) and disease activity in MS patients. The HHV-6 has been associated with several diseases such as meningo–encephalitis, autoimmune diseases, and MS. High levels of HHV-6 DNA have been detected in the CNS, sera and cerebrospinal fluids of MS patients [18]. Results of earlier studies indicated that MS patients had increased titers of serum antibodies to HHV-6 and that 50-70% of them were positive for HHV-6 IgM [25]. The results of this study showed that the frequencies and concentrations of anti-HHV-6 IgM and IgG in the MS patients were significantly higher than those in the control group. Accordingly, these findings confirm an association between HHV-6 antibodies and the incidence of MS and illustrate a correlation between HHV-6 reactivation and eruption of activity of the MS disease. To the best knowledge of the authors, almost all related earlier studies have failed to detect evidence for an association between HHV-6 and MS. For example, a study of MS patients in Kuwait failed to find evidence of HHV-6 DNA in the blood of a small sample of people with MS [26]. Enbom et al. (1999) detected anti-HHV-6 IgM in only one of 55 MS patients [27]. In fact, none of these studies detected these HHV-6 markers in all the subjects with MS whereas all were found in some of the control subjects. Several studies have found indicators of that measles or mumps viruses exist in significantly higher concentrations in MS patients than in control subjects [28, 29]. Adams and Imagawa (1962) were the first to propose a possible link between measles virus infections and MS. Our results showed that anti-measles IgM was significantly higher in the MS patients (54%) than in the control group (27%), while there was no difference in prevalence of anti-measles IgG between the two groups. The increased levels of anti-measles IgM in the MS patients suggest a reactivation or primary immune response in these patients. Our results also showed that the frequencies of detectable anti-mumps IgM and IgG in the MS patients were significantly higher than those observed in the control group. Hence, our results reassert a strong association between MS and mumps virus infection in this geographic area. Many earlier studies affirmed such results, though some studies did not. These discrepancies may be due to differences in geographical locations and/or differences between patients in genetic backgrounds. The increase in specific antibody titers of HHV-6, and the measles and mumps viruses may reflect a different course of these infections or a genetically determined difference in the immune response of those individuals susceptible to MS. Conclusion: This study found association between the incidence of MS and the antibodies to HHV-6 and the measles and mumps viruses, however MS is a multifactorial disease and a viral association may not be seen in all patients. The increases in MS incidence in recent years may be related to national programs of vaccination against measles, mumps and rubella viruses. Large epidemiological studies are needed to obtain more reliable data to further confirm the above-mentioned associations. References [1] Sospedra M, Martin R. Immunology of multiple sclerosis. Annual review of immunology. 2005;23:683-747. [2] Winquist RJ, Kwong A, Ramachandran R, Jain J. The complex etiology of multiple sclerosis. Biochemical pharmacology. 2007 Nov 1;74(9):1321-9. [3] Oger J. HTLV-1 infection and the viral etiology of multiple sclerosis. Journal of the neurological sciences. 2007 Nov 15;262(1-2):100-4. [4] Bar-Or A, Antel J. Cross-reactivity between epidemiology and immunology in multiple sclerosis. Neurology. 2008 Oct 7;71(15):1132-3. [5] Soldan SS, Jacobson S. Role of viruses in etiology and pathogenesis of multiple sclerosis. Advances in virus research. 2001;56:517-55. [6] Ordonez G, Martinez-Palomo A, Corona T, Pineda B, Flores-Rivera J, Gonzalez A, et al. Varicella zoster virus in progressive forms of multiple sclerosis. Clinical neurology and neurosurgery. 2010 Oct;112(8):653-7. [7] Ascherio A. Epstein-Barr virus in the development of multiple sclerosis. Expert review of neurotherapeutics. 2008 Mar;8(3):331-3. [8] Lunemann JD, Tintore M, Messmer B, Strowig T, Rovira A, Perkal H, et al. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Annals of neurology. 2010 Feb;67(2):159-69. [9] Castellazzi M, Tamborino C, Cani A, Negri E, Baldi E, Seraceni S, et al. Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2010 Jul;16(7):883-7. [10] Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. Jama. 2001 Dec 26;286(24):3083-8. [11] Fogdell-Hahn A, Soldan SS, Jacobson S. Association of chronic progressive neurological disease and ubiquitous viral agents: lessons from human herpesvirus 6 and multiple sclerosis. Molecular psychiatry. 2002;7 Suppl 2:S29-31. [12] Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010 Apr 6;74(14):1127-35. [13] Willis SN, Stadelmann C, Rodig SJ, Caron T, Gattenloehner S, Mallozzi SS, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009 Dec;132(Pt 12):3318-28. [14] Ghandehari K, Riasi HR, Nourian A, Boroumand AR. Prevalence of multiple sclerosis in north east of Iran. Multiple sclerosis (Houndmills, Basingstoke, England). 2010 Jun 9. [15] Maghzi AH, Ghazavi H, Ahsan M, Etemadifar M, Mousavi S, Khorvash F, et al. Increasing female preponderance of multiple sclerosis in Isfahan, Iran: a population-based study. Multiple sclerosis (Houndmills, Basingstoke, England). 2010 Mar;16(3):359-61. [16] 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. Annals of neurology. 2001 Jul;50(1):121-7. [17] Lindsey JW, Hatfield LM. Epstein-Barr virus and multiple sclerosis: Cellular immune response and cross-reactivity. Journal of neuroimmunology. 2010 Dec 15;229(1-2):238-42. [18] Alvarez-Lafuente R, Martin-Estefania C, de las Heras V, Castrillo C, Cour I, Picazo JJ, et al. Prevalence of herpesvirus DNA in MS patients and healthy blood donors. Acta neurologica Scandinavica. 2002 Feb;105(2):95-9. [19] Zivadinov R, Zorzon M, Weinstock-Guttman B, Serafin M, Bosco A, Bratina A, et al. Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry. 2009 Jun;80(6):620-5. [20] Nociti V, Frisullo G, Marti A, Luigetti M, Iorio R, Patanella AK, et al. Epstein-Barr virus antibodies in serum and cerebrospinal fluid from multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy and amyotrophic lateral sclerosis. Journal of neuroimmunology. 2010 Aug 25;225(1-2):149-52. [21] Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, et al. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009 Jul 7;73(1):32-8. [22] Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, et al. Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. Jama. 2005 May 25;293(20):2496-500. [23] DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Archives of neurology. 2006 Jun;63(6):839-44. [24] Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet neurology. 2007 Oct;6(10):887-902. [25] Caselli E, Boni M, Bracci A, Rotola A, Cermelli C, Castellazzi M, et al. Detection of antibodies directed against human herpesvirus 6 U94/REP in sera of patients affected by multiple sclerosis. Journal of clinical microbiology. 2002 Nov;40(11):4131-7. [26] Al-Shammari S, Nelson RF, Voevodin A. HHV-6 DNAaemia in patients with multiple sclerosis in Kuwait. Acta neurologica Scandinavica. 2003 Feb;107(2):122-4. [27] Enbom M, Wang FZ, Fredrikson S, Martin C, Dahl H, Linde A. Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls. Clinical and diagnostic laboratory immunology. 1999 Jul;6(4):545-9. [28] Tucker WG, Andrew Paskauskas R. The MSMV hypothesis: measles virus and multiple sclerosis, etiology and treatment. Medical hypotheses. 2008 Nov;71(5):682-9. [29] Ahlgren C, Oden A, Toren K, Andersen O. Multiple sclerosis incidence in the era of measles-mumps-rubella mass vaccinations. Acta neurologica Scandinavica. 2009 May;119(5):313-20. Legends: Table 1: Demographic characteristics of the MS patients and the control group *SD; standard deviation MS: Multiple Sclerosis Table 2: The seroprevalence of antibodies to Epstein-Barr virus, human herpesvirus 6, parainfluenza virus, and the measles and mumps viruses in Iranian MS patients 1; Multiple sclerosis, 2; Odds ratio, 3; Seropositive/Seronegative, 4; Mean of antibody±standard deviation, 5; Epstein-Barr virus, 6; human herpesvirus 6, 7; parainfluenza, 8; Optical density Table 1: Demographic characteristics of the MS patients and the control group Group Number Gender Male/Female Mean age± SD* MS patients 61 9/52 32±17 Control group 60 10/50 35±15 *SD; standard deviation MS: Multiple Sclerosis Table 2: The seroprevalence of antibodies to Epstein-Barr virus, human herpesvirus 6, parainfluenza virus, and the measles and mumps viruses in Iranian MS patients Groups Anti-viral antibodies MS1 Patients n=61 SP/SN(Mean±SD)4 Controls n=60 SP/SN(Mean±SD) OR2 (95%CI) p.value (SP/SN)3 Anti-EBV5 IgM≥ 22U/mL 0/61 (2.8±0.83) 0/60 (2.7±0.9) - N.S Anti-EBV IgG≥22U/mL 49/12 (166±114) 39/21 (156±146) - N.S Anti-HHV-66 IgM≥2 positive 46/15 25/35 4.3 (2-9.3) 0.001 Anti-HHV-6 IgG≥0.9 OD8 37/24 (1.2±0.65) 26/34 (1.02±0.7) 2(1-4) 0.04 Anti-PI7 IgM≥12U/mL 2/59 (4±7) 0/60 (2.6±2.2) - N.S Anti-PI IgG≥12U/mL 57/4 (107±54) 60/0 (96±48) - N.S Anti-measles IgM≥ 0.45 OD 33/28 (0.53±0.3) 16/44 (0.4±0.2) 3.2 (1.5-6.9) 0.002 Anti-measles IgG≥12U/mL 51/10 (405±450) 53/7 (168±230) - N.S Anti-mumps IgM≥ 0.31 OD 39/22 (0.54±0.2) 18/42 (0.4±0.17) 4.1 (1.9-8.8) 0.0001 Anti-mumps IgG≥ 0.47 OD 57/4 (1.3±0.47) 36/24 (1.2±0.46) 9.5 (3-29.6) 0.0001 1; Multiple sclerosis, 2; Odds ratio, 3; Seropositive/Seronegative, 4; Mean of antibody±standard deviation, 5; Epstein-Barr virus, 6; human herpesvirus 6, 7; parainfluenza, 8; Optical density
چکیدهAbstract Objectives: Multiple sclerosis (MS) is a multifactorial disease. Many viruses have been reported to be associated with MS, though none of the associations has proved to be a definitive causative agent. The aim of present study is to evaluate the viral antibodies in Iranian new MS patients. Methods: In a cross sectional study sera from 61 MS patients and 60 healthy individuals were collected from January 2009 to March 2010 in Immunology Department of Arak University of Medical Sciences and examined for the presence of the anti-Epstein-Barr virus , human herpesvirus 6, measles, mumps, and para-influenza viruses IgG and IgM using an enzyme-linked immunosorbent assay or immunofluorescence. Results: Results showed that there were significant differences between the MS patients and the healthy individuals (control) in seroprevalence of anti-HHV-6 IgM (OR=4.3, 95% CI=2-9.3, p=0.001); anti-HHV-6 IgG (OR=2, 95% CI=1-4, p=0.04); anti-measles IgM (OR=3.2, 95% CI=1.5-6.9, p=0.002); and the anti-mumps IgM (OR=4.1, 95% CI=1.9-8.8, p=0.0001) and IgG (OR=9.5, 95% CI=3-29.6, p=0.0001). Almost all MS patients and the control individuals were negative to EBV and parainfluenza IgM. Conclusion: These results confirm an association between the incidence of MS and the antibodies to HHV-6 and the measles and mumps viruses, and show induction of a primary immune response (IgM), or virus reactivation, in MS patients. These viruses may have important role in development of MS as initial trigger in this geographical area. Key words: Multiple Sclerosis, Epstein-Barr virus, human herpesvirus 6, measles virus, mumps virus, para-influenza virus
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نویسنده نفر چندم مقاله
محسن خاکیاول
محمد رفیعیچهارم
احسان اله غزنوی رادششم
کیوان قسامیسوم
علی قضاویدوم
قاسم مسیبیهفتم و مسئول
محمد علی پایانیپنجم

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