Sex differences in the incidence or severity of disease characterize many autoimmune and neurodegenerative diseases. Multiple sclerosis is a complex disease with both autoimmune and neurodegenerative aspects and is characterized by sex differences in susceptibility and progression. Research in the study sex differences is a way to capitalize on a known clinical observation, mechanistically disentangle it at the laboratory bench, then translate basic research findings back to the clinic as a novel treatment trial tailored to optimally benefit each sex. This “Bedside to Bench to Bedside” approach based on sex differences in MS will be reviewed here, first for disease susceptibility then for disability progression.
WhitacreCCReingoldSCO’LooneyPA. A gender gap in autoimmunity. Science1999; 283(5406): 1277–1278.
2.
Koch-HenriksenNSorensenPS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol2010; 9(5): 520–532.
3.
VoskuhlRRGoldSM. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol2012; 8(5): 255–263.
4.
PonsonbyALLucasRMvan der MeiIA, et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: The AusImmune Study. Neurology2012; 78(12): 867–874.
5.
KleinSLFlanaganKL. Sex differences in immune responses. Nat Rev Immunol2016; 16(10): 626–638.
6.
LibertCDejagerLPinheiroI. The X chromosome in immune functions: When a chromosome makes the difference. Nat Rev Immunol2010; 10(8): 594–604.
7.
MoldovanIRCotleurACZamorN, et al. Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens. J Neuroimmunol2008; 193(1–2): 161–169.
8.
ClaytonJACollinsFS. Policy: NIH to balance sex in cell and animal studies. Nature2014; 509(7500): 282–283.
9.
ArnoldAP. Sex chromosomes and brain gender. Nat Rev Neurosci2004; 5(9): 701–708.
10.
SasidharMVItohNGoldSM, et al. The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY. Ann Rheum Dis2012; 71(8): 1418–1422.
11.
Smith-BouvierDLDivekarAASasidharM, et al. A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med2008; 205(5): 1099–1108.
12.
ItohYGoldenLCItohN, et al. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J Clin Invest2019; 130: 3852–3863.
13.
VoskuhlRRSawalhaAHItohY. Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression. Mult Scler2018; 24(1): 22–31.
14.
ReddyJWaldnerHZhangX, et al. Cutting edge: CD4+CD25+ regulatory T cells contribute to gender differences in susceptibility to experimental autoimmune encephalomyelitis. J Immunol2005; 175(9): 5591–5595.
15.
SpachKMBlakeMBunnJY, et al. Cutting edge: The Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J Immunol2009; 182(4): 1789–1793.
16.
ArnoldAP. Y chromosome’s roles in sex differences in disease. Proc Natl Acad Sci U S A2017; 114(15): 3787–3789.
17.
ChitnisTGravesJWeinstock-GuttmanB, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol2016; 3(12): 897–907.
18.
HellwigKChenLHStancyzkFZ, et al. Oral contraceptives and multiple sclerosis/clinically isolated syndrome susceptibility. PLoS ONE2016; 11(3): e0149094.
19.
AlonsoAClarkCJ. Oral contraceptives and the risk of multiple sclerosis: A review of the epidemiologic evidence. J Neurol Sci2009; 286(1–2): 73–75.
20.
VoskuhlRKleinS. Sex is a biological variable—In the brain too. Nature2019; 568(7751): 171.
21.
MeyerCEKurthFLeporeS, et al. In vivo magnetic resonance images reveal neuroanatomical sex differences through the application of voxel-based morphometry in C57BL/6 mice. Neuroimage2017; 163: 197–205.
22.
LudersEGaserCNarrKL, et al. Why sex matters: Brain size independent differences in gray matter distributions between men and women. J Neurosci2009; 29(45): 14265–14270.
23.
WootenGFCurrieLJBovbjergVE, et al. Are men at greater risk for Parkinson’s disease than women. J Neurol Neurosurg Psychiatry2004; 75(4): 637–639.
24.
UchoaMFMoserVAPikeCJ. Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol2016; 43: 60–82.
25.
MielkeMMVemuriPRoccaWA. Clinical epidemiology of Alzheimer’s disease: Assessing sex and gender differences. Clin Epidemiol2014; 6: 37–48.
26.
PikeCJ. Sex and the development of Alzheimer’s disease. J Neurosci Res2017; 95(1–2): 671–680.
27.
ConfavreuxCVukusicSAdeleineP. Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process. Brain2003; 126(Pt. 4): 770–782.
28.
WeinshenkerBG. Natural history of multiple sclerosis. Ann Neurol1994; 36(Suppl): S6–S11.
29.
KochMKingwellERieckmannP, et al. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry2010; 81(9): 1039–1043.
30.
RibbonsKAMcElduffPBozC, et al. Male sex is independently associated with faster disability accumulation in relapse-onset ms but not in primary progressive MS. PLoS ONE2015; 10(6): e0122686.
31.
SchoonheimMMPopescuVRueda LopesFC, et al. Subcortical atrophy and cognition: Sex effects in multiple sclerosis. Neurology2012; 79(17): 1754–1761.
32.
BeattyWWAupperleRL. Sex differences in cognitive impairment in multiple sclerosis. Clin Neuropsychol2002; 16(4): 472–480.
33.
SavettieriGMessinaDAndreoliV, et al. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. J Neurol2004; 251(10): 1208–1214.
34.
GeczJShoubridgeCCorbettM. The genetic landscape of intellectual disability arising from chromosome X. Trends Genet2009; 25(7): 308–316.
35.
DuSItohNAskarinamS, et al. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A2014; 111(7): 2806–2811.
36.
BoveRHealyBCMusallamA, et al. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort. Mult Scler2016; 22(7): 935–943.
37.
De GiglioLMarinelliFBarlettaVT, et al. Effect on cognition of estroprogestins combined with interferon beta in multiple sclerosis: Analysis of secondary outcomes from a randomised controlled trial. CNS Drugs2017; 31(2): 161–168.
38.
VoskuhlRRWangHWuTC, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: A randomised, placebo-controlled, phase 2 trial. Lancet Neurol2016; 15(1): 35–46.
39.
MacKenzie-GrahamABrookJKurthF, et al. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav2018; 8(9): e01086.
40.
KimRYManguDHoffmanAS, et al. Oestrogen receptor beta ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis. Brain2018; 141(1): 132–147.
41.
VoskuhlRRItohNTassoniA, et al. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci U S A2019; 116(20): 10130–10139.
42.
BoveRMusallamAHealyBC, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler2014; 20(12): 1584–1592.
43.
KurthFLudersESicotteNL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin2014; 4: 454–460.
44.
HussainRGhoumariAMBieleckiB, et al. The neural androgen receptor: A therapeutic target for myelin repair in chronic demyelination. Brain2013; 136(Pt. 1): 132–146.
45.
ZiehnMOAvedisianAADervinSM, et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci2012; 32(36): 12312–12324.
