Table 1 Environmental and genetic risk factors for multiple sclerosis

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]