Page 926 - Clinical Immunology_ Principles and Practice ( PDFDrive )

894 Part Seven Organ-Specific Inflammatory Disease

observed in Europe, Australasia, and Japan. Population migration Although infectious agents, such as EBV, have been implicated
studies indicate that the geographical risk of MS is established in MS pathogenesis, other pathogens may have a therapeutic
prior to adolescence. Prepubescent children who migrate assume effect. It has been suggested that in addition to high levels of
the risk of their adopted country, whereas adults carry forward sunlight exposure, endemic helminth infection is one of the
the risk of the location where they spent their childhood. An factors responsible for the low prevalence of MS in tropical
environmental agent that is encountered in childhood and acts as regions. Infection with helminths, including Heligmosomoides
predisposing factor for the development of MS later in life must polygyrus, Fasciola hepatica, Schistosoma mansoni, and Trichinella,
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be responsible, but this agent has yet to be definitely identified. has been shown to be protective in animal models of MS.
Several small prospective studies showed that patients with MS
Vitamin D naturally infected with different species of parasitic worms had
The discovery of the protective role of vitamin D in MS may a milder disease course and lower MRI inflammatory activity
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explain, in part, its geographical distribution. Ultraviolet light compared with uninfected patients. Antiparasite treatment
catalyzes the conversion of vitamin D to its bioactive form, and the was associated with exacerbation of MS. Mechanistic substud-
prevalence of MS is highest in regions with relatively low annual ies have suggested that parasites modulate MS disease activity
sunlight exposure. In a large prospective study, the risk of MS by boosting the frequency of IL-10 and transforming growth
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decreased with increasing serum levels of 25-hydroxyvitamin D. factor-beta (TGF-β)–producing regulatory T and/or B cells. A
Therefore interventions that raise the level of 25-hydroxyvitamin phase I safety study of orally administered Trichuris suis ova
D levels might have a prophylactic protective effect on healthy (TSO) has been conducted in RRMS, and a number of clinical
individuals who are predisposed to develop MS, such as the trials of TSO or dermally administrated hookworm Necator
first-degree relatives of patients with MS. Indeed, numerous americanus as disease-modifying therapy in MS are planned or
independent prospective studies have found an inverse relationship underway.
between dietary or supplemental vitamin D intake in adults and
future risk of MS. Furthermore, there is accumulating evidence Obesity
that low serum 25-hydroxyvitamin D levels and low dietary Observational studies have found that individuals who are obese
vitamin D intake during pregnancy increase the risk of MS in in early adulthood, as measured by elevated body mass index
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the offspring. Whether vitamin D levels influence the clinical (BMI), have an approximately twofold increased risk of MS.
course of individuals with established MS is more controversial. Obesity in girls is associated with an increased risk of pediatric
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A randomized controlled trial of vitamin D supplementation in MS or clinically isolated syndrome. Furthermore, higher weight
patients with MS is currently underway in 16 academic centers in adolescence and young adulthood is associated with an earlier
(ClinicalTrials.gov identifier: NCT01490502). The results of that age at onset of MS. A mendelian randomization analysis of large
trial should bring clarity to the issue. GWAS for MS and BMI, respectively, found that one standard
deviation (SD) increase in genetically determined BMI conferred
Infection a 41% increase in the odds of MS. A number of theories have
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In addition to low levels of vitamin D, another prognostic factor been proposed for a mechanistic link between obesity and MS
for development of MS is primary infection with Epstein-Barr risk. First, obesity is known to cause a systemic proinflamma-
virus (EBV) in adulthood, as indicated by the emergence of tory state, possibly mediated by an adipose-derived hormone
EBV-specific IgM antibodies in serum. Analysis of serial serum that could create a milieu conducive to the differentiation
samples stored in the US Department of Defense Serum Reposi- and/or activation of autoimmune effector cells. Alternatively,
tory revealed that MS risk was extremely low among individuals there is some evidence that genetically elevated BMI decreases
not infected with EBV but increased sharply in the same individu- 25-hydroxyvitamin D levels.
als following seroconversion to positivity for antibodies against
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EBV. The odds of MS were recently estimated to be >10 times Modifiable Habits
higher among EBV-positive persons than among EBV-negative A substantial body of literature indicates that cigarette smoking
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persons. One way in which EBV infection could promote MS increases the risk of MS. A recent meta-analysis revealed a dose–
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pathogenesis is via “molecular mimicry,” which occurs when a response relationship between cigarette pack-years and MS risk.
microbial epitope shares sequence similarities with a self peptide, On the basis of data collected from the Swedish National MS
in this case a myelin peptide (Chapter 50). T-cell receptors Registry, it was estimated that each additional year of smoking
(TCRs) that cross-react with structurally homologous EBV and after diagnosis accelerates the time to conversion to SPMS by
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myelin antigens have been discovered in the peripheral CD4 4.7%. There is growing evidence that exposure to passive
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TCR repertoire of individuals with MS. Peripheral CD4 T cells smoking is also a risk factor for MS. Acrolein, a component of
that express such cross-reactive TCRs could be activated during cigarette smoke, was found to exacerbate the clinical course of
EBV infection, enabling them to cross the blood–brain barrier an animal model of MS, in association with enhanced microglial
(BBB), encounter their cognate myelin antigen within CNS white activation. 28
matter, and initiate MS lesion formation. An alternative theory Another behavior that has come under scrutiny in relationship
involves infiltration of the CNS by EBV-infected B cells. B cells to MS is dietary sodium intake. In one study, exacerbation rates
expressing EBV small RNA and proteins have been detected in were found to be 2.75–3.95-fold higher in patients with RRMS
meningeal follicle–like structures and inflamed cortical lesions with medium or high sodium intakes, respectively, compared
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in SPMS brain tissue. EBV-driven expansion and activation of with the low-intake group. In contrast, high salt intake was
meningeal B cells could potentially contribute to the formation not associated with decreased time to relapse in pediatric-onset
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of the follicle-like structures, which have been associated with MS. High-salt conditions promote the induction of highly
large subpial cortical lesions and a more aggressive clinical pathogenic myelin-reactive T cells in vitro and in animal models
course. 6 in vivo. 31