Multiple SclerosisA look at genetic and environmental factors
Lauren E. Hansen
2008
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Multiple Sclerosis Defined• Immune system attacks the body’s central
nervous system (brain, spinal cord, optic nerves)
– CD4+ T cells initiate the attack on the myelin coating of the axons of the CNS and scar tissue (sclerosis) is formed
– Scars result in slowed or blocked function of the affected nerves, causing symptoms
– Specific antigen not known
McFarland & Martin, 2007
Symptoms of MS
• Vary over time and by severity and by person
• May include: – Numbness, paralysis, loss of coordination,
loss of vision, fatigue, balance problems, bladder & bowel dysfunction, dizziness, pain, cognitive difficulty, emotional changes, depression, and many others…
Types of MS
• Relapsing-Remitting (85%)
• Primary-Progressive (10%)
• Secondary-Progressive (50% of RR w/in 10 yrs)
• Progressive-Relapsing (5%)
National Multiple Sclerosis Society
Diagnosis of MS
• No definitive diagnostic test
• Tests used to indicated presence of MS– Medical History & Neurologic Exam– MRI of brain and/or spinal cord– Visual evoked potential (VEP)– Cerebrospinal fluid analysis (spinal tap)
• Presence of oligoclonal bands (90-95%)
– Blood tests to rule out other conditions
National Multiple Sclerosis Society
Demographics of MS
• 2.5 mil. Worldwide; 400,000 in the U.S.– 200 people diagnosed every week in U.S.
• 2-3 times more common in women
• Most diagnosed between 20 and 50 years of age– Later onset associated with more progressive form
• Most common in Caucasians of N. European ancestry– But also present in those of African, Asian & Hispanic ethnicity – Not present in Inuit, Aborigine, Maori populations
National Multiple Sclerosis Society
Demographics of MS
• Heredity plays a factor– Risk in general population = 1/750– Risk if close relative is affected = 1/40– Risk if identical twin is affected = 1/25
Treatments
• No cure exists• Exacerbations may be treated with
corticosteroids• 6 Disease-Modifying Drugs
– Avonex (interferon beta-1a)– Rebif (interferon beta-1a) – Betaseron (interferon beta-1b)– Copaxone (glatiramer acetate)– Novatrone (mitoxantrone)– Tysabri (natalizumab)
Genetic Risk Factors
• Three major players have been found so far– HLA-DRB1*1501 locus on the HLA– IL7R– IL2R
• These factors combined account for 50% of the inheritability found for MS
Gregory et al. 2007
Human Leukocyte Antigen
• Protein on the surface of cells that controls how the immune system identifies foreign tissue
• HLA-DRB1*1501 locus associated with MS– OR=5.80 (95%CI, 3.53 to 9.53; P=1.83x10-17)– Gene dosage effect: homozygosity for this allele
results in greater risk compared to heterozygosity
The International Multiple Sclerosis Genetics Consortium, 2007
Interleukins
• Cytokines (messenger proteins) that regulate immune cells (T, B and natural killer cells)– Evidence of dysfunction of regulatory T cells
(which have power to turn off immune system attacks) in MS
• Genome-wide study indicates MS is a polygenic autoimmune disorder – Lots of common gene variations that each confer
small risk
The International Multiple Sclerosis Genetics Consortium, 2007
Interleukin 7 receptor chain
• rs6897932 SNP in the IL7R gene is associated with a small increase in risk of developing MS– OR=1.18; 95%CI, 1.11 to 1.26; P=2.94x10-7
• IL7R aids in development of gamma & delta T cells (some of earliest T cells observed in inflammatory lesions of MS)
The International Multiple Sclerosis Consortium, 2007
Interleukin 2 receptor chain
• rs12722489 SNP – OR=1.25; 95%CI, 1.16 to 1.36; P=2.96x10-8
• rs2104286 SNP– OR=1.19; 95%CI, 1.11 to 1.26; P=2.16x10-7
• In studies using a monoclonal antibody to target the IL2R chain, clinical efficacy was observed
The International Multiple Sclerosis Consortium, 2007
Environmental Risk Factors
• Epstein-Barr Virus (EBV)
• Human herpesvirus 6 (HHV-6)
• Vitamin D
• Smoking
Epstein-Barr Virus• EBV is a B-lymphotropic human DNA
herpesvirus that can cause asymptomatic latent infections and infectious mononucleosis.
• Serafini et al. (2007) found abnormal accumulation of EBV infected B cells and plasma cells in the brains of nearly 100% MS patients studied– Not seen in any other inflammatory neurological
disorders
Epstein-Barr Virus• IgG antibodies to EBNA -1 and EBNA-complex
can be found an average of 5 years before MS onset
• 4-fold increase in EBNA-1 and ENBA-complex titers corresponds to a 3-fold increase in risk of developing MS – (EBNA complex: RR 3.0; 95% CI, 1.3-6.5; P=.007)– (EBNA-1: RR 3.0; 95% CI, 1.2-7.3; P=.01)
Levin et al. 2005
Hygiene Hypothesis
• Pro: Early EBV infection is associated with a reduced risk of MS.– Found in developing countries, the tropics, Asia
and among Eskimos in Greenland
• Con: Those who are EBV negative are 10 times less likely to develop MS
Ascherio & Munger, 2008
Revised Hygiene Hypothesis
Ascherio & Munger, 2008
• Individuals infected with EBV who subsequently develop mononucelosis are 2 to 3 times more likely to develop MS
Human herpesvirus 6
• Virtanen et al. (2007) found seroprevalence to HHV-6A in 100% of patients with MS versus 69.2% of patients with other autoimmune disorders
• Levels found in those with MS higher than those without
Virtanen et al. 2007
Vitamin D and risk of MS
• Vitamin D intake > 400 IU/d, RR=.59 (95% CI = .38 to .91, p=.006)
Munger et al. 2004
• Serum levels of vitamin D > 99nmol/L, RR=.38
Munger et al. 2006
Islam et al. 2007• Examined sun exposure as explanation for latitude
gradient
• Surveyed 193 disease-discordant twin pairs
• Compared survey answers to calculated sun index (SI)
• For each 1 unit increase in SI, risk decreased by 25%– OR=.75; 95%CI, .62-.90; p=.004 (adjusted for potential
confounders)
Vitamin D - additional findings
• Latitude gradient for MS – Risk of MS for migrants is equal to the average risk
of birthplace and final residence
• Reduced risk of MS in Norway coastal villages
• Injection of vitamin D prevents EAE (experimental autoimmune encephalomyelitis), while vitamin D deficiency accelerates onset
Ascherio & Munger 2008
Smoking• Combined longitudinal studies report increase risk of
MS from smoking (p<.0001)
• Risk of MS among women reporting 25 or more pack-years was 70% higher than those who never smoked (p<.01)
• Increased risk of transition from relapsing-remitting MS to secondary-progressive MS
• Smoking shown to be risk factor for other autoimmune disorders as well
Ascherio & Munger, 2008
Resources• Ascherio, A. & Munger, K. (2008) Epidemiology of multiple sclerosis: from risk factors to
prevention. Seminars in Neurology, 28 (1), 17-28.• Gregory, G., Schmidt, S., Seth, P. et al. (2007). Interleukin 7 receptor a chain (IL7R) shows
allelic and functional association with multiple sclerosis. Nature Genetics, (39) 9, 1083-1091.
• The International Multiple Sclerosis Genetics Consortium (2007). Risk alleles for multiple sclerosis identified by a genomewide study. The New England Journal of Medicine, 357 (9), 851-862.
• Islam, T., Gauderman, W.J., Cozen, W. & Mack, T.M. (2007). Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology, 69, 381-388.
• Levin, L.I., Munger, K.L., Rubertone, M.V. et al. (2005). Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA, 293 (20), 2496-2500.
• McFarland, H.F. & Martin R. (2007). Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunology, 8 (9), 913-919.
• The National Multiple Sclerosis Society www.nmss.org• Serafini, B., Rosicarelli, B., Franciotta, D. et al. (2007). Dysregulated Epsetin-Barr virus
infection in the multiple sclerosis brain. The Journal of Experimental Medicine, 201 (12), 2899-2912.
• Virtanen, J.O., Farkkila, M., Multanen, J. et al. (2007). Evidence for human herpesvirus 6 variant A antibodies in multiple sclerosis: diagnostic and therapeutic implications. Journal of NeuroVirology, 13, 347-352.
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