Table 1.

Environmental and genetic risk factors for multiple sclerosis

MS risk factor	Risk*		Observations	Postulated mechanism	Alternative mechanism
				1. Compromise of MS-protective immune reactions favouring the biosynthesis of MLN
Human endogenous retrovirus-W (HERV-W)	X	F	HERV-W and/or syncytin-1 more frequently detectable/elevated in MS, increased levels of antibodies against HERV GAG and ENV antigens in MS, related to the activity of disease [4-8]	Overexpression of the syncytin-1 gene encoded by HERV-W disturbs redox regulation in glial cells [9]
Time in life of infection	E●●●	P	Virtually all MS patients experienced previous EBV-infection and had elevated levels of anti- EBV-EBNA1 antibody in comparison with control groups [3,10,11]. Previous EBV-infection years or decade(s) before onset of MS [12]. Expanded T-helper cell populations recognizing an epitope of the EBV antigen EBNA1 in MS patients [13]	Infection with EBV early in life can establish MS protective immunity [3,10,11,14]. Infection with EBV delayed in life after immune response against an epitope nested in FENIAEGLRALLARSHVER (partial sequence of EBNA-1) is primed (see next entry) to form T- helper cells instead of regulatory T-cells essential for MS protection [14]	(Irrespective of time in life): Clonal expansion of lymphocytes in the CNS, or EBV infection triggers autoimmunity via molecular mimicry
with Epstein-Barr virus (EBV)	§
	E	F
Involvement of infection with measles, varicella and herpes simplex viruses and with 12 or more other pathogens	E●●●	P	Higher antibody-levels against diverse pathogens in particular measles, varicella, herpes simplex viruses, and EBV in MS-patients [10,15,16], intrathecal synthesis of antibodies against these viruses (including as in particular also rubella virus) [17,18]	Immune responses against diverse agents generates MS-protection by cross-reaction of a self-specific CD8+-T-cell response against a peptide MPVPSAPSTMPVPSAPST belonging to the human endogenous retrovirus W (HERV-W), encoded on the complementary DNA-strand of the syncytin-1 gene [14,19]	Immunological trigger for inflammatory demyelination
	§
	§
Infection with Chlamydia pneumoniae and/or human herpes virus-6	E §	F	More frequent detection of genomes of these agents in MS [15,20,21] More frequent IgM-specific antibodies against Chlamydia pneumoniae in paediatric onset MS [15]	Persisting infections can prime immune response against an epitope nested in FENIAEGLRALLARSHVER (partial sequence of EBV EBNA-1) to induce T-helper cells [14]
Worm infestation	E●●	P	Worm infestation less frequent in MS and treatment of worm infections leads to relapse of MS [22]	Contributes an immune stimulatory context that favours the generation of regulatory T-cells
Antihistamines	E w	P	Protective effects of antihistamines in MS [23]	Antihistamines suppress unfavourable allergic reactions competing with 'anti-parasite’-like reactions
HLA-polymorphism	G	P	Main HLA class I molecule A*0201 for the HLA-A0201 associated with a significantly reduced MS risk (OR = 0.52, P = 0.0015) [24]	Ability of HLA-polymorphism for immune presentation of the peptide MPVPSAPSTMPVPSAPST is good such as with HLA-A0201 (frequency of about 30% in a European population) [14]	See the text
Interleukin-2 receptor α (IL-2Rα)	G	P	Mutations in IL-2Rα gene in MS more frequent [25]	Component of the CD-25 molecule of regulatory T-cells, critical involvement of these cells in MS-protection
Interleukin-7 receptor α (IL-7Rα)	G	P	Mutations in IL-7Rα gene in MS more frequent [26]	Important for maintenance of CD8+-T-cell memory, critical is a long-persisting MS-protective cellular immune reaction
n-3-polyunsaturated fatty acids	E	P	Reduced MS risk with diet rich in n-3 poly-unsaturated fatty acids [27]	Dietary factors leading to an enrichment of ganglioside-content of T-cells. The MS-protective immune reaction seems to be an immune repair mediated by gangliosides [14,19,28,29]
				2. Factors favouring the biosynthesis of MLN not predominantly involving the immune system
Vitamin D-deficiency	E●●● §	F	Month of birth-effect [30,31]. Low levels of vitamin D in MS patients [32-34]	Deficiency pre-birth and after birth reduces intracellular glutathione [35]	Levels of vitamin D experienced in utero can have long-lasting effects on the development of numerous organ systems, including the CNS; during life, vitamin D has clear immunomodulatory functions
Low sun exposure	E●●	F	Influence of place of residence, MS risk increases with higher latitude [3,32]	Reduced exposure to sunlight rich in UV-B dependent on geographical latitude [3,32]
Selenium deficiency	E w	F	MS more frequent in regions with low levels of selenium in soil [36,37]	Selenium deficiency reduces levels of the seleno-enzyme glutathione-peroxidase [38]
Female sex hormones	E §	F	Dependence of MS risk on gender. MS risk in young children indepedent from gender but increased girl/boy rate in puberty [31,32]. Reduced MS risk in pregnancy, elevated MS risk after pregnancy and after the menopause [39]	Syncytin-1 gene has a sensitivity for female sex hormones, (gene product has physiological role in placenta) [39]	Altered antigen reactivity, tolerance, epigenetic effects
Smoking	E●●	F	Higher risk of MS in cigarette smokers [40]	Nicotine accumulates in melanin containing cells and interferes with melanin synthesis [41]	Nitric oxide-mediated demyelination, axonal loss and epigenetic effects
Iron-load	E	F	MS association to eating of meat [27]. Iron accumulation early in MS plaques [42,43]	Melanoma-melanin is incorporating iron [44-48]
				3. Oxidative charging of MLN
Vitamin D-deficiency	E●●●	F	See above	See above, glutathione is needed for discharging of MLN
	§
Low sun exposure	E●●	F	See above	See above, glutathione is needed for discharging of MLN
Selenium deficiency	E w	F	See above	See above, glutathione-peroxidase is needed for discharging of MLN Iron containing MLN is charged by ionizing radiation/ cosmic radiation [49]. Cosmic radiation
Geomagnetic disturbances/ Cosmic radiation	E●●	F	MS relates to geomagnetic 60° latitude [1]
	E	F	MS association to mountain regions [50]
				4. Physiological influence on activity of neuromelanin
Visible light	E §	P	Increased risk of MS onset (1st attack) in the lightest months of the year [31,51]	The hormone melatonin regulates the daily activity of neuromelanins (light-triggered day-night rhythm)
				5. Formation of short living reactive oxygen species and radicals (ROS) by mitochondria
Psycho-physical trauma	E	F	Increased MS risk in relations to psycho-physical trauma, detection of ROS-related products in MS [52]	Traumatic events lead to the generation of ROS by mitochondria	Dysregulation of the hypothalamic-pituary-adrenal axis
Heat/fever	E	F	Heat as attack provoking factor in MS [53,54]	Heat leads to the generation of ROS by mitochondria
	E	F	MS protective effect of the introduction of anti-pyretics [53] and of the antibiotic penicillin [55]	Fever leads to the generation of ROS by mitochondria
Chronic stress reaction	E w	F	Decreased ubiquinone, and increased endogenous digoxin and metabolites of oxidative stress in MS [56]	Over-activation of the cellular mevalonate pathway with decrease of ubiquinone, and increase of endogenous digoxin and ROS production by mitochondria [56]	As above
				6. Formation of long-living reactive oxygen species and radicals (ROS) requiring typically nitrogen oxide as a co-substrate
Infection/Inflammation	E	F	A small blood vessel is often running through the plaque, the end stage of MS pathology [57]	Adherent polymorph nuclear cells in small blood vessels form nitrogen oxide (NO) that is not readily cleared
Gout	E	P	MS is extremely rare in patients with gout and levels of uric acid are about 10 to 15% lower in patients with MS [58]	Radical scavenger function of uric acid for nitrogen-containing ROS [58]
decreased uric acid	E	F
Glatiramer-acetate	E	P	An agent with therapeutic benefit in MS	Inhibition of NO synthase of mononuclear cells [59]

Categorization of risks (see footnotes), observations, postulated mechanisms with respect to a hypothetical melanoma-like neuromelanin (MLN) ordered in groups of 6 aspects, and alternative mechanisms as suggested in ref [32].

* E = environmental risk, G = genetic risk, ^X = genetic factor but indirectly environmental risk; P = protective, F = fatal; ^●●● = very strong evidence; ^●● = strong evidence; ^w = evidence weak. § In a group of German patients with onset of MS in childhood, studied by Hanefeld and co-workers, diverse observations were made more or less in the same study group. Categorization for the evidence of these observations is based on comparison of p-values by multiple testing with Bonferroni-correction as described in ref. [15].