Infectious hypothesis of multiple sclerosis and the role of HHV6A/B as one of the disease factors: epidemiological analysis



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Abstract

In the present study, we analyzed epidemiological evidence suggesting a possible infectious nature of multiple sclerosis. Within the framework of the infectious theory, we considered potential determinants of the latitude gradient of multiple sclerosis (increase in the incidence and/or prevalence of disease with increasing distance from the equator), including differences in the intensity of circul

About the authors

Elena Nikolaevna Filatova

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Email: el.filatova83@mail.ru
ORCID iD: 0000-0002-6683-7191
SPIN-code: 1986-8147

Candidate of Sciences in Biology, leading researcher

Russian Federation

Oleg V. Utkin

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Email: utkino2004@mail.ru
ORCID iD: 0000-0002-7571-525X
SPIN-code: 1174-6500

PhD (Biology), Head of Laboratory of Molecular Biology and Biotechnology

Russian Federation, 603950, Nizhny Novgorod, Malaya Yamskaya st., 71

Nikolai A. Sakharnov

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Email: sakharnov_n@mail.ru
ORCID iD: 0000-0003-3965-2033
SPIN-code: 8457-3501

PhD (Biology), Senior Researcher of Laboratory of Molecular Biology and Biotechnology

Russian Federation, 603950, Nizhny Novgorod, Malaya Yamskaya st., 71

Alexey vgenievich Khrulev

Nervous Diseases of Privolzhsky Research Medical University

Email: alexey_khrulev@mail.ru
ORCID iD: 0000-0003-0169-3956
SPIN-code: 1051-9769

Doctor of Science in Medical Sciences, associate professor, professor of Department of nervous Diseases

Russian Federation, 603005, Russia, Nizhny Novgorod, Minin and Pozharsky pl., 10/1

Natalia Nikolaevna Zaitseva

Blokhina Scientific Research Institute of Epidemiology and Microbiology of Nizhny Novgorod

Author for correspondence.
Email: nniiem@yandex.ru
ORCID iD: 0000-0001-5370-4026
SPIN-code: 4123-6552

Doctor of Science in Medical Sciences, professor, director

Russian Federation

References

  1. Егорова Н.Ю., Ситникова И.В. «Демографический» фактор рождаемости: оценка потенциала территории на примере Нижегородской области // Вопросы Управления. 2024. Т. 18, № 4. С. 25-40.
  2. Ким Е.Р. Особенности течения рассеянного склероза в Нижегородской популяции // Нижегородский медицинский журнал. 2003. № 3-4. С. 91-95.
  3. Попкова М. И., Уткин О.В. Особенности эпидемического процесса инфекционного мононуклеоза в Нижегородской области в современный период // Здоровье населения и среда обитания. 2021. № 4 (337). С. 79–86.
  4. Попкова М. И., Уткин О.В., Брызгалова Д.А. Сравнительная характеристика бета-герпес-вирусов человека 6А и 6В. Современный взгляд на проблему // Журнал инфектологии. 2021. Т. 13, № 3. С. 5-18.
  5. Соломай, Т.В., Семененко Т.А., Блох А.И. Распространённость антител к вирусу Эпштейна–Барр в разных возрастных группах населения Европы и Азии: систематический обзор и метаанализ // Здравоохранение Российской Федерации. 2021. Т. 65, № 3. С. 276–286.
  6. Филатова Е.Н., Сахарнов Н.А., Суслов Н.А., Попкова М.И., Уткин О.В. Первые данные о молекулярно-генетическом разнообразии ВГЧ6В и его влиянии на клинико-лабораторное течение мононуклеозподобного синдрома у детей // Инфекция и иммунитет. 2025. Т. 15, № 3. С. 476–88.
  7. Филатова Е.Н., Солнцев Л.А., Уткин О.В. Влияние сезонных факторов на динамику уровня заболеваемости инфекционным мононуклеозом в разных возрастных группах (на примере Нижнего Новгорода) // Эпидемиология и инфекционные болезни. 2017. Т. 22, № 2. С. 79–85.
  8. Филатова, Е.Н., Уткин О.В., Зайцева Н.Н., Хрулев А.Е. Разработка и обоснование внутривидовой классификации молекулярно-генетического разнообразия ВГЧ6А и ВГЧ6В // Инфекция и иммунитет. 2025. Т. 15, № 6. С. 1087–1100.
  9. Akel O., Zhao L.P., Geraghty D.E., Lind A. High-Resolution HLA Class II Sequencing of Swedish Multiple Sclerosis Patients. International Journal of Immunogenetics, 2022, vol. 49. No. 5, pp. 333-339
  10. Akhyani N., Berti R., Brennan M.B., Soldan S.S., Eaton J.M., McFarland H.F., Jacobson S. Tissue Distribution and Variant Characterization of Human Herpesvirus (HHV)-6: Increased Prevalence of HHV-6A in Patients with Multiple Sclerosis. The Journal of Infectious Diseases, 2000, vol. 182, no. 5, pp. 1321-1325.
  11. Alonso A., Hernan M. Temporal trends in the incidence of multiple sclerosis. Neurology, 2008, vol. 71, no. 2, pp. 129-135.
  12. Alonso-Magdalena L., Zia E., Carmolova I Codina O., Pessah-Rasmussen H., Sundstrom P. Incidence and Prevalence of Multiple Sclerosis in Malmö, Southern Sweden. Multiple Sclerosis Internationa, 2022, vol. 1, pp. 5464370.
  13. Alter M., Leibowitz U., Speer J. Risk of Multiple Sclerosis Related to Age at Immigration to Israel. Archives of Neurology, 1966, vol. 15, no. 3, pp. 234–237.
  14. Alvarez-Lafuente R., de las Heras V., Bartolomé M., Picazo J.J., Arroyo R. Relapsing-Remitting Multiple Sclerosis and Human Herpesvirus 6 Active Infection. Archives of Neurology, 2004, vol. 61, no. 10, pp. 1523-1527.
  15. Alvarez-Lafuente R., Martín-Estefanía C., de Las Heras V., Castrillo C., Picazo J.J., Varela de Seijas E., Gonzalez R.A. Active Human Herpesvirus 6 Infection in Patients with Multiple Sclerosis. Archives of Neurology, 2002, vol. 59, no. 6, pp. 929-933.
  16. Arnason B.G., Berkovich R., Catania A., Lisak R.P., Zaidi M. Mechanisms of Action of Adrenocorticotropic Hormone and Other Melanocortins Relevant to the Clinical Management of Patients with Multiple Sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England), 2013, vol. 19, no. 2, pp. 130-136.
  17. Astier A.L., Meiffren G., Freeman S., Hafler D.A. Alterations in CD46-Mediated Tr1 Regulatory T Cells in Patients with Multiple Sclerosis. The Journal of Clinical Investigation, 2006, vol. 116, no. 12, pp. 3252-3257.
  18. Auer D.P., Schumann E.M., Kümpfel T., Gössl C., Trenkwalder C. Seasonal Fluctuations of Gadolinium-Enhancing Magnetic Resonance Imaging Lesions in Multiple Sclerosis. Annals of Neurology, 2000, vol. 47, no. 2, pp. 276–277.
  19. Beaumont K.A., Newton R.A., Smit D.J., Leonard J.H., Stow J.L., Sturm R.A. Altered Cell Surface Expression of Human MC1R Variant Receptor Alleles Associated with Red Hair and Skin Cancer Risk. Human Molecular Genetics, 2005, vol. 14, no. 15, pp. 2145-2154.
  20. Bjornevik K., Cortese M., Healy B.C., Kuhle J., Mina M.J., Leng Yu., Elledge S.J., Niebuhr D.W., Scher A.I., Munger K.L., Ascherio A. Longitudinal Analysis Reveals High Prevalence of Epstein-Barr Virus Associated with Multiple Sclerosis. Science (New York, N.Y.), 2022, vol. 375, no. 6578, pp. 296-301.
  21. Boullerne A.I., Goudey B., Paganini J., Erlichster M., Gaitonde S. Feinstein D.L. Validation of Tag SNPs for Multiple Sclerosis HLA Risk Alleles across the 1000 Genomes Panel. Human Immunology, 2024, vol. 85, no. 3. pp. 110790.
  22. Breuer J., Schwab N., Schneider-Hohendorf T., Marziniak M., Mohan H., Bhatia U., Gross C.C., Clausen B.E., Weishaupt C., Lunger T.A., Meuth S.G., Loser K., Wiendl H. Ultraviolet B Light Attenuates the Systemic Immune Response in Central Nervous System Autoimmunity. Annals of Neurology, 2014, vol. 75, no. 5, pp. 739-758.
  23. Cermelli C., Berti R., Soldan S.S., Mayne M., D’ambrosia J.M., Ludwin S.K., Jacobson S. High Frequency of Human Herpesvirus 6 DNA in Multiple Sclerosis Plaques Isolated by Laser Microdissection. The Journal of Infectious Diseases, 2003, vol. 187, no. 9, pp. 1377-1387.
  24. Cheng W., Ma Ya., Gong F., Hu Ch., Qian L., Huang Q., Yu Q., Zhang J., Chen Sh., Liu Z., Chen X., Zhou T., Zhang D. Cross-Reactivity of Autoreactive T Cells with MBP and Viral Antigens in Patients with MS. Frontiers in Bioscience (Landmark Edition), 2012, vol. 17, no. 5, pp. 1648-1658.
  25. De Bolle L., Van Loon J., De Clercq E., Naesens L. Quantitative Analysis of Human Herpesvirus 6 Cell Tropism. Journal of Medical Virology, 2005, vol. 75, no. 1, pp. 76-85.
  26. Dean G. Disseminated Sclerosis in South Africa; Its Relationship to Swayback Disease and Suggested Treatment. British Medical Journal, 1949, vol, 1, no. 4610, pp. 842–845.
  27. Dewin D.R., Catusse J., Gompels U.A. Identification and Characterization of U83A Viral Chemokine, a Broad and Potent Beta-Chemokine Agonist for Human CCRs with Unique Selectivity and Inhibition by Spliced Isoform. Journal of Immunology (Baltimore, Md.: 1950), 2006, vol. 176, no. 1, pp. 544-556.
  28. Dominguez G., Dambaugh T.R., Stamey F.R., Dewhurst S., Inoue N., Pellett P.E. Human Herpesvirus 6B Genome Sequence: Coding Content and Comparison with Human Herpesvirus 6A. Journal of Virology, 1999, vol. 73, no. 10, pp. 8040-8052.
  29. Donati D., Martinelli E., Cassiani-Ingoni R., Ahlqvist J., Hou J., Major E.O., Jacobson S. Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes. Journal of Virology, 2005, vol. 79, no. 15, pp. 9439-9448.
  30. Dopico X.C., Evangelou M., Ferreira R.C., Gou H., Pekalski M.L., Smyth D.J., Cooper N., Burren O.S., Fulford A.J., Henning B.J., Prentice A.M., Ziegler A.-G., Bonifacio E., Wallance C., Todd J.A. Widespread Seasonal Gene Expression Reveals Annual Differences in Human Immunity and Physiology. Nature Communications, 2015, vol. 6, pp. 7000.
  31. Douglas A. S., Brown T., Reid D. Infectious Mononucleosis and Hodgkin’s Disease--a Similar Seasonality. Leukemia & Lymphoma, 1996, vol. 23, no. 3-4, pp. 323-331.
  32. Dwyer T., van der Mei I., Ponsonby A.-L., Taylor B.V., Stankovich J., McKay J.D., Thompson R.J., Polamowski A.M., Dickinson J.L. Melanocortin 1 Receptor Genotype, Past Environmental Sun Exposure, and Risk of Multiple Sclerosis. Neurology, 2008, vol. 71, no. 1, pp. 583-589.
  33. El-Salem K., Al-Shimmery E., Horany K., Al-Refai A., Al-Hayk K., Khader Yu. Multiple Sclerosis in Jordan: A Clinical and Epidemiological Study. Journal of Neurology, 2006, vol. 253, no. 9, pp. 1210-1216.
  34. Engdahl E., Gustafsson R., Huang J., Bostrom M., Lima Bomfim I., Stridh P., Khademi M., Brenner N., Butt J., Michel A., Jons D., Hortlund M., Alonso-Magdalena L., Hedstrom A.K., Flamand L., Ihira M., Yoshikawa T., Andersen O., Hillert J., Alfredsson L., Waterboer T., Sundstrom P., Olsson T., Kockum I., Fogdell-Hahn A. Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis. Frontiers in Immunology, 2019, vol. 10, pp. 2715.
  35. Eskandarieh Sh., Sistany N., Malihe Sadeghi A., Ali Sahraian M. Increasing Prevalence of Familial Recurrence of Multiple Sclerosis in Iran: A Population Based Study of Tehran Registry 1999-2015. BMC Neurology, 2018, vol. 18, no. 1, pp. 15.
  36. Feng X., Wang Z., Howlett-Prieto Q., Einhorn N., Causevic S., Reder A.T. Vitamin D Enhances Responses to Interferon-β in MS. Neurology(R) Neuroimmunology & Neuroinflammation, 2019, vol. 6, no. 6, pp. e622.
  37. Ferretti L., Wymant C., Petrie J., Tsallis D., Kendall M., Ledda A., Di Lauro F., Fowler A., Di Francia A., Panovska-Griffiths J., Abeler-Dorner L., Charalambides M., Briers M., Fraser Ch. Digital Measurement of SARS-CoV-2 Transmission Risk from 7 Million Contacts. Nature, 2024, vol. 626, no. 7997, pp. 145–150.
  38. Fguirouche A., Naji Ya., Guennouni M., Hazime R., Zahlane S., Chraa M., Kissani N., Louhab N., Admou B. HLA-DRB1 and DQB1 Allelic Polymorphism and Multiple Sclerosis in a Moroccan Population. Current Issues in Molecular Biology, 2025, vol. 47, no. 6, pp. 458.
  39. Fitzgerald K.C., Munger K.L., Köchert K., Arnason B.G.W., Comi G., Cook S., Goodin D.S., Filippi M., Hartung H.-P., Jeffery D.R., O’Connor P., Suarez G., Sandbrink R., Kappos L., Pohl Ch., Ascherio A. Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b. JAMA Neurology, 2015, vol. 72, no. 12, pp. 1458–1465.
  40. Foulon S., Maura G., Dalichampt M., Alla F., Debouverie M., Moreau Th., Weill A. Prevalence and Mortality of Patients with Multiple Sclerosis in France in 2012: A Study Based on French Health Insurance Data. Journal of Neurology, 2017, vol. 264, no. 6, pp. 1185-1192.
  41. Gao K. The Genetic Architecture of Multiple Sclerosis. Nature Medicine, 2019, vol. 25, no. 11, pp. 1647.
  42. Gay F. The Risk of Multiple Sclerosis on the Orkney Islands. A Review of the Search for Distinctively Orcadian Risks, with a Hypothesis for Further Investigations. Multiple Sclerosis and Related Disorders, 2024, vol. 82, pp. 105386.
  43. Ghaseminejad-Raeini A., Ghaderi A., Sharafi A., Nematollahi-Sani B., Moossavi M., Derakhshani A., Sarab G.A. 2023 г. «Immunomodulatory Actions of Vitamin D in Various Immune-Related Disorders: A Comprehensive Review». Frontiers in Immunology, 2023, vol. 14, pp. 950465.
  44. Giovannoni G., Hawkes C.H., Lechner-Scott J., Levy M., Pohl D. Air Pollution and Multiple Sclerosis Risk. Multiple Sclerosis and Related Disorders, 2021, vol. 48, pp. 102797.
  45. Godoy S., Parrón I., Millet J.-P., Cayla J.A., Follia N., Carol M., Orcau A., Alseda M., Toledo D., Plans P., Ferrus G., Barrabeig I., Clotet L., Dominguez A., Godoy P., Tuberculosis Transmission Working Group of Catalonia [Spain]. Risk of Tuberculosis among Pulmonary Tuberculosis Contacts: The Importance of Time of Exposure to Index Cases. Annals of Epidemiology, 2024, vol. 91, pp. 12–17.
  46. Goodman A.D., Mock D.J., Powers J.M., Baker J.V., Blumberg B.M. Human Herpesvirus 6 Genome and Antigen in Acute Multiple Sclerosis Lesions. The Journal of Infectious Diseases, 2003, vol. 187, no. 9, pp. 1365-1376.
  47. Goris A., Vandebergh M., McCauley J.L., Saarela J., Cotsapas Ch. Genetics of Multiple Sclerosis: Lessons from Polygenicity. The Lancet. Neurology, 2022, vol. 21, no. 9, pp. 830–842.
  48. Grassivaro F., Puthenparampil M., Pengo M., Saiani M., Venturini M., Stropparo E., Perini P., Rinaldi F., Freddi N., Cadaldini M., Colledan L., Piccinno M.G., Pedrazzoli E., Gallo P. Multiple Sclerosis Incidence and Prevalence Trends in the Province of Padua, Northeast Italy, 1965-2018. Neuroepidemiology, 2019, vol. 52, no. 1-2, pp. 41-46.
  49. Grytten N., Torkildsen O., Myhr K.-M. Time Trends in the Incidence and Prevalence of Multiple Sclerosis in Norway during Eight Decades. Acta Neurologica Scandinavica, 2015, vol. 132, no. 199, pp. 29-36.
  50. Gu B., Zhang G.-F., Li L.-Yu., Zhou F., Feng D.-J., Ding Ch.-L., Chi J., Zhang Ch., Guo D.-D., Wang J.-F., Zhou H., Yao K., Hu W.-X. Human Herpesvirus 6A Induces Apoptosis of Primary Human Fetal Astrocytes via Both Caspase-Dependent and -Independent Pathways. Virology, 2011, vol. 8, pp. 530.
  51. Haahr S., Munch M., Christensen T., Møller-Larsen A., Hvas J. Cluster of Multiple Sclerosis Patients from Danish Community. Lancet (London, England), 1997, vol. 349, no. 9056, pp. 923.
  52. Handel A.E., Williamson A.J., Disanto G., Handunnetthi L., Giovannoni G., Ramagopalan S.V. An Updated Meta-Analysis of Risk of Multiple Sclerosis Following Infectious Mononucleosis. PloS One, 2010, vol. 5, no. 9, pp. e12496.
  53. Harding K., Tilling K., MacIver C., Willis M., Joseph F., Ingram G., Hirst C., Wardle M., Pickersgill T., Ben-Shlomo Yo., Robertson N. Seasonal Variation in Multiple Sclerosis Relapse. Journal of Neurology, 2017, vol. 264, no. 6, pp. 1059-1067.
  54. Hart P.H., Jones A.P., Trend S., Cha L., Fabis-Perdini M.J., Cooper M.N., d’Este C., Geldenhuys S., Carrol W.M., Byrne S.N., Booth D.R., Cole J.M., Lucas R.M., Kermode A.G. A Randomised, Controlled Clinical Trial of Narrowband UVB Phototherapy for Clinically Isolated Syndrome: The PhoCIS Study. Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2018, vol. 4, no. 2, pp. 2055217318773112.
  55. Heine M., Maartens D., Hanekom S., Derman W. Multiple Sclerosis in Sub-Saharan Africa - a Scoping Review. Multiple Sclerosis and Related Disorders, 2020, vol. 42, pp. 102133.
  56. Hittle M., Culpepper W.J., Langer-Gould A., Marrie R.A., Cutter G.R., Kaye W.E., Wagner L., Topol B., LaRocca N.G., Nelson L.M., Wallin M.T. Population-Based Estimates for the Prevalence of Multiple Sclerosis in the United States by Race, Ethnicity, Age, Sex, and Geographic Region. JAMA Neurology, 2023, vol. 80, no. 7, pp. 693-701.
  57. Houzen H., Kano T., Kondo K., Takahashi T., Niino M. The Prevalence and Incidence of Multiple Sclerosis over the Past 20 Years in Northern Japan. Multiple Sclerosis and Related Disorders, 2023, vol. 73, pp. 104696.
  58. Hrastelj J., Robertson N.P. A role for the Epstein–Barr virus in multiple sclerosis aetiology? Journal of Neurology, 2022, vol. 269, no. 7, pp. 3962-3963.
  59. International Multiple Sclerosis Genetics Consortium. Multiple Sclerosis Genomic Map Implicates Peripheral Immune Cells and Microglia in Susceptibility. Science (New York, N.Y.), 2019, vol. 365, no. 6460, pp. eaav7188.
  60. James L.M., Georgopoulos A.P. Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries. Journal of immunological sciences, 2021, vol. 5, no. 2, pp. 40-46.
  61. Jaworska J., Gravel A., Flamand L. Divergent susceptibilities of human herpesvirus 6 variants to type I interferons. Proceedings of the National Academy of Sciences, 2010, vol. 107, no. 18, pp. 8369-8374.
  62. Kapica-Topczewska K., Kułakowska A., Kochanowicz J., Brola W. Epidemiology of Multiple Sclerosis: Global Trends, Regional Differences, and Clinical Implications. Neurologia I Neurochirurgia Polska, 2025, vol. 59, no. 4, pp. 375-384.
  63. Karampampa K., Gyllensten H., Friberg E., Murley Ch., Kavaliunas A., Hillert J., Olsson T., Alexanderson K. Disease-Modifying Therapies and Cost-of-Illness Progression among People Newly Diagnosed with Multiple Sclerosis: A National Register-Based Cohort Study Covering Treatment Initiation with Interferons, Glatiramer Acetate or Natalizumab. BMJ Open, 2023, vol. 13, no. 5, pp. e067516.
  64. Khalesi Z., Tamrchi V., Razizadeh M.H., Letafati A., Moradi P., Habibi A., Heidari J., Noori M., Nahid Samiei M., Azarash Z., Hoseini M., Saadati H., Bahavar A., Farajzade M., Saeb S., Hadadi M., Sorouri Majd M., Mothlaghzaden S., Fazli P., Asgari K., Kiani S.J., Ghorbani S. Association between Human Herpesviruses and Multiple Sclerosis: A Systematic Review and Meta-Analysis. Microbial Pathogenesis, 2023, vol. 177, pp. 106031.
  65. Khan G., Jawad Hashim M. Epidemiology of Multiple Sclerosis: Global, Regional, National and Sub-National-Level Estimates and Future Projections. Journal of Epidemiology and Global Health, 2025, vol. 15, no. 1, pp. 21.
  66. Khdair S.I., Al-Khareisha L., Abusara O.H., Hammad A.M., Khudair A. HLA-Class II Genes Association with Multiple Sclerosis: An Immunogenetic Prediction among Multiple Sclerosis Jordanian Patients. PloS One, 2025, vol. 20, no. 2, pp. e0318824.
  67. Killestein J., Rep M. H. G., Meilof J.F., Ader H.J., Uitdehaag B.M.J., Barkhof F., van Lier R.a.W., polman C.H. Seasonal Variation in Immune Measurements and MRI Markers of Disease Activity in MS. Neurology, 2002, vol. 58, no. 7, pp. 1077-1080.
  68. Kobelt G., Thompson A., Berg J., Gannedahl M., Eriksson J. New insights into the burden and costs of multiple sclerosis in Europe. Multiple Sclerosis (Houndmills, Basingstoke, England), 2017, vol. 23, no. 8, pp. 1123–1136.
  69. Komaroff A., Pellett Ph.E., Jacobson S. Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation. Clinical Microbiology Reviews, 2020, vol. 34, no. 1, pp. e00143-20.
  70. Kong H., Baerbig Q., Duncan L., Shepel N., Mayne M. Human Herpesvirus Type 6 Indirectly Enhances Oligodendrocyte Cell Death. Journal of Neurovirology, 2003, vol. 9, no. 5, pp. 539–550.
  71. Kurtzke J. F. Geographic Distribution of Multiple Sclerosis: An Update with Special Reference to Europe and the Mediterranean Region. Acta Neurologica Scandinavica, 1980, vol. 62, no. 2, pp. 65–80.
  72. Kurtzke J. F., Hyllested K., Heltberg A. Multiple Sclerosis in the Faroe Islands: Transmission across Four Epidemics. Acta Neurologica Scandinavica, 1995, vol. 91, no. 5, pp. 321-325.
  73. Langer-Gould A., Lucas R., Xiang A.H., Chen L.H., Wu J., Gonzalez E., Haraszti S., Smith J.B., Quach H., Barcellos L.F. MS Sunshine Study: Sun Exposure But Not Vitamin D Is Associated with Multiple Sclerosis Risk in Blacks and Hispanics. Nutrients, 2018, vol. 10, no. 3, pp. 268.
  74. Leibovitch E.C., Caruso B., Ha S.K., Schindler M.K., Lee N.J., Luciano L.J., Billioux B.J., Guy J.R., Yen C., Sati P., Silva A.C., Reich D.S., Jacobson S. Herpesvirus Trigger Accelerates Neuroinflammation in a Nonhuman Primate Model of Multiple Sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 2018, vol. 115, no. 44, pp. 11292-11297.
  75. Loken-Amsrud K.I., Holmøy T., Bakke S.J., Beiske A.G., Bjerve K.S., Bjornara B.T., Hovdal H., Lilleas F., Midgard R., Pedersen T., Benth J.S., Sandvik L., Torkildsen O., Wergeland S., Myhr K.-M. Vitamin D and Disease Activity in Multiple Sclerosis before and during Interferon-β Treatment. Neurology, 2012, vol. 79, no. 3, pp. 267–273.
  76. Makkawi S., Aljabri A., Lajdam G.B., Albakistani A., Aljohani A., Labban S., Felemban R. Effect of Seasonal Variation on Relapse Rate in Patients With Relapsing-Remitting Multiple Sclerosis in Saudi Arabia. Frontiers in Neurology, 2022, vol. 13, pp. 862120.
  77. Maroufi H., Mortazavi S.H., Sahraian M.A., Eskandarieh S. Environmental Risk Factors of Multiple Sclerosis in the Middle East and North Africa Region: A Systematic Review. Current Journal of Neurology, 2021, vol. 20, no. 3, pp. 166-184.
  78. Meier D.S., Balashov K.E., Healy B., Weiner H.L., Guttmann C.R.G. Seasonal Prevalence of MS Disease Activity. Neurology, 2010, vol. 75, no. 8, pp. 799–806.
  79. Melker H. de, Pebody R.G., Edmunds W.J., Levy-Bruhl D., Valle M., Rota M.C., Salmaso S., van den Hof S., Berbers G., Saliou P., Spaendonck M.C.V., Crovari P., Davidkin I., Gabutti G., Hesketh L., Morgan-Capner P., Plesner A.M., Raux M., Tische A., Miller E. The Seroepidemiology of Measles in Western Europe. Epidemiology and Infection 126 (2): 249–59.
  80. Mirsaeedi, F., Sheikhalishahi M., Mohammadi M., Pirayesh A., Ivanov D. Compartmental Models in Epidemiology: Bridging the Gap with Operations Research for Enhanced Epidemic Control. Annals of Operations Research, 2025, pp. s10479-025-06893-1.
  81. Moccia M., Vincenzo M., Morra B., Lanzillo R., Loperto I., Giordana R., Fumo M.G., Pertuzzo M., Capasso N., Triassi M., Sormani M.P., Palladino R. Multiple Sclerosis in the Campania Region (South Italy): Algorithm Validation and 2015-2017 Prevalence. International Journal of Environmental Research and Public Health, 2020, vol. 17, no. 10, pp. 3388.
  82. Mokry L.E., Ross S., Ahmad O.S., Forgetta V., Smith G.D., Leong A., Greenwood C.M.T., Thanassoulis G., Richards J.B. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Medicine, 2015, vol. 12, no. 8, pp. e1001866.
  83. Morra V.B., Coppola G., Orefice G., De Michele G., Vacca G., Filla A., Bonavita V. Interferon-Beta Treatment Decreases Cholesterol Plasma Levels in Multiple Sclerosis Patients. Neurology, 2004, vol. 62, no. 5, pp. 829-830.
  84. Müller L., Di Benedetto S. Immunosenescence and Cytomegalovirus: Exploring Their Connection in the Context of Aging, Health, and Disease. International Journal of Molecular Sciences, 2024, vol. 25, no. 2, pp. 753.
  85. Mykicki N., Herrmann A.M., Schwab N., Deenen R., Sparwasser T., Limmer A., Wachsmuth L., Klotz L., Kohrer K., Faber C., Wiendl H., Luger Th.A., Meuth S.G., Loser K. Melanocortin-1 Receptor Activation Is Neuroprotective in Mouse Models of Neuroinflammatory Disease. Science Translational Medicine, 2016, vol. 8, no. 362, pp. 362ra146.
  86. Nabizadeh F., Valizadeh P., Tabrizi M.Ya., Moayyed K., Ghomashi N., Mirmosayyeb O. Seasonal and Monthly Variation in Multiple Sclerosis Relapses: A Systematic Review and Meta-Analysis. Acta Neurologica Belgica, 2022, vol. 122, no. 6, pp. 1447-1456.
  87. Nordström I., Eriksson K. HHV-6B Induces IFN-Lambda1 Responses in Cord Plasmacytoid Dendritic Cells through TLR9. PloS One, 2012, vol. 7, no. 6, pp. e38683.
  88. Odoardi F., Sie Ch., Streyl K., Ulaganathan V.K., Schlager Ch., Lodygin D., Heckelsmiller K., Nietfeld W., Ellwart J., klinkert W.E.F., Lottaz C., Nosov M., Brinkmann V., Spang R., Lehrach H., Vingron M., Wekerie H., Flugel-Koch C., Flugel A. T Cells Become Licensed in the Lung to Enter the Central Nervous System. Nature, 2012, vol. 488, no. 7413, pp. 675-679.
  89. Ogawa G., Mochizuki H., Kanzaki M., Kaida K., Motoyoshi K., Kamakura K. Seasonal Variation of Multiple Sclerosis Exacerbations in Japan. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2004, vol. 24, no. 6, pp. 417–419.
  90. Opsahl M.L., Kennedy P.G.E. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain, 2005, vol. 128, no. 3, pp. 516-527.
  91. Ostkamp P., Salmen A., Pignolet B., Gorlich D., Andlauer T.F.M., Schulte-Mecklenbeck A., Gonzalez-Escamilla G., Bucciarelli F., Gennero I., Breuer J., Antony G., Schneider-Hohendorf T., Mykicki N., Bayas A., Then Bergh F., Bittner S., Hartung H.-P., Friese M.A., Linker R.A., Luessi F., Lehmann-Horn K., Muhlau M., Paul F., Stangel M., Tackenberg B., Tumani H., Warnke C., Weber F., Wildemann B., Zettl U.K., Ziemann U., Muller-Myshok B., Kumpfel T., Klotz L., Meuth S.G., Zipp F., Hemmer B., Hohfeld R., Brassat D., Gold R., Gross C.C., Lukas C., Groppa S., Loser K., Wiendl H., Schwab N., German Competence Network Multiple Sclerosis (KKNMS) and the BIONAT Network. Sunlight Exposure Exerts Immunomodulatory Effects to Reduce Multiple Sclerosis Severity. Proceedings of the National Academy of Sciences of the United States of America, 2021, vol. 118, no. 1, pp. e2018457118.
  92. Patel M.M., Pitzer V.E., Alonso W.J., Vera D., Lopman B., Tate J., Viboud C., Parashar U.D. Global Seasonality of Rotavirus Disease. The Pediatric Infectious Disease Journa, 2013, vol. 32, no. 4, pp. e134-e147.
  93. Pebody R.G., Andrews N., Brown D., Gopal R., De Melker H., Francois G., Gatcheva N., Hellenbrand W., Jokinen S., Klavs I., Kojouharova M., Kortbeek T., Kriz B., Prosenc K., Roubalova K., Teocharov P., Thierfelder W., Valle M., Van Damme P., Vranckx R. The Seroepidemiology of Herpes Simplex Virus Type 1 and 2 in Europe. Sexually Transmitted Infections, 2004, vol. 80, no. 3, pp. 185-191.
  94. Perkin M.R., Strachan D.P. The Hygiene Hypothesis for Allergy – Conception and Evolution. Frontiers in Allergy, 2022, vol. 3, pp. 1051368.
  95. Pormohammad A., Azimi T., Falah F., Faghihloo E. Relationship of Human Herpes Virus 6 and Multiple Sclerosis: A Systematic Review and Meta-Analysis. Journal of Cellular Physiology, 2018, vol. 233, no. 4, pp. 2850-2862.
  96. Pugliatti M., Solinas G., Sotgiu S., Castiglia P., Rosati G. Multiple Sclerosis Distribution in Northern Sardinia: Spatial Cluster Analysis of Prevalence. Neurology, 2002, vol. 58, no. 2, pp. 277-282.
  97. Reynaud J.M., Horvat B., Joséphine M., и Branka Horvat. б. д. Human Herpesvirus 6 and Neuroinflammation. ISRN Virology, 2013, vol. 2013, pp. 834890.
  98. Rhead B., Bäärnhielm M., Gianfrancesco M., Mok A., Shao X., Quach H., Shen L., Schaefer C., Link J., Gyllenberg A., Hedstrom A.K., Olsson T., Hillert J., Kockum I., Glymour M.M., Alfredsson L., Barcellos L.F. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurology: Genetics, 2016, vol. 2, no. 5, pp. e97.
  99. Riise T., Grønning M., Klauber M.R., Barrett-Connor E., Nyland H., Albrektsen G. Clustering of Residence of Multiple Sclerosis Patients at Age 13 to 20 Years in Hordaland, Norway. American Journal of Epidemiology, 1991, vol. 133, no. 9, pp. 932-939.
  100. Rocca M.A., Preziosa P., Barkhof F., Brownlee W., Calabrese M., De Stefano N., Granziera C., Ropele S., Toosy A.T., Vidal-Jordana A., Di Filippo M., Filippi M. Current and Future Role of MRI in the Diagnosis and Prognosis of Multiple Sclerosis. The Lancet Regional Health. Europe, 2024, vol. 44, pp. 100978.
  101. Rotstein D.L., Chen H., Wilton A.S., Kwong J.C., Marrie R.A., Gozdyra P., Krysko K.M., Kopp A., Copes R., Tu K. Temporal Trends in Multiple Sclerosis Prevalence and Incidence in a Large Population. Neurology, 2018, vol. 90, no. 16, pp. e1435–e1441.
  102. Sabel C.E., Pearson J.F., Mason D.F., Willoughby E., Abernethy D.A., Taylor B.V. The Latitude Gradient for Multiple Sclerosis Prevalence Is Established in the Early Life Course. Brain: A Journal of Neurology, 2021, vol. 144, no. 7, pp. 2038–2046.
  103. Sattarnezhad N., Kockum I., Thomas O.G., Liu Yi., Ho P.P., Barrett A.K., Comanescu A.I., Wijeratne T.U., Utz P.J., Alfredsson L., Steinman L., Robinson W.H., Olsson T., Lanz T.V. Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. Proceedings of the National Academy of Sciences of the United States of America, 2025, vol. 122, no. 11, pp. e2424986122.
  104. Schapira K., Poskanzer D.C., Miller H. Familial and Conjugal Multiple Sclerosis. Acta Neurologica Scandinavica, 1966, vol. 42, no. S19, pp. 83–84.
  105. Sibley W.A., Bamford C.R., Clark K. Clinical viral infections and multiple sclerosis. Lancet (London, England), 1985, vol. 325, no. 8441, pp. 1313–1315.
  106. 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. Journal of Neurology, Neurosurgery, and Psychiatry, 2011, vol. 82, no. 10, pp. 1132-1141.
  107. Sutherland J. M., Tyrer J.H., Eadie M.J. The Prevalence of Multiple Sclerosis in Australia. Brain: A Journal of Neurology, 1962, vol. 85, pp, 149–164.
  108. Tao Ch., Simpson S., van der Mei I., Blizzard L., Havrdova E., Horakova D., Shaygannejad V., Lugaresi A., Izquierdo G., Trojano M., Duquette P., Girard M., Grand’Maison F., Grammond P., Alroughani R., Terzi M., Oreja-Guevara C., Sajedi S.A., Iuliano G., Sola P., Lechner-Scott J., Pesch V.V., Pucci E., Bergamaschi R., Barnett M., Ramo C., Singhal B., LA Spitaleri D., Slee M., Verheul F., Fernandez Bolanos R., Amato M.P., Cristiano E., Granella F., Hodgkinson S., Fiol M., Gray O., McCombe P., Saladino M.L., Sanchez Menoyo J.L., Shuey N., Vucic S., Shaw C., Deri N., Arruda W.O., Butzkueven H., Spelman T., Taylor B.V., MSBase Study Group. Higher Latitude Is Significantly Associated with an Earlier Age of Disease Onset in Multiple Sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 2016, vol. 87, no. 12, pp. 1343-1349.
  109. Torkildsen O., Grytten N., Aarseth J., Myhr K.-M., Kampman M.T. Month of Birth as a Risk Factor for Multiple Sclerosis: An Update. Acta Neurologica Scandinavica. Supplementum, 2012, vol. 195, pp. 58-62.
  110. Wang J., Jelcic I., Muhlenbruch L., Haunerdinger V., Toussaint N.C., Zhao Yi., Cruciani C., Faigle W., Naghavian R., Foege M., Binder T.M.C., Eiermann Th., Opitz L., Fuentes-Font L., Reynolds R., Kwok W.W., Nguyen J.T., Lee J.-H., Lutterotti A., Munz Ch., Rammensee H.-G., Hauri-Hohl M., Sospedra M., Stevanovic S., Martin R. HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. Cell, 2020, vol. 183, no. 5, pp. 1264-1281.e20.
  111. Westlund K. B., Kurland L.T. Studies on Multiple Sclerosis in Winnepeg, Manitoba, and New Orleans, Louisiana. I. Prevalence; Comparison between the Patient Groups in Winnipeg and New Orleans. American Journal of Hygiene, 1953, vol. 57, no. 3, pp. 380-396.
  112. Yousuf W., Ibrahim H., Harfouche M., Abu-Hijleh F., Abu-Raddad L. Herpes simplex virus type 1 in Europe: systematic review, meta-analyses and meta-regressions. BMJ Global Health, 2020, vol. 5, no. 7, pp. e002388.
  113. Zhang G.X., Carrillo-Vico A., Zhang W.T., Gao S.S., Izquierdo G. AyusoIncidence and Prevalence of Multiple Sclerosis in China and Other Asian Countries. Neurologia, 2023, vol. 38, no. 3, pp. 159-172.

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In the present study, we analyzed epidemiological evidence suggesting a possible infectious nature of multiple sclerosis. Within the framework of the infectious theory, we considered potential determinants of the latitude gradient of multiple sclerosis (increase in the incidence and/or prevalence of disease with increasing distance from the equator), including differences in the intensity of circulation of common pathogens, age of primary infection, differences in the seasonality of viral infections. We also examined the contribution of genetic and latitude-related factors (insolation) as modifiers of antiviral immune responses. Studies of migration impact upon the risk of multiple sclerosis were analyzed and found to be consistent with the hypothesis of a critical “window” of susceptibility to the disease during childhood and adolescence. Particular attention was given to the association of multiple sclerosis with putative etiological agents – human herpesvirus 6A (HHV6A) and human herpesvirus 6B (HHV6B) – and their potential role in pathogenesis of multiple sclerosis. Within an infectious model of disease development, ubiquitous distribution of both viruses, primary infection in childhood and adolescence, establishment of lifelong latent infection with reactivation episodes support the proposition that HHV6A and HHV6B may act as cofactors of multiple sclerosis. Ability of viruses to infect cells of the immune system and the nervous tissue (including glial cells), to promote chronic neuroinflammation and to contribute to demyelinating processes provides a plausible mechanism of their potential pathogenic effects. HHV6A is considered to be more neurotropic, while HHV6B has higher prevalence and earlier primary infection, so we compared experimental evidence regarding the potential roles of two viruses in multiple sclerosis development. We additionally addressed how molecular genetic polymorphism of HHV6A and HHV6B may modulate the nature of immune responses to infection and thereby influence the risk of disease. We also propose a potential association between the population frequencies of distinct HHV6A and HHV6B genovariants and multiple sclerosis incidence in certain countries of Northern European and North American with unusually high disease prevalence. Using Nizhny Novgorod Region as a case study, we compared long-term cycles of multiple sclerosis incidence with frequencies of HHV6B genovariants in the European part of Russia.


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