Environmental risk factors and medical conditions associated with Multiple Sclerosis

Ongoing clinical trails, worldwide, can be interrogated at ClinicalTrials.Gov a service of the US National Institutes of Health :

Epidemiology at Multiple sclerosis International federation

VIRUSES AND MULTIPLE SCLEROSIS

Vitamin D and MS Pubmed

Post a job in the UK

Risk factors do not cause the disease by themselves; for example millions are infected with the Epstein-Barr virus and not all develop multiple sclerosis. However they might work together with other risk factors and with genes, and these effects might be additive, or perhaps cancel each other out. Similarly, protective factors might be interdependent, or might not work under certain conditions. However, some of these factors, for example diet or vitamins, are accessible or avoidable, and it may be appropriate to avoid the bad and favour the good.

KEGG pathway analysis of over 300 multiple sclerosis susceptibility genes -(immune networks, pathogen defence and pathogen entry pathways.)

Papers related to this page:

• Epstein–Barr and other viral mimicry of autoantigens, myelin and vitamin D-related proteins and of EIF2B, the cause of vanishing white matter disease:massive mimicry of multiple sclerosis relevant proteins by the Synechococcus phage Immunology and Immunotoxocology, 2011 Full text
  • Autoantigen homology with viral risk factors MBP,MOG and CLDN11 CRYAB, CNP, MAG, EIF2B5
  • Epstein-Barr virus and Synechococcus phage homology with human proteins
• Toxoplasmosis and polygenic diseases: Extensive T.Gondii host/pathogen interactome enrichment in nine psychiatric or neurological disorders J.Pathogens, 2012
• Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.Pathogens and disease, 2013 see also pathway analyses of interactome genes related to multiple sclerosis genes and others.

Genome.gov GWAS studies

ACP5 AHI1 ASAP1 BACH2 BATF C16orf47 C1GALT1 C1orf125 C20orf46 CBLB CBLN2 CD6 CD40 CD58 CD86 CENPC1 CLEC16A CLECL1 CSMD1 CUEDC1 CXCR4 CXCR5 CYP24A1 CYP27B1 DBC1 DDAH1 DDEF1 DDEF2 DKKL1 DLEU1 HLA-DQA1 EN1 EOMES EXTL2 FLJ11017 FLJ16641 FLJ34870 FOXG1B FUT8 GPC5 GPR65 HHEX HLA-A HLA-B HLA-DQB1 HLA-DRA HLA-DRB HLA-DRB1 IL12A IL12B IL2RA IL7RA IL22RA2 IRF8 JARID2 KCNB2 KIAA0350 KIF1B LOC100289506 LOC132321 MALT1 MAMSTR MANBA MAPK1 MERTK MET METTL1 MGC13125 MGC45800 MLANA MMEL1 MPHOSPH9 MPV17L2 MYB MYC MYNN NDFIP1 NFKBIA NLRP11 ODF3B PDZRN4 PLEK POPDC3 PTGER4 PTPRK PVR PVT1 RAB38 RELN RFK RGS14 RPL5 RPS6KB1 SAE1 SGCD SH3GL2 SLC15A2 SLC25A36 SLC30A7 SOX8 SP140 STAT3 SUMF1 SYK TAGAP TCF7 TNFSF14 TNFRSF1A TRIM2 VAV2 WDR7 YWHAG ZBTB46 ZFP36L1 ZIC1 ZMIZ1 ZNF433 ZNF767 AGBL2
BCL10 C10orf55 CARD11 CCR4 CDH3 CENPO CLEC16A CTSH CXCR5 DDAH1 ELMO1 EPS15L1 FCRL1 FLJ16341 FOXP1 IKZF1 IKZF3 IQGAP1 JAZF1 LTBR MAF MAPK3 MIR548AN NDFIP1 NPEPPS PHGDH PLEKHG5 PRDX5 PXT1 RGS14 RMI2 SLAMF7 SLC2A4RG SLC44A2 SLC9A8 STAT4 TCF7 TET2 TRAF3 TREH WWOX

Pre GWAS and other: Mostly from MsGene developed by the Max Planck Institute for molecular genetics, Berlin; Johanes Gutenberg University, Mainz, and the Alzheimer Research forum See also The Genetic Association database at NIH ... Genotator at Harvard University and HUGE navigator
ACE ADAMTS14 AGAP2 AGER AGT ALK ANKRD55 APOC1 APOC2 APOE ARSA ATG10 ATP6 ATP7B ATXN2 B3GALT5 BCL2 BDNF BTG1 BTLA BTNL2 C10orf27 C19orf48 C4A C5 C6orf10 C7 CASP8 CASP9 CAV1 CCL1 CCL11 CCL13 CCL14 CCL15 CCL2 CCL3 CCL5 CCL7 CCR2 CCR5 CD14 CD1A CD1E CD207 CD226 CD24 CD28 CD4 CD46 CD48 CDC37 CEP192 CHUK CIITA CNR1 CNTF CNTNAP2 CRHR1 CRYAB CTLA4 CTSS CXCL10 CXCL12 CYP21A2 CYTB DCC DCDC2 DEXI DHCR7 DLG3 DMD DQB1*02 DQB1*03 DRB1*03 EBF1 EIF2AK2 ERAP1 ERBB3 ESR1 EVI5 FAM164A FAM20A FAM69A FAS FASLG FBXO39 FCGR2A FCGR3B FCRL3 FDX1L FOXP3 FXYD2 GABRA3 GAP43 GHSR GIPR GLO1 GPD1L GRN GSK3B GSTM1 GSTM3 GSTP1 GSTT1 GTF2H4 H6PD HEATR7B2 HFE HLA-C HLA-DQA1 HS3ST3B1 HSPA1L ICAM1 ICOS IFI30 IFIH1 IFIT1 IFNA17 IFNA2 IFNAR1 IFNAR2 IFNB IFNG IFNGR2 IGH@ IGSF23 IL10 IL12B IL1B IL1RN IL2 IL21 IL21R IL22RA2 IL23A IL23R IL2RB IL4 IL4R IL5RA IL6 IL7 IL8 INPP5A IRF1 IRF5 ITGAM JAG1 KANK1 KCNC2 KCNH7 KIF21B KIF5A KIR2DL1 KIR2DL2 KIR2DL3 KIR2DL5 KIR2DS1 KIR2DS2 KIR3DL1 KIR3DS1 KLC1 KLRB1 LAG3 LILRA3 LOC340094 LPCAT3 LRFN3 LRP5 LST1 LTA LY6G6D MBP MC1R MEFV MERTK MICB MIF MMEL1 MMP12 MMP2 MMP3 MMP9 MOG MPO MT-DLOOP MTHFR MT-L2 MT-ND1 MT-ND2 MT-ND3 MT-ND4 MT-ND5 MT-TT MX1 NCOR1 NDUFS5 NDUFS7 NFKBIA NFKBIL1 NGF NIPA1 NOD2 NOS2 NOS3 NOTCH4 NQO1 NR3C1 OAS1 OLIG3 OR2T2 OR4A47 OS9 P2RX7 PDCD1 PDE4B PLA2G7 PLAT PLCB4 PLCL1 PNMT PNPLA1 PON1 POU2AF1 PPARG PRF1 PRKCA PRM1 PRM2 PSMB8 PSMB9 PSORS1C1 PTAFR PTGS2 PTPN2 PTPRC RAC2 RALGAPA1 RETN RGMA RGS1 RMI2 RTN2 RYR3 SCGB1A1 SCIN SELE SELPLG SERPINE1 SH2B3 SHD2A SIPA1L3 SLC11A1 SLC25A27 SLC35C1 SLC4A5 SMARCD2 SOCS1 SP2 SPAST SPP1 ST7L ST8SIA1 STAB2 STAT1 STK31 SYN3 TAC1 TAP2 TEKT3 TGFB1 THSD7A TMEM39A TMEM98 TNF TNFRSF10A TNFRSF10B TNFSF10 TOMM40 TRB@ TRD@ TYK2 UCP2 VAV1 VDR WDR36 WDYHV1 ZC3HAV1 ZGPAT ZNF283 ZNF45 ZNF532 ZNRD1-AS1

Epistasis

• (CHRM3 / MYLK) (ACTN1/MYH9) (PLCB1/PLCB4) Motsinger et al, 2007
• HLA-DRB1, HLA-DQA1 and HLA-DQB1 Lincoln et al, 2009
• MicroRNA's implicated (in progress) Links are to miRBASE: MicroRNA's can have several thousand targets
• MIR155 MIR338 MIR491 Noorbakhsh et al, 2011
• MIR21, MIR146a, MIR146b Fenoglio et al, 2011
• MIR23A MIR223 Ridolfi et al, 2013

Need KEGG mapping GRIN2A OPN TBC1D2 HLA-G CX3CR1 SIRT4 HDAC11 .HDAC9 SLC40A1 . HAMP PLD4 DPP6 HMOX1 CBS RFC1 IL18 TRIM5 TRIM22 BST2 IL17F CXCL16 TLR9 (ND1 ND2 ND3 ND4 ND5 ND6) INPP4B EIF2B5 ASF1B VLA4 SLC9A9 CYTH4 NRG1 STK11 TNFAIP3 IL17A

Infectious agents NCBI free book Brogden KA, Guthmiller JM, editors. Polymicrobial Diseases. Washington (DC): ASM Press; 2002.Other NCBI free books Review The role of pathogens in multiple sclerosis Libbey et al, 2013

• Infection with the Epstein-Barr virus HHV-4 Ascherio and Munger, 2010
• The EBNA2 Epstein-Barr viral protein binds to genomic regions associated with multiple sclerosis , particularly overlapping with Vitamin D receptor (VDR) binding sites Ricigliano et al, 2015.
• Associated with the retrovirus HERV-W Dolei and Perron, 2009
  • The HERV-W retrovirus is activated by the Epstein-Barr virus Mameli et al, 2012
• Association with the HERV-Fc1 virus Nexø et al, 2011
• Association with Herpes simplex type II seropositivityHawkes et al, 2006
• Increased prevalence of JC polyomavirus in multiple sclerosis Gorelik et al, 2010 see also Sadik et al, 2010
• Influenza infection has been reported to precipitate onset Kazmierski et al, 2004
• Cytomegalovirus (HHV-5) seropositivity was associated with a better clinical outcome Zivadinov et al, 2006
  • and can reduce the risk of developing MS in paediatric cases , where herpes simplex can increase or decrease risk depending upon possession of the DRB1*15 allele (the odds ratio changes from 0.07 (DRB1 positive) to 4.11 (DRB1 negative) Waubant et al, 2011
• Relapses in MS patients have been associated with cytomegalovirus seropositivity: anti-EBV viral capsid antigen positivity was associated with progression on MRI measuresHorakova et al, 2013
• Chicken pox infection has been associated with a lower risk of childhood multiple sclerosis Mikaeloff et al, 2009
• Measles , chickenpox, rubella, whooping cough and mumps at age prior to the age of 7 has been associated with multiple sclerosis in adulthood Pekmezovic et al, 2004
• Mumps and measles antibody titres reported to be elevated in MS Berr et al, 1989 Measles antibodies increase over time in MS patients Ahlgren et al, 2012
• Elevated antibody reactivity to measles virus NCORE protein in multiple sclerosis patients and their healthy siblings with intrathecal oligoclonal immunoglobulin G production Persson et al, 2014.
• Rubella and vaccinia virus CSF antibodies have been reported at higher titre in MS affected twins Woyciechowska et al, 1985
• Herpes simplex (HSV-1) and Human herpesvirus 8 have been detected in urine or monocytes Pietropaolo et al, 2005
  • HSV-1 was associated with an increased risk of paediatric MS in those without a DRB1*15 allele , an effect reversed in those who were DRB1*15-positive Waubant et al, 2011.
• Higher HSV-2 seroprevalence has been reported Hawkes et al, 2006
• Bornavirus DNA has been detected at a higher frequency in peripheral blood mononuclear cells Wang et al, 2008 see also Zhang et al, 2013
• Increased frequency of Multiple sclerosis-related retrovirus (MSRV) Pol copy numbers in multiple sclerosis patients Zawada et al, 2003
• local production of antibodies against measles virus was found in the CNS in 57%, against rubella virus in 19%, mumps virus in 15%, herpes simplex virus type 1 in 11%, and parainfluenza virus type 1 (Sendai) in 3%. A local production in the CNS of antibodies against any of the viruses studied was found in 71% of multiple sclerosis patients. Norrby et al, 1974
• Association with HHV-6 infection Campadelli-Fiume at al, 1999 and Voumvourakis et al, 2010 Other Pubmed
• Antibodies to HIV-1, HIV-2 and HTLV-1 retroviruses have been reported in MS Perron et al, 1991
• Infectious mononucleosis is associated with increased Multiple Sclerosis susceptibility Ramagopalan et al, 2009
  • This association is reinforced by concurrent obesity Hedström et al, 2014
• In identical twins, a higher CSF titre of rubella antbodies were found in the afffected twins , in non-identical twins, higher titres of of Vaccina antibodies were found in the affected twins Woyciechowska et al, 1985
• In non-identical twins, measles, mumps, and Epstein-Barr virus-IgG antibody levels were more often elevated in the multiple sclerosis affected twin Kinnunen et al, 1990
• MS has been associated with Lyme disease( Borreliosis ) Chmielewska-Badora et al, 2000
• High bovine leukemia virus antibody titres have been observed in some patients Clausen et al, 1990
• Childhood measles, mumps, rubella and Varicella occurred later, while pertussis occured earlier in patients later developing multiple sclerosis Bachmann and Kesselring, 1998
• Varicella or Herpes zoster have been associated with the development of multiple sclerosis Perez-Casari et al, 2005
  • In a further study with 315,550 patients with herpes zoster (chicken pox or shingles virus) and 946,650 randomly selected controls the risk of devloping MS was 3.96 times greater than controls Kang et al, 2011.
• A correlation between the geographical distribution of Varicella and Multiple Sclerosis Ross and Cheang, 1995
• Antibodies to the BK polyoma virus have been detected at higher frequency in MS Ribeiro et al, 2010
• Antibodies to parvovirus B19 have been deteced at higher frequencsy in MS Nakashima et al, 1999
• Associated with tonsillitis under the age of 15 Gusev et al, 1999
• Previous measles infection has been associated with increased risk Martinez et al, 2001 . Bansil et al, 1997
• Polio has been associated with an increased risk of developing multiple sclerosis Nielsen et al, 2000
• Multiple sclerosis risk was inversely related to tuberculosis infection before the age of 7 Andersen et al. 1981
• Infectious mononucleosis increases the risk of multiple sclerosis Handel et al, 2010
• Brucellosis can cause multiple sclerosis-like symptoms Kyger and Hayden, 1948
• Streptococcal infections have been linked to multiple sclerosis Topkaya et al, 2007
• Mycobacterium avis avium subsp. paratuberculosis has been associated with multiple sclerosis Cossu et al, 2011
• Multiple sclerosis has been reported at high frequency in research workers studying swayback disease in sheep Dean et al, 1985
• Canine distemper virus antibodies have occasionally been associated with MS ( see dog ownership below) Cook et al, 1979
• Higher levels of antibodies to Acinetobacter and Pseuodomonas aeruginosa have been reported Hughes et al, 2001
• High titres of Chlamydophila pneumoniae CSF antibodies have been reported in oligoclonal bands Yao et al, 2001
• Increased serum antibodies to streptococcal antigens have been reported Topkaya et al, 2007
• Spinal fluid lymphocyte responses to mycobacterial extracts were reported to be increased in multiple sclerosis Birnbaum et al, 1993
• Serum antibody levels to staphylococcus antigens were lower in sera from patients with multiple sclerosis , while CSF titres were higher Aasjord et al, 1986
• The presence of antibodies to cytomegalovirus may have a protective effect Zivadinov et al, 2006
• Helicobacter pylori infection may have a protective effect Li et al, 2007
• Vaccinations for smallpox, tetanus and diphtheria were less common in multiple sclerosis Kurtzke et al, 1997
• Hepatitis B vaccination has been associated with MS risk Mikaelof et al, 2009 see also Le'Houzec, 2014
• Yellow fever vaccination has been associated with increased relapse rate Farez and Correale, 2011
• Hepatitis B antibodies have been reported at a lower frequency in MS patients Ram et al, 2008
• Tetanus vaccination may have a beneficial effect on risk Hernan et al, 2006
• Asthma Inverse association Tremlett et al, 2002
• Positive association with dental caries . Craelius, 1978
• Multiple sclerosis risk is reduced by higher infant contact Ponsonby et al, 2005
• Hepatitis B antibodies are less frequent in Multiple sclerosis, Sjogrens syndrome and Systemic lupus erythematosus Ram et al, 2008
• The Hygiene Hypothesis: Lack of exposure to infections in early life increases susceptibility to allergic and autoimmune diseases
• Viral mimicry: Antibodies to Human Coronavirus cross react with Myelin Boucher et al, 2007
• Human transaldolase epitopes cross-react with Epstein-Barr and Herpes Simplex (HSV-1) proteins Esposito et al, 1999
• Mimicry: Proteins from common gut bacterial flora are homologous to myelin basic protein (an autoantigen in Multiple Sclerosis) Westfall, 2006
• Cross-reactivity between MOG and a cytomegalovirus peptide Zheng and Zhang, 2014
• Demyelinating lesions have been reported with interferon alpha treatment and hepatitic C infection Höftberger et al, 2007
• Parasite ( Helminth )infection can reduce the number of exacerbations in multiple sclerosis Correale and Farez 2007
  • See Wikipedia Helminthic therapy and Pubmed
• Lack of association with the Torque Teno mini virus Komijani et al, 2011
  • Torque Teno virus replication is stimulated by the Epstein Barr virus Borkosky et al, 2012
• Digoxin, possibly synthesised from cholesterol by archaea in the microbiome may contribute to multiple sclerosis and other autoimmune disorders Kurup and Kurup, 2012
• Clostridium perfringens type B, and its epsilon toxin have been linked to multiple sclerosis: Clostridium perfringens type A presence lower in MS patients Rumah et al, 2013
• Antibodies to diverse fungal Candida strains observed in CSF samples of some MS patients Pisa et al, 2013
• Microbiome: Increased Archaea Species (Methanobrevibacteriaceae) in the Gut Microbiome of Multiple Sclerosis Subjects: Lower levesl of the Butyricimonas genus from the Bacteroidetes phylum Jhangi et al,2014
• predominance of Proteobacteria in progressive multiple sclerosis patients' white matter, associated with increased inflammatory gene expression. Bacterial peptidoglycan levels correlated with demyelination and neuroinflammation in MS brains Branton et al, 2016
• Lower levels of a bacterial lipopeptide, Lipid 654, from commensal bacteria in MS patients Farrokhi et al, 2013
• Antivirus immune activity in multiple sclerosis correlates with subsequent disease activity on MRI scans Latham et al, 2005
• EBNA2 (Epstein-Barr viral protein) binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy Ricigliano et al, 2015.
• Intrathecal production of antibodies against neurotropic viruses (measles , rubella and Varicella-Zoster) , the so called MRZ reaction (MRZR) can be used as a diagnostic biomarker in multiple sclerosis Huss et al, 2016.
• evidence for correlation of antiviral immune responses in the blood with subsequent disease activity on MRI scans Latham et al, 2016.

Relapse has been reported following infection with:-

• Coxsackievirus B VI and V Feng et al, 2008
• Epstein-Barr and HTLV-1 Ferrante et al, 1997
• Herpes simplex HSV-1 Ferrante at el, 2000
• Herpesvirus HHV-6 Alvarez-Lafuente et al, 2007
• Hepatitis A can worsen symptoms (Case report) Owen et al, 1980
• Varicella Zoster Sotelo et al, 2008 and 2014
• Multiple sclerosis-associated retrovirus Sotgiu et al, 2006
• Upper respiratory infections Panitch 1994
• Adenovirus antibodies Andersen et al, 1993
• Picornavirus infections Kriesel et al, 2004 (Picornaviruses incude the common cold and human and animal enteroviruses
• T cells isolated from a multiple sclerosis patient respond to Torque teno viral antigens (single case study) Sospedra et al, 2005
• Bacterial infection Rapp et al, 1995
• Staphylococcus Aureus Enterotoxin A has been associated with symptom exacerbation Mulvey et al, 2011
• Following childbirth Rinta et al, 2010
• Related to inhalable airborne particulate matter concentrations Oikonen et al, 2003 MS relapse rate relates to particulate matter exposure (PM10) Angelici et al, 2016 (nanoparticles activate the Epstein-Barr virus) Sattler et al, 2017
• An italian study showed that relapses are positively correlated with temperature and negatively with wind speed: Admissions during the summer were related to high temperature and low windspeed.Salvi et al, 2010

Demyelinating viruses and related diseases

• JC polyomavirus Progressive multifocal leukoencephalopathy (human)
• Malaria caused by Plasmodium falciparum and Plasmodium vivax (human) Mani et al, 2011
• Acute disseminated encephalomyelitis related to many viral or bacterial infections. Candidates include influenza , enterovirus, measles, mumps, rubella, varicella zoster, Epstein Barr virus, cytomegalovirus, herpes simplex virus, hepatitis A, and coxsackievirus; Bacteria include Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and beta-hemolytic Streptococci.
• Theiler's Murine Encephalomyelitis Virus (mice)
• Mouse hepatitis coronovirus Lane and Hoskings, 2010
• Murine hepatitis virus Pachner, 2011
• Visna-Maedi virus (sheep) Stowring et al, 1985
• Vaccinia virus (Rhesus monkeys) Simon et al, 1980
• A simian herpesvirus is associeated with a disease ressembling multiple sclerosis in Japanese Macaques Axthelm et al, 2011.
• Listeria (chickens) Kurazono et al, 2003 and Man (case report) Smiatacz et al, 2006
• Experimental autoimmune encephalomyelitis: (EAE) A laboratory model where antigen injection of myelin related proteins (spinal cord homogenate, purified myelin, MBP, PLP and MOG) can induce demyelination
• Lipids from Porphyromonas gingivalis and other common bacteria, particularly phosphoethanolamine dihydroceramide can worsen pathology in the EAE model Nichols et al, 2009
• The human commensal Bacteroides fragilis can protect against demyelination in EAE Ochoa-Repáraz et al, 2010
• Cortical demyelination is observed in schizophrenia Bartzokis and Altshuler, 2005 along with oligodendrocyte cell loss Uranova et al, 2001

Protective parasitic pathogens

• Schistosomiasis: Parasitic worms causing Bilharzia La Flamme et al, 2004

• Low ultraviolet exposure (sunlight) is associated with increased risk: UV is essential for Vitamin D synthesis Beretich and Beretich 2009 See alo Orton et al, 2011
• This relates to the correlation of MS with higher latitudes (away from the equator) feed
• Vitamin D may improve or even prevent Multiple Sclerosis Cantorna, 2008
• In the USA new lesions are higher in March-August than during the rest of the year, and correlate with regional climate data, in particular solar radiation Meier et al, 2010
• In Bosnia and Herzegovina MS was more prevalent in the municipalities with colder climate and more winter precipitation and less prevalent in the warmer coastal region without winter precipitation Klupka-Saric and Galic 2010.
• See Lucas et al, 2011 forcombined and separate effects of sunlight and vitamin D

• Inadequate intake of carbohydrates, dietary fibre, vitamin E, calcium and zinc coupled with higher intake of saturated fat, protein, vitamin A, vitamin C, folate and iron in womenTimmermann et al, 1999
• In a Croation study MS risk was associated with alcohol consumption, animal fats/dried meat products consumption, nitrate salting, strong spice, mixed bread , oat and oat products consumption Perkovic et al, 2010.
• Protective effecs of certain nutrients, including vegetable protein, dietary fibre, cereal fibre, vitamin C, thiamin, riboflavin, calcium, and potassium.Ghadirian et al, 1998
• Positive association with high energy (Kilocalories)and animal fat intake Ghadirian et al, 1998
• The consumption of unpasteurized high fat milk, animal fat, smoked meat and potatoes with lard can be nutritional risk factors Sepcic et al, 1993
• Association with cow milk consumption Malosse and Perron, 1993
• Multiple sclerosis distribution has beem associated with cow milk production per inhabitant, national bovine density per inhabitant, and local bovine geographic density Malosse and Perron 1993.
• The mediterranean diet can be beneficial Materljan et al, 2009
• Relative deficiency of selenium and sulfate, and abundance of barium, calcium, chloride, chromium, magnesium, manganese, molybdenum, nitrate plus nitrite, strontium and zinc in water associated with increased risk Irvine et al, 1989
• Early childhood and adolescent obesity are significant risk factors for multiple sclerosis susceptibility Gianfrancesco and Barcellos, 2016

Multiple sclerosis clusters

• A cluster of 30-40 cases in Galion, Ohio was possibly related to heavy metal contaminants (mainly cadmium and chromium) in river water and sewage Ingalls, 1989
• A cluster was observed in DePue, Illinois, possibly related to heavy metal soil contamination (Zinc) Schiffer et al, 2001
• A cluster focus was oberved in Henribourg, Saskatchewan, with no identified cause Hader et al, 1990

Autoantigens

• Arrestin and beta-arrestin (ARRB1 ARRB2)Ohguro et al, 1993
• AQP4 aquaporin ( Vision and motion improvenent was improved by antibody removal) Munemoto et al, 2011
• ATP2C1 Somers et al, 2008
• 2',3'-cyclic nucleotide 3' phosphodiesterase CNP Walsh and Murray. 1998
• Beta-amyloid APP Quintana et al, 2008
• bullous pemphigoid antigen BPAG1 Laffitte et al, 2005
• Claudin 11 CLDN11 Bronstein et al, 1999
• Contactin CNTN2 Derfuss et al, 2009
• CRYAB Van Noort et al, 1995
• DKFZp686A1481 Somers et al, 2008
• CD46 Pintér et al, 2000
• CD59 Pintér et al, 2000
• EBNA-1 (Epstein Barr virus antigen) cross-reacting with a lymphocyte protein p542 Vaughan et al, 1996
• Neurofilament light NEFL Ehling et al, 2004
• Neurone specific Enolase ENO2 Forooghian et al, 2007
• glyceraldehyde-3-phosphate dehydrogenase GAPDH Kolln et al, 2006
• heterogeneous nuclear ribonucleoprotein B1 HNRNPA2B1 Sueoka et al, 2004
• Heat shock proteins HSP27 (= SOD1 ) HSP32 (=HMOX1) HSP40 (=DNAJB1) HSP47 (= SERPINH1) HSP60 (=HSPD1) HSP70 (=HSPA4) HSP71(=HSPA8) HSP90 (=HSP90AA1) Quintana et al, 2008
• IFNB Interferon beta (in IFNB treated patients) Buck et al, 2011
• KIAA1279 Somers et al, 2008
• KCNJ10 potassium inwardly-rectifying channel, subfamily J, member 10 Kir4.1): Srivastava et al, 2012
• Myelin Wagjt 1981 myelin basic protein MBP Bernard et al, 1981
  • MBP cross-reactivity with HHV-6 herpesvirus Tejada-Simon et al, 2003
  • MBP / adenovirus shared epitope Andersen et al, 1993
• Myelin associated glycoprotein MAG Wagjt and Gorny 1983
• Myelin-associated oligodendrocyte basic protein MOBP Kauchansky et al, 2010
• Myelin oligodendrocye glycoprotein MOG Bernard et al, 1997
• Neurofascin NFASC Mathey et al, 2007
• oligodendrocyte specific protein OSP Aslam et al, 2010
• PACSIN2 Somers et al, 2008
• PGAM1 phosphoglycerate mutase Sakurai et al, 2011
• PLP1 proteolipid protein 1 Pelfrey et al, 1993
• PMP2 myelin protein 2 Quintana et al, 2008
• RBPJ – recombination signal binding protein for immunoglobulin kappa J region (only in CSF) Querol et al, 2013
• sperm associated antigen 16 SPAG16 Somers et al, 2008
• Transaldolase TALDO1Colombo et al, 1997
  • TALDO1 cross reactivity with Epstein-Barr and herpes simplex virus type 1 proteins Esposito et al, 1999
• Transketolase TKT Lovato et al, 2008
• Triosephosphate isomerase TPI1 Kolln et al, 2006
• Antibodies to the proteasome PSMA1 PSMA3 Mayo et al, 2002
• Antibodies to DNA have been reported Ershova et al, 2003
• Antibodies to phosholipids Chapman 2004
• Antibodies to retina proteins incl. retinal arrestin ARR3 Gorczyca et al, 2004
• Ganglioside GM4 ; Tetrasialoganglioside Lactosylceramide; lysophosphatidylserine ; 15-ketocholestene, 15-ketocholestane and 15a-hydroxycholestene Quintana et al, 2008

Drugs and treatments

• Oestrogens may have beneficial effects in women Niino et al, 2009
• Testosterone may have beneficial effects in men Gold et al, 2009
• Cannabis extracts have been reported to be beneficial in MS related spasticity Lakhan and Rowland 2009

• Associated with Type 1 Diabetes IMSGC, 2009 IMSGC
• Associated with ulcerative colitis and inflammatory bowel disease Pokorny et al, 2007
• Associated with a history of migraine or insomnia Martinez et al, 2001
• Inverse association with lung cancer Handel et al, 2010
• Often associated with depression Marrie et al, 2009
• and with psychotic disorders Kosmidis et al, 2010
• secondary urolithiasis (urinary stones) due to urinary tract infection Rached et al, 2011

• Pregnancy, particularly during the third trimester has a protective effect while relapse reoccurs after giving birth Moreau et al, 2010
• Exposure to organic solvents may be a risk factor Riise at al, 2002
• Smoking may increase the risk of multiple sclerosis Hedstrom et al, 2009 particularly in combination with the presence of antibodies to Epstein-Barr virus nuclear antigens Simon et al, 2010 or in relation to human leukocyte antigen genes (gene/environment interaction) Hedstrom et al, 2011
  • Smoking alone can also increase the risk of autoimmune diseases Marrie et al, 2011
• Multiple sclerosis has beeen associated with contact with small house pets Cook and Dowling 1977 and dog ownershipCook et al, 1978 . Bansil et al, 1997
• MS has been associated with oat cultivation Lauer, 1988
• and with higher rates on loam and clay subsoils Lauer and Firnhaber, 1984
• Gluten, gliadin and casein antibodies have occasionally been observed in multiple sclerosis Reichelt and Jensen, 2004
• Onset is age-dependent: rare prior to age 10, unusual prior to age 15, prevalent in the mid 20s: Associating with puberty Sandyk, 1993
• Multiple sclerosis is more common in Women Nicot, 2009
• Relatively low concordance in identical twins eg 24% : (Low genetic influence) Hansen et al, 2005
• An inverse association between risk of MS and birth order position Isager at al, 1980
• Associated with the number of pregnacies or children in women Martinez et al, 2001
• Multiple Sclerosis prevalence is reportedly lower in Bulgarian and Spanish Gypsies Milanov et al, 1999 Fernandez et al, 2008
• CSF cortisol levels are reduced Heidbrink et al, 2010
• MS and pneumonia, with an onset age of under 7 years have been associated, as has food allergy between ages 7 and 15 or the presence of industrial plants in the locality Goncharova and Baliazin, 2009
• Serum mercury levels have been linked to multiple sclerosis Attar et al,2012
  • ..."Patients with autoimmune thyroiditis and other autoimmune diseases, such as multiple sclerosis, psoriasis, systemic lupus erythematosus and atopic eczema, show increased lymphocyte reactivity in vitro to inorganic mercury, nickel and other metals compared to healthy controls" Hybenova et al, 2010
• High serum copper and low zinc levels have been observed Ghazavi et al, 2012
• Multiple sclerosis incidence associated with soil lead and arsenic concentrations Tsai and Lee, 2013
• abnormal iron deposition has been observed in and around multiple sclerosis plaques Habib et al, 2012
• decreased circulating levels of microRNAs miR-15b, miR-23a and miR-223 observed in MS patients Fenoglio et al, 2013
• Increased serum lactate in MS patients Amorini et al, 2014

The geographical distribution of Multiple sclerosis (from Wikipedia user Lokal_profil)