THE GALE ENCYCLOPEDIA OF NEUROLOGICAL DISORDERS
LIMITING MODIFYING THE INFLAMMATION RELATED COMPONENT OF THE DISEASE SO THAT THE MAIN PART OF THE RESEARCH ACTIVITY AND TREATMENTS HAS BEEN FOCUSED ON THE RRMS FORM WHILE THE MS SYMPTOMS ARE MAINLY MANAGED BY MEANS OF NON SPECIFIC EPIDEMIOLOGY ENVIRONMENTAL AGENTS AND GENETICS MS IS THE MOST FREQUENTLY DIAGNOSED NEUROLOGICAL DISEASE LEADING TO NON TRAUMATIC DISABILITY AMONG YOUNG ADULTS AFFECTING MORE THAN 2 MILLION INDIVIDUALS WORLDWIDE 1 AS WITH MANY OTHER AUTOIMMUNE DISEASES THE PREVALENCE OF MS IS 2 3 TIMES AS HIGH IN WOMEN AS IN MEN AND THIS RATIO SEEMS TO HAVE INCREASED SLIGHTLY OVER TIME MAINLY IN THE POLAR LATITUDE COUNTRIES 2 THE INCIDENCE OF MS HAS INCREASED IN VARIOUS COUNTRIES DUE BOTH TO THE IMPROVEMENT IN DIAGNOSTIC TOOLS AND TO THE LENGTHENING OF PATIENTS LIVES TOGETHER WITH THE IMPROVEMENT IN HYGIENE CONDITIONS OVER THE LAST CENTURY MS CAN AFFECT INDIVIDUALS AT ANY AGE WITH THE FIRST CLINICAL SIGNS OCCURRING MOST FREQUENTLY BETWEEN 20 AND 40 YEARS OF AGE ALTHOUGH THE DISEASE CAN OCCUR EVEN IN INDIVIDUALS OVER 50 YEARS OF AGE PEDIATRIC MS HAS ALSO BEEN RECOGNIZED AND DIAGNOSTIC CRITERIA HAVE RECENTLY BEEN REDEFINED 4 5 THE PREVALENCE OF THE DISEASE HAS BEEN SHOWN TO INCREASE FROM THE EQUATOR TO THE POLE WITH IMPORTANT EXCEPTIONS SUCH AS THE SARDINIAN AND THE INUIT POPULATIONS IN THE MEDITERRANEAN AND CANADA RESPECTIVELY MOREOVER THE MIGRATION STUDIES WHICH HAVE SHOWN CHANGES IN THE RISK OF MS SUSCEPTIBILITY IN INDIVIDUALS MOVING TO DIFFERENT MS RISK AREAS BEFORE PUBESCENCE 6 AND THE FLUCTUATIONS IN THE RATES OF MS PATIENTS IN SOME AREAS SUCH AS THE NORTH ATLANTIC ISLANDS HAVE SUGGESTED A STRONG INTERACTION BETWEEN GENETICALLY BASED AND ENVIRONMENTAL FACTORS I E VIRUSES VITAMIN D DEFICIENCY AND OTHER FACTORS 1 THANKS TO THESE EPIDEMIOLOGICAL STUDIES A HYGIENE HYPOTHESIS HAS BEEN PUT FORWARD SUGGESTING THAT THE HIGHER INCIDENCE OF MS IN INDUSTRIALIZED COUNTRIES IS DUE TO CERTAIN INFECTIONS OR INAPPROPRIATE RESPONSES TO CERTAIN SUBSTANCES 8 THIS NOTION IS SUPPORTED BY ANALOGIES OF THE GEOGRAPHICAL DISTRIBUTION OF CERTAIN INFECTIONS 9 AND BY THE FACT THAT IN DEVELOPED COUNTRIES CERTAIN TYPICAL CHILDHOOD DISEASES SUCH AS MEASLES OR MONONUCLEOSIS ARE CONTRACTED AT LATER AGES AND ALSO BY A RECENT STUDY THAT NOTED AN AMELIORATION OF THE CLINICAL COURSE OF MS IN THE PRESENCE OF PARASITIC INFESTATIONS SOME SCIENTISTS HAVE ASSOCIATED MS WITH THE SEASONS AND CONSEQUENTLY WITH SEASONAL INFECTIONS SUCH AS ARBOVIRUS AND EPIDEMIC INFLUENZA OR WITH ZOONOSES SUCH AS VISNA FROM SHEEP AND THE CANINE DISTEMPER VIRUS FROM DOGS MS AND INFECTIOUS AGENTS PARTICULARLY VIRUSES AND MORE RECENTLY THE HUMAN MICROBIOME HAVE BEEN WIDELY STUDIED IN ORDER TO INVESTIGATE THE MANNER IN WHICH THEY INTERACT WITH EACH OTHER AND WITH THE HUMAN GENOME TO INFLUENCE THE RISK OF MS HOWEVER UNTIL NOW THERE HAS BEEN AN ABSENCE OF CONCLUSIVE DATA FURTHERMORE THE DIFFERENT PATHOLOGICAL LESIONS DESCRIBED AND CLASSIFIED IN MS PROBABLY DERIVE FROM MULTIPLE MECHANISMS OF PATHOGENESIS AND THIS ACCOUNTS FOR THE FACT THAT THERE COULD BE MULTIPLE CAUSES AND MECHANISMS INVOLVED IN ITS IN PARTICULAR VIRUSES HAVE BEEN WIDELY DETECTED IN MS PATIENTS DUE TO THEIR ABILITY TO INDUCE DEMYELINATION AND AXONAL LOSS THROUGH MANY DIFFERENT MECHANISMS DIRECTLY AND INDIRECTLY RECENT REPORTS HAVE FOCUSED ON HERPESVIRUSES I E HHV6 13 AND CHLAMYDIA PNEUOMONIAE 14 ALL UBIQUITOUS AND ESSENTIALLY ASYMPTOMATIC INFECTIONS OCCURRING ESPECIALLY IN CHILDHOOD WHILE EPSTEIN BARR VIRUS EBV ANTIGENS SUCH AS EBNA 1 AND VCA ARE MORE FREQUENTLY PRESENT IN MS PATIENTS 15 IN FACT THE PRESENCE OF EBV LATENCY ASSOCIATED GENES HAS BEEN DEMONSTRATED IN INFLAMED TISSUE AND LESIONS OF MS BRAINS 16 ALTHOUGH EBV DETECTION IN CSF CEREBROSPINAL FLUID AND CSF ASSOCIATED CELLS HAS SHOWN NO VARIATION IN RESULTS BETWEEN MS AND OTHER NEUROLOGICALLY AFFECTED PATIENTS 17 THE DISCOVERY OF HUMAN ENDOGENOUS RETROVIRUSES HERVS HAS RAISED OTHER QUESTIONS REGARDING THEIR RELATIONSHIP WITH AUTOIMMUNE DISEASES IN PARTICULAR MSRV MS ASSOCIATED RETROVIRAL VIRUS HAS BEEN CORRELATED WITH PROGRESSION OF THE DISEASE 18 AT THE MOMENT THERE IS NO DEFINITIVE VIRUS IDENTIFIED THAT TRIGGERS MS THE LANDMARK DISCOVERY OF A GROUP OF SURFACE MOLECULES HAS INCREASED UNDERSTANDING REGARDING THE WAY IN WHICH THE HOST RAPIDLY RESPONDS TO INVADING PATHOGENS THIS GROUP INCLUDES NAMED PATTERN RECOGNITION RECEPTORS PRRS SUCH AS CD14 2 INTEGRINS CR1 CD35 CR2 CD21 ALL RECEPTORS OF CONSERVED STRUCTURES OF BACTERIA AND ALSO INCLUDES TOLL LIKE RECEPTORS TLRS 19 PROOF THAT INFECTIONS MIGHT PLAY A ROLE IN TRIGGERING MS COMES FROM A RECENT POST INFECTIOUS MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS EAE NOT ONLY PATHOGENIC BUT ALSO COMMENSAL BACTERIA MAY BE INVOLVED IN THE INDUCTION AND MODULATION OF CNS AUTOIMMUNITY THE GUT MICROBIOTA FOR EXAMPLE INFLUENCE T HELPER CELLS TH POLARIZATION AND THE DEVELOPMENT OF EAE 21 BY DIRECT ACTIVATION OF T CELLS INFLUENCING THE LOCAL SYSTEM OF THE ANTIGEN PRESENTING CELLS APC AND RELEASING IMMUNOACTIVE METABOLITES THEREBY CONTRIBUTING TO THE GENERATION OF A PROINFLAMMATORY CONTEXT AND THE BREAKDOWN OF TOLERANCE ACCORDINGLY AUTOIMMUNE CELLS SEEM TO BE PRIMED IN THE PERIPHERAL TISSUES BEFORE INVADING THE CNS 22 THE ENCOUNTER OF PATHOGENIC AND NON PATHOGENIC MICROBES PROFOUNDLY MODIFIES THE IMMUNE SYSTEM WITH EFFECTS THAT CAN RANGE FROM PROTECTION TO THE INDUCTION OF AUTOIMMUNITY 23 BOTH TYPES OF MICROBIAL AGENTS AND THE INDIVIDUAL GENETIC BACKGROUND MODULATE THE BALANCE BETWEEN THESE POSSIBLE OUTCOMES INFECTIOUS AGENTS MAY PROMOTE AUTOIMMUNITY OF THE CNS THROUGH DISTINCT MECHANISMS ON THE ONE HAND THEY MAY DIRECTLY INFECT THE CNS AND EITHER ALTER THE BLOOD BRAIN BARRIER BBB OR INDUCE THE RELEASE OF SEQUESTERED AUTOANTIGENS ON THE OTHER HAND THEY MAY PRIME SELF REACTIVE T CELLS IN THE PERIPHERY BY ANTIGENIC CROSS REACTIVITY MOLECULAR MIMICRY AND THESE MAY MIGRATE INTO THE CNS AND CONTRIBUTE TO ITS DAMAGE FINALLY THE OCCURRENCE AND OR SEVERITY OF MS MAY BE THE RESULT OF AN ENCOUNTER WITH SEVERAL INFECTIOUS AGENTS EACH CONTRIBUTING IN DIFFERENT WAYS TO THE FULL BLOWN DISEASE THE ACTIVE FORM OF VITAMIN D THE 1 25 DIHYDROXYVITAMIN D3 PLAYS A CENTRAL ROLE IN THE MODULATION OF THE IMMUNE RESPONSE 24 AND ITS RECEPTOR VITAMIN D RECEPTOR VDR LEVELS AND KINETICS ARE CRUCIAL FOR T CELL PROLIFERATION 25 A GROWING BODY OF EVIDENCE HAS CONNECTED VITAMIN D AND AUTOIMMUNE DISEASES WITH REGARD TO THE GEOGRAPHICAL DISTRIBUTION OF MS THE SUNLIGHT EXPOSURE NECESSARY FOR THE PRODUCTION OF THE ACTIVE FORM OF VITAMIN D HAS BEEN CORRELATED WITH MS SUSCEPTIBILITY 26 RECENT STUDIES HAVE INVESTIGATED THE VDR GENE POLYMORPHISMS AND THEIR RELATIONSHIP WITH MS 27 ILLUSTRATING WHY DIFFERENT PATIENTS RESPOND DIFFERENTLY TO VITAMIN D ADMINISTRATION ALTHOUGH MS CANNOT BE STRICTLY INCLUDED IN THE CATEGORY OF MENDELIAN GENETIC HEREDITARY DISEASES BOTH THE INCREASED MS RISK IN MONOZYGOTIC TWINS AND ITS PREVALENCE IN DIZYGOTIC TWINS 14 25 AND 2 5 RESPECTIVELY 29 TAKEN TOGETHER WITH THE FAMILY CLUSTERING OF THE DISEASE AND THE GEOMETRICAL FALL OF MS OCCURRENCE BEYOND FIRST DEGREE RELATIVES SUGGEST THAT MS IS A POLYGENETIC DISEASE WHILE THE HUMAN LEUKOCYTE ANTIGEN HLA DRB1 1501 GENE AND HAPLOTYPE ASSOCIATION TO MS HAVE BEEN CLEARLY RECOGNIZED SEVERAL OTHER GENES AND GENETIC TRAITS HAVE BEEN ASSOCIATED WITH A SUSCEPTIBILITY FACTOR FOR MS AS WELL AS AFFECTING THE COURSE OF THE DISEASE 30 BESIDES THE MERE ASSOCIATION BETWEEN MS AND GENETIC TRAITS THE ROLE OF THE EPIGENOME IN MS IS GRADUALLY GAINING GROUND BASED ON EPIDEMIOLOGICAL STUDIES AND INCREASED KNOWLEDGE OF THE MECHANISMS RESPONSIBLE FOR GENE EXPRESSION CONTROL EXERTED BY SEVERAL ENVIRONMENTAL FACTORS I E UV LIGHT EXPOSURE AND VITAMIN D SYNTHESIS WHILE THE ETIOLOGY OF THE DISEASE HAS NOT YET BEEN CLARIFIED ON THE CLINICAL SIDE SEVERAL ATTEMPTS HAVE BEEN MADE TO DEFINE CLEAR CRITERIA BOTH TO DIAGNOSE MS AND TO ASSOCIATE DIFFERENT CLINICAL MANIFESTATIONS WITH PARTICULAR FORMS OF MS UNDER NORMAL CONDITIONS THE IMMUNE SYSTEM HAS THE TASK OF DEFENDING THE BODY FROM EXTERNAL AGENTS MAINLY VIRUSES AND BACTERIA AND EXERTS THIS CONTROL THROUGH LYMPHOCYTES MACROPHAGES AND OTHER CELLS THAT CIRCULATE IN THE BLOOD AND THAT IN CASE OF NECESSITY ATTACK AND DESTROY THE FOREIGN MICROORGANISMS BOTH DIRECTLY AND THROUGH THE RELEASE OF ANTIBODIES AND OTHER CHEMICALS IN MS THE IMMUNE SYSTEM ATTACKS PARTS OF THE CNS MISTAKING THEM FOR EXTRANEOUS AGENTS THIS MECHANISM OF DAMAGE IS DEFINED AS AUTOIMMUNE OR MORE GENERALLY DYSIMMUNE ONE OF THE MAIN TARGETS OF AN IMPAIRED IMMUNE RESPONSE TO MYELIN IS THE MYELIN BASIC PROTEIN MBP WHICH IS ONE OF THE CONSTITUENTS OF MYELIN ITSELF THE CELLS OF THE IMMUNE SYSTEM OVERCOME THE BBB AND PENETRATE THE CNS CAUSING INFLAMMATION AND LOSS OF MYELIN THE CAUSES OF THIS ALTERATION IN THE FUNCTIONING OF THE IMMUNE SYSTEM ARE MANY AND ARE THE SUBJECT OF COUNTLESS