Sex and gender issues in multiple sclerosis

Multiple sclerosis (MS) is universally found to be more prevalent in women than men. This has led to extensive studies of differences in the immune system or nervous system between women and men, which might be caused by the effects of gonadal hormones, genetic differences, and different environmental exposures and modern lifestyle in men and women. We review the effects of sex and gender from a genetic, immunological and clinical point of view. We discuss the effects of sex on the clinical expression of MS and responses to therapy, as well as issues concerning pregnancy.

[1]  Bing Zhang,et al.  Early pregnancy factor treatment suppresses the inflammatory response and adhesion molecule expression in the spinal cord of SJL/J mice with experimental autoimmune encephalomyelitis and the delayed-type hypersensitivity reaction to trinitrochlorobenzene in normal BALB/c mice , 2003, Journal of the Neurological Sciences.

[2]  R. Gold,et al.  Parenthood and immunomodulation in patients with multiple sclerosis , 2010, Journal of Neurology.

[3]  I. Cohen,et al.  The rapid isolation of clonable antigen‐specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis , 1981, European journal of immunology.

[4]  C. Azqueta,et al.  HLA‐DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population , 2011, European journal of neurology.

[5]  G. Giovannoni,et al.  Breastfeeding and multiple sclerosis relapses: a meta-analysis , 2012, Journal of Neurology.

[6]  N. Risch,et al.  Twin concordance and sibling recurrence rates in multiple sclerosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Oturai,et al.  X chromosome inactivation in females with multiple sclerosis , 2007, European journal of neurology.

[8]  L. Airas,et al.  Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland , 2010, Multiple sclerosis.

[9]  T. Olsson,et al.  FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4+CD25high T cells in multiple sclerosis , 2012, Clinical and experimental immunology.

[10]  D. Hinton,et al.  Self-antigen-induced Th2 responses in experimental allergic encephalomyelitis (EAE)-resistant mice. Th2-mediated suppression of autoimmune disease. , 1995, Journal of immunology.

[11]  H. Weiner,et al.  Population structure and HLA DRB1*1501 in the response of subjects with multiple sclerosis to first-line treatments , 2011, Journal of Neuroimmunology.

[12]  A. Compston,et al.  Multiple sclerosis. , 2002, Lancet.

[13]  C. Selmi The X in sex: how autoimmune diseases revolve around sex chromosomes. , 2008, Best practice & research. Clinical rheumatology.

[14]  A. Verma,et al.  Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study , 2008 .

[15]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[16]  P. Vermersch,et al.  Neuromyelitis optica and pregnancy , 2012, Neurology.

[17]  A. Tselis,et al.  Evidence for Viral Etiology of Multiple Sclerosis , 2011, Seminars in neurology.

[18]  L. Blizzard,et al.  Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[19]  Pierre Grammond,et al.  Geographical Variations in Sex Ratio Trends over Time in Multiple Sclerosis , 2012, PloS one.

[20]  C. Willer,et al.  Microchimerism in autoimmunity and transplantation: potential relevance to multiple sclerosis , 2002, Journal of Neuroimmunology.

[21]  E. Celius,et al.  Change in sex ratio, disease course and age at diagnosis in Oslo MS patients through seven decades , 2009, Acta neurologica Scandinavica. Supplementum.

[22]  N. Risch,et al.  A genetic basis for familial aggregation in multiple sclerosis , 1995, Nature.

[23]  J. Haselkorn,et al.  The Gulf War era multiple sclerosis cohort: age and incidence rates by race, sex and service. , 2012, Brain : a journal of neurology.

[24]  A. Finkelsztejn,et al.  What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta‐analysis of the literature , 2011, BJOG : an international journal of obstetrics and gynaecology.

[25]  N. Yosef,et al.  Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells , 2013, Nature.

[26]  A. Synnes,et al.  Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic review , 2013, Neurology.

[27]  K. Kyvik,et al.  Concordance for multiple sclerosis in Danish twins: an update of a nationwide study , 2005, Multiple sclerosis.

[28]  J. Alferink,et al.  T Cell Awareness of Paternal Alloantigens During Pregnancy , 1995, Science.

[29]  S. Gold,et al.  Estrogen and testosterone therapies in multiple sclerosis. , 2009, Progress in brain research.

[30]  L. Steinman,et al.  Vitamin D, pregnancy, breastfeeding, and postpartum multiple sclerosis relapses. , 2011, Archives of neurology.

[31]  D. Branch Physiologic Adaptations of Pregnancy , 1992, American journal of reproductive immunology.

[32]  H. Harbo,et al.  The genetics of multiple sclerosis: an up‐to‐date review , 2012, Immunological reviews.

[33]  K. Spach,et al.  Vitamin D3 Confers Protection from Autoimmune Encephalomyelitis Only in Female Mice1 , 2005, The Journal of Immunology.

[34]  B. Uitdehaag,et al.  Long-term effects of childbirth in MS , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[35]  A. Ascherio,et al.  Epstein–Barr Virus Infection and Multiple Sclerosis: A Review , 2010, Journal of Neuroimmune Pharmacology.

[36]  J. Hillert,et al.  HLA‐DR15 is associated with lower age at onset in multiple sclerosis , 2000, Annals of neurology.

[37]  K. T. Jørgensen,et al.  Reproductive History and Risk of Multiple Sclerosis , 2011, Epidemiology.

[38]  P. Mccombe,et al.  Role of gender in multiple sclerosis: Clinical effects and potential molecular mechanisms , 2011, Journal of Neuroimmunology.

[39]  Lin Zhao,et al.  Induction of regulatory T cells by physiological level estrogen , 2008, Journal of cellular physiology.

[40]  R. Bergamaschi Prognostic factors in multiple sclerosis. , 2007, International review of neurobiology.

[41]  A. Arnold,et al.  A role for sex chromosome complement in the female bias in autoimmune disease , 2008, The Journal of experimental medicine.

[42]  D. Clayton,et al.  Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. , 1996, Brain : a journal of neurology.

[43]  A. MacKenzie-Graham,et al.  Gender differences in autoimmune demyelination in the mouse: Implications for multiple sclerosis , 1996, Annals of neurology.

[44]  K. Vandenbroeck,et al.  Pharmacogenomics and Multiple Sclerosis: Moving Toward Individualized Medicine , 2011, Current neurology and neuroscience reports.

[45]  C. Polman,et al.  Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women , 2009, Multiple sclerosis.

[46]  R. Gold,et al.  A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis , 2011, Journal of the Neurological Sciences.

[47]  B. Weinshenker,et al.  CD95 polymorphisms are associated with susceptibility to MS in women A population-based study of CD95 and CD95L in MS , 2004, Journal of Neuroimmunology.

[48]  P. Duquette,et al.  Gender Issues in Multiple Sclerosis: An Update , 2010, Women's health.

[49]  J. Hillert,et al.  HLA-DRB1⁎15 and cerebrospinal-fluid-specific oligoclonal immunoglobulin G bands lower age at attainment of important disease milestones in multiple sclerosis , 2009, Journal of Neuroimmunology.

[50]  A. W. F. EDWARDS,et al.  Population structure , 1974, Nature.

[51]  B. Lie,et al.  Importance of Human Leukocyte Antigen (HLA) Class I and II Alleles on the Risk of Multiple Sclerosis , 2012, PloS one.

[52]  K. Myhr,et al.  Pregnancy, delivery and birth outcome in different stages of maternal multiple sclerosis , 2008, Journal of Neurology.

[53]  G. Ebers,et al.  HLA B*44: Protective effects in MS susceptibility and MRI outcome measures , 2011, Neurology.

[54]  Arthur W Toga,et al.  Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis , 2012, Journal of neuroscience research.

[55]  R. Voskuhl,et al.  Sex Hormones in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis , 2001, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[56]  David Haig,et al.  Sex-Specific Parent-of-Origin Allelic Expression in the Mouse Brain , 2010, Science.

[57]  F. Asefi,et al.  Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis , 2012 .

[58]  S. Sawcer,et al.  Genes in the HLA class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis. , 2004, Tissue antigens.

[59]  E. Smeraldi,et al.  HL-A antigens and multiple sclerosis. , 1972, Lancet.

[60]  L. Garay,et al.  Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[61]  Y. Fragoso,et al.  The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis , 2013, Clinical Neurology and Neurosurgery.

[62]  M. Hutchinson,et al.  Rate of Pregnancy-Related Relapse in Multiple Sclerosis , 1998 .

[63]  J. Correale,et al.  Increase in multiple sclerosis activity after assisted reproduction technology , 2012, Annals of neurology.

[64]  Stephen L. Hauser,et al.  The genetics of multiple sclerosis: SNPs to pathways to pathogenesis , 2008, Nature Reviews Genetics.

[65]  B. Weinshenker,et al.  Association of APOE polymorphisms with disease severity in MS is limited to women , 2004, Neurology.

[66]  R. Gold,et al.  Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment , 2011, Multiple sclerosis.

[67]  P. Sørensen,et al.  The changing demographic pattern of multiple sclerosis epidemiology , 2010, The Lancet Neurology.

[68]  Christian Confavreux,et al.  Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. , 2004, Brain : a journal of neurology.

[69]  G. Adamus,et al.  Gonadal hormones influence the immune response to PLP 139–151 and the clinical course of relapsing experimental autoimmmune encephalomyelitis , 1998, Journal of Neuroimmunology.

[70]  A. Odén,et al.  High nationwide prevalence of multiple sclerosis in Sweden , 2011, Multiple sclerosis.

[71]  P. Tienari,et al.  Month of birth is associated with multiple sclerosis but not with HLA-DR15 in Finland , 2012, Multiple sclerosis.

[72]  M. Sandberg‐Wollheim,et al.  Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy , 2011, Multiple sclerosis.

[73]  E. Celius,et al.  Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway , 2013, Journal of Neurology.

[74]  S. Gold,et al.  Sex-related factors in multiple sclerosis susceptibility and progression , 2012, Nature Reviews Neurology.

[75]  Daniel J. Bauer,et al.  The reproductive effects of beta interferon therapy in pregnancy , 2005, Neurology.

[76]  A. Synnes,et al.  Neonatal and Delivery Outcomes in Women with Multiple Sclerosis , 2011, Annals of neurology.

[77]  N. Sicotte,et al.  Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol 1 , 2003, The Journal of Immunology.

[78]  J. Bunn,et al.  Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice1 , 2009, The Journal of Immunology.

[79]  T. Shima,et al.  REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T‐Cell Paradigm in Pregnancy , 2010, American journal of reproductive immunology.

[80]  Hans Lassmann,et al.  Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. , 2006, Brain : a journal of neurology.

[81]  H. Kim,et al.  Influence of pregnancy on neuromyelitis optica spectrum disorder , 2012, Neurology.

[82]  J. Hillert,et al.  HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. , 1991, Tissue antigens.

[83]  A. Sadovnick,et al.  Parent-of-origin effects in MS , 2008, Neurology.

[84]  B. Lie,et al.  [New gene map for multiple sclerosis]. , 2011, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[85]  R. Gold,et al.  Low vitamin D and elevated immunoreactivity against Epstein–Barr virus before first clinical manifestation of multiple sclerosis , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[86]  J. Correale,et al.  Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis , 2009, Annals of neurology.

[87]  H. Harbo,et al.  Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis , 2000, Journal of the Neurological Sciences.

[88]  P. D. de Bakker,et al.  Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci , 2011, Annals of neurology.

[89]  S J Nelson,et al.  Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures. , 2009, Brain : a journal of neurology.

[90]  M. Hutchinson,et al.  Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. , 1999, The New England journal of medicine.

[91]  E. Steegers,et al.  First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis , 2009, Multiple sclerosis.

[92]  O. Kantarci Genotype–Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures , 2009 .

[93]  M. Clanet,et al.  Increased risk of multiple sclerosis relapse after in vitro fertilisation , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[94]  M. Ban,et al.  Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility , 2008, PloS one.

[95]  A. Sadovnick,et al.  Multiple sclerosis in stepsiblings: recurrence risk and ascertainment , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[96]  H. Link,et al.  HLA haplotypes in families with high frequency of multiple sclerosis. , 1976, Archives of neurology.

[97]  N. Gilhus,et al.  Pregnancy, delivery, and birth outcome in women with multiple sclerosis , 2005, Neurology.

[98]  A. Ponsonby,et al.  Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis , 2010, BMJ : British Medical Journal.

[99]  R. Voskuhl,et al.  Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis , 2004, Journal of Neuroimmunology.

[100]  P. Mccombe,et al.  Female reproductive issues in multiple sclerosis , 2013, Multiple sclerosis.

[101]  R. Ransohoff,et al.  The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis , 2004, The Journal of experimental medicine.

[102]  C. Pozzilli,et al.  Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis , 2010, Neurology.

[103]  K. Dear,et al.  Offspring number, pregnancy, and risk of a first clinical demyelinating event , 2012, Neurology.

[104]  M. Melbye,et al.  Familial risk of multiple sclerosis: a nationwide cohort study. , 2005, American journal of epidemiology.

[105]  A. Sadovnick,et al.  Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[106]  Geneva,et al.  Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis , 2005, Neurology.