Sex-Specific Environmental Impacts on Initiation and Progression of Multiple Sclerosis

Abstract

The immunological mechanisms that contribute to multiple sclerosis (MS) differ between males and females. Females are 2–3 times more likely to develop MS compared to males, however the reason for this discrepancy is unknown. Once MS is established, there is a more inflammatory yet milder form of disease in females whereas males generally suffer from more severe disease and faster progression, neural degradation, and disability. Some of these differences relate to genetics, including genetic control of immune regulatory genes on the X-chromosome, as well as immune modulatory properties of sex hormones. Differences in MS development may also relate to how sex interacts with environmental risk factors. There are several environmental risk factors for MS including late-onset Epstein Barr virus infection, low serum vitamin D levels, low UV radiation exposure, smoking, obesity, and lack of physical activity. Most of these risk factors impact males and females differently, either due to biological or immunological processes or through behavioral differences. In this review, we explore these differences further and focus on how the interaction of environmental risk factors with sex hormones may contribute to significantly different prevalence and pathology of MS in males and females.

Increasing incidence and prevalence of multiple sclerosis in the Greater Hobart cohort of Tasmania, Australia

“…There is no reason to expect this increased incidence in females is attributable to bias of increased and earlier detection by sex, and may more likely reflect some of the factors which underlie the female preponderance for MS, such as hormonal or genetic effects 27–29. It is possible that these factors, including environmental and lifestyle, may interact with sex-specific characteristics to realise the changes in sex ratios observed here 30. Further investigation of these interactions should be undertaken, both to better our understanding of the pathophysiology of MS as well as to identify possible points of intervention.…”

Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis

“…In patients with undifferentiated ON, we found female sex to be a significant independent predictor of MS risk (aHR 2.20, P < 0.005, Fig. 3a ), an association well-established in the literature but not fully understood, reflecting a complex interplay between genetic, epigenetic, immunological, hormonal and environmental factors 39 , 40 . Binary age at onset of ON (between 18 and 50 years) was also significantly associated with MS risk (aHR 2.43, P < 0.005).…”

Epstein–Barr virus infection, B‐cell dysfunction and other risk factors converge in gut‐associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis

“…MS is 2–3 times more common in females than in males 122,123 . It is well‐established that females respond more strongly to viral infections than males and this also applies to EBV, as we have recently reviewed 124 . As a result, EBNA‐1‐specific IgG antibody levels are generally higher in females than in males 125,126 and this likely contributes to some of the increased risk of MS in females.…”

“… 122 , 123 It is well‐established that females respond more strongly to viral infections than males and this also applies to EBV, as we have recently reviewed. 124 As a result, EBNA‐1‐specific IgG antibody levels are generally higher in females than in males 125 , 126 and this likely contributes to some of the increased risk of MS in females. Sex‐related differences in the function of CD11c + /T‐bet + MBCs and MZ B cells might also contribute.…”