Further evidence of a genetic factor in the causation of MS is the finding that certain histocompatibility locus antigens (HLAs) are more frequent in patients with MS than in control subjects. The strongest association is with the DR locus on chromosome 6. Other HLA haplotypes that are overrepresented in MS (HLA-DR2 and, to a lesser extent, -DR3, -B7, and -A3) are thought to be markers for an MS “susceptibility gene”—possibly an immune response gene. The presence of one of these markers increases the risk that an individual will develop MS by a factor of 3 to 5. These antigens may indeed prove to be related to the frequency of the disease, but their presence is not invariable and their exact role is far from clear. A genome-wide association study identified several alleles, interleukin (IL)-2Rα, and IL7Rα in addition to the previously established HLA loci, as heritable risk factors for MS (International Multiple Sclerosis Genetics Consortium). These findings, although they apply to a small number of individuals, support the concept that dysregulation of the immune response is a factor in the risk for developing MS.
The low conjugal incidence of MS, on the other hand, indicates that any common exposure to an inciting infection or environmental agent must occur early in life. To test this hypothesis, Schapira and coworkers determined the periods of common exposure (common habitation periods) in members of families with 2 or more cases. From this they calculated the mean common exposure to have happened before 14 years of age, with a latency of about 21 years—figures that are in general agreement with those derived from the migration studies quoted above.
Several studies from northern Europe and Canada suggest that the likelihood of developing MS is somewhat greater among rural than among urban dwellers; studies of American army personnel indicate the opposite (Beebe et al). A number of surveys in Great Britain intimate that the disease is more frequent in the higher socioeconomic groups than in the lower ones. Yet in the United States, no clear relationship has been established to socioeconomic status. Numerous other environmental factors (surgical operations, trauma, anesthesia, exposure to household pets, cobalamin deficiency or resistance, mercury in silver amalgam fillings in teeth) have been proposed but are unsupported by firm evidence and probably are spurious associations.
These epidemiologic data point to both a genetic susceptibility and some environmental factor that is encountered in childhood and, after years of latency, evokes the disease. Over the years, data favoring an infection have had periods of support (see above). A body of indirect evidence has been marshaled in support of this idea, based largely on alterations in humoral and cell-mediated immunity to viral agents. To this day, however, no virus (including all known members of the human retrovirus family) has been consistently isolated from tissues of patients with MS. Moreover, no satisfactory viral model of MS has been produced experimentally. The bacterial agents Chlamydia pneumoniae and Borrelia burgdorferi (the agent of Lyme disease) and herpesvirus type 6 have been similarly implicated by the finding of their genomic material in MS plaques, but the evidence for their direct participation in the disease is, at the moment, not compelling.