Intercurrent Factors With Possible Association

Although the prevailing wisdom is that MS is an immune-mediated condition (102), it fulfills few of the criteria of an autoimmune disease (103). Rose and Bona (104) stated that''... with new knowledge gained from molecular biology and hybridoma technology, as well as the original Witebsky postulates, ... [evidence that] a human disease is autoimmune in origin includes direct evidence from transfer of pathogenic antibody or pathogenic T-cells; indirect evidence based on reproduction of the autoimmune disease in experimental animals; and circumstantial evidence from clinical clues.'' But MS certainly cannot fulfill Koch's postulates (direct evidence) due to the ethical problems of the necessary experiment, and satisfies their criteria only by the indirect evidence of experimental autoimmune encephalomyelitis (EAE). The problem with this is that there are important pathological as well as clinical differences between EAE and MS, as remarked by Chaudhuri and Behan (103), who have

rrrrr

Time Line of Life

Conception

Environmental Factors

Figure 4 Some environmental factors suggested as contributing to disease initiation occurring within a period of susceptibility. Multiple environmental triggers may be necessary within an unknown endogenous context.

argued persuasively that because the pathologies differ the presence of sensitized T-cells is nonspecific and there are no disease-specific immune markers for MS; this is in fact a metabolic neurodegenerative disorder in which infectious agents(s) could be involved either in direct damage to the white matter or in inducing inflammatory responses that secondarily affect the brain (105).

The evidence that MS is an autoimmune disease is indirect and based upon animal models (104). Different mechanisms suggested for disease initiation include epitope spreading, thymic dysregulation, and molecular mimicry, the latter based upon the hypothesis that microbial pathogens resemble human proteins and that exposure to these similar microbial epitopes may trigger an "auto" immune response against the host. This may be due to a direct homology between epitopes, bystander activation of host sensitive immune cells, or molecular mimicry. Therefore, infectious agents or other antigen-carrying vectors (diet, toxins, etc.) may be responsible for the activation of the autoimmune cascade. On the other hand, there are significant data that suggest that infectious agents(s) could be involved in direct damage to the white matter (105).

Many factors, whether geographical or event-based, suggest that environment plays a role in triggering MS and we will review new evidence on various environmental influences in initiating the disease (Fig. 4).

Prior ecologic correlations suggesting that a higher intake of saturated fats and a lower intake of polyunsaturated fats might increase the risk of MS have been contradicted by the results of Zhang (106) who found no relationship between intakes of total fat or major specific types of fat and the risk of MS.

Sievers (107) examined all the reports that vaccinations caused or exacerbated MS, and determined that such studies indicate that vaccinations neither increase the risk of symptom exacerbation in patients with MS nor constitute a causative agent of the disease. The risk from aniline dyes or other substances used in the leather industry was found to be increased (108), but the role of organic solvents remains undetermined (109).

Ultraviolet Radiation and Vitamin D

The geographical variation in prevalence rates has prompted speculation that climate may play a role in disease initiation and susceptibility, so ultraviolet radiation (UVR)

Diet

Toxins has been studied closely, especially since it may have an immune-suppressive effect. An inverse association between MS prevalence and UVR has been reported from Australia (110). MS prevalence data for six Australian regions were compared with UVR levels of the largest city in each region. A close association was found between the theoretical MS prevalence predicted from UVR levels, and the actual prevalence and mortality from MS was negatively associated with both residential and occupational exposure to sunlight. Regional variation in MS prevalence, predicted by regional UVR levels, is consistent with the hypothesis that UVR exposure may reduce the risk of MS, possibly via T-lymphocyte-mediated immunosuppression (111,112).

Ponsonby (113) reviewed the epidemiological evidence that UVR plays a protective role in MS and other autoimmune diseases, noting that a gradient of increasing prevalence with increasing latitude has been observed for both MS and Type 1 diabetes mellitus in Europe and North America, with seasonal influences on disease incidence and clinical course. The authors considered that there may be a beneficial immunomodulatory role for UVR, but the data were inconclusive, although ultraviolet B can specifically attenuate these processes in part through an UVR-induced increase in serum vitamin D levels (113,114). The potential protective effect of vitamin D on the risk of MS was further examined in both of the U.S. Nurses' Health Studies (NHS). The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 and the intake of vitamin D from supplements was also inversely associated with risk of MS. The relative risk comparing women with an intake of 400IU/day or more with women with no supplemental vitamin D intake was 0.59 (115). The relevance of vitamin D receptor gene (VDRG) polymorphism in the pathogenesis of MS was investigated in 77 conventional MS patients and 95 healthy controls (116). The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P = 0.007 and P = 0.0321, respectively), suggesting that VDRG polymorphism may be associated with susceptibility to MS. These data are excitingly suggestive; however, the precise method whereby vitamin D exerts such a protective effect remains undetermined.

Stress

Although some patients with MS report that stress can trigger disease exacerbations, a study of coping behaviors in 36 patients (mean age 44.4 years) with relapsing forms of MS indicated that coping strategies (including distraction, instrumental, palliative or emotional preoccupation) moderate somewhat only the relationship between stress and MS disease activity (117). Using logistic regression, Ackerman (118) showed that exacerbations are more likely during at-risk periods following major life events but are relatively independent of the threat level and type of stressor. Disability levels, medication usage, cardiovascular reactivity, baseline heart rate, and life event density explained 30% of the variance in the proportion of weeks "ill."

While anecdotal reports and small (usually retrospective clinical or MRI) studies have shown that physical neuro-trauma and psychological or other stresses may precede the onset of MS or may influence its course, no clear causative relationship (at least between physical trauma and MS) has yet been proven. Nevertheless, the nervous and immune system interactions both through the hypothalamic-pituitary-adrenal axis and by autonomic pathways are putative mechanisms underlying any correlation that may eventually be proved (119-122).

Seasonal Variation

Seasonal variation in MS exacerbations have been noted (123); in Japan, attacks are most common in the warmest and coldest months of the year. The heat of summer in warmer, low latitude areas may be a risk factor for MS attacks. Seasonally changing concentrations of air pollutants predispose individuals to transmissible infections, induce systemic immune responses, and enhance existing peripheral inflammation, so may enhance the seasonal changes in MS relapse rates by increasing susceptibility to transmissible triggers (124).

Antecedent Infections

There is good evidence that one or more infectious agents may be responsible for the induction of MS (105) as suggested by the different geographic gradients in frequency among Europoids, changes in prevalence due to migration and the effect of age at migration, the suggestion of epidemics and clusters of cases in some small communities, and anecdotal reports. The infectious hypothesis is also supported by the different temporal patterns of the disease in different geographic areas and by the fact that the presence of oligoclonal bands in the cerebrospinal fluid (CSF) may indicate the presence of an infecting agent (125), though how such an external agent triggers induction or worsening of MS is unknown. As Gilden (125) suggests, infection may induce host immune-responsiveness in a damaging way. The response of the host or the infective event itself could lead to the production of an agent that induces relapse. Supporting this is the fact that stress has been shown to be capable of reactivating viruses latent in the central nervous system (CNS) or in mononuclear cells (125).

From another angle, the original observations of Leibowitz et al. (126) suggesting that the risk of MS is increased in subjects who spent their early years in households characterized by a high level of sanitation have been superbly re-examined by Bach (127), who concluded that some childhood infections actually seem to protect against immune-mediated diseases such as asthma, Crohn disease, and type 1 diabetes as well as MS, through bystander suppression, antigenic competition, or another (still undefined) mechanism.

There is, however, no evidence that any single agent is responsible either for induction or protection, and analytical studies testing the association between MS and various previous infections have not allowed definitive conclusions to be drawn (128). The following sections summarize some recent studies on the relation between antecedent infections and the induction of MS.

Paramyxoviruses

In previous editions of this book, the possible roles of paramyxoviruses such as measles and canine distemper virus were reviewed. A suggestive association was detected by inference, but proof of causality was considered lacking. One recent observation showed that MS patients experienced several childhood infectious diseases (varicella, rubella, mumps) at higher ages than did normal controls (129), but no further data have appeared on this subject and interpretation is impossible.

Influenza Virus

In a Polish study, Kazmierski (130) found a positive correlation between the incidences of influenza and of MS, both in the same year and five years later, but not between the incidence of MS and other environmental factors, and suggested that influenza infection could precipitate MS onset.

Epstein-Barr Virus

Wagner (131) found a significant (100%) Epstein-Barr virus (EBV)-seropositivity and a significant lack of primary EBV infections among 107 patients with MS in comparison with age- and gender-matched healthy controls in north Germany, indicating that all of these MS patients had been infected with EBV before the development of MS. Although there were no differences in reactivities of EBV-specific anti-early antigen immunoglobulin G (-IgG), -IgM, and -IgA antibodies between each group, MS patients had significant lower anti-Epstein-Barr nuclear antigen 1-IgG antibody titers. This is a possible serological sign of defective control of the typically persistent latent EBV carrier state. Numerous other case-control and similar studies [systematically reviewed by Marrie (67)] are in disagreement about any relationship.

Chlamydia pneumoniae

Munger (132) examined the association between Chlamydia pneumoniae (Cpn) infection and MS in the two U.S. NHS. Among 32,826 women in the NHS and 29,722 women in the NHS II, 141 incident cases of definite or probable MS were documented. Cpn immunoglobulin G seropositivity was positively associated with risk of MS. This association did not change after adjusting for age at blood collection, ancestry, latitude of residence at birth, and smoking. Seropositivity for Cpn was moderately associated with risk of relapsing-remitting MS and strongly associated with the risk of progressive MS. These results support a positive association between Cpn infection and progressive MS. However, in a follow-up prospective study (133), the authors reported that neither seropositivity nor serum antibody levels suggested any association between Chlamydia infection and MS. In another study, Cpn-specific IgG titers were significantly higher in the CSF of MS than in controls, but these elevated titers did not significantly correlate with disease duration, disease course, clinical or MRI disease activity, and disability or presence of oligoclonal IgG (134). Overall, the association between MS and Cpn infection is judged to be weak (109).

Herpesvirus 6 and 7

The role of HHV-6 in MS is controversial and more extensive understanding of its neurotropism and association with disease is required (135). HHV-6 virus has been detected in MS plaques in the brain, and patients with MS have been shown to have an aberrant immune response to HHV-6 (136,137). A systematic review of 28 studies using 12 different experimental techniques (138) showed that four of these techniques did provide evidence for an association between HHV-6 and MS, but none showed a causal relationship. Tomsone (139) reported that the prevalence of HHV-6 was significantly higher in patients with MS than in those with nondemyelinating diseases of the CNS, with demyelinating diseases of the peripheral nervous systems, or in blood donors. HHV-6 viremia was found only in patients with MS, especially in the active phase of the disease. However, active HHV-6 infection could not be demonstrated in patients suffering from active clinically definite MS in Kuwait (140). Given the clinical implications of the presence of antibodies against HHV-6 in MS patients, viral reactivation cannot be excluded as an environmental factor (141).

Two forms of HHV-6 exist; the B variant accounts for human disease but the A variant has not hitherto been regarded as pathogenetic. HHV is neurotropic, acquired almost universally early in life, can be reactivated by infections or other physiological stresses, according to some reports induces IgM antibody responses in MS subjects when compared with controls, and is detectable within CNS cells in MS patients but not controls (though not all of these claims have been replicated). However, there is recent evidence that in patients with active relapsing-remitting MS (RRMS) there is a heavy viral load of HHV-6A (only) (142), raising the possibility that this is indeed an external pathogen of real relevance in MS precipitation. Only further studies that confirm these results will decide the issue.

A significantly higher frequency of HHV-7 reactivation in patients with peripheral nervous system demyelinating diseases has also suggested its association with demyelinating processes (140).

Herpesvirus 1

There is some evidence that HSV-1 may be implicated in the etiopathogenesis of MS. In one study (143), HSV-1 mRNA and DNA were found in a significant number of acute MS patients but not in the control group. The data are insufficient to allow further comment.

Varicella Zoster Virus

Although a recent survey showed that varicella zoster virus (VZV) infection occurred at an earlier age in an MS cohort than in controls (144), another review of the epidemiological evidence for the etiological role of VZV concluded that the five studies with the best methodology failed to show an increased risk of MS associated with varicella or zoster infections and that there was insufficient evidence for a role of VZV in the development of MS (145).

Hepatitis B Vaccination

Touze et al. (146) investigated the relationship between hepatitis B (HB) vaccination and a first CNS demyelinating event in adults and showed that adjusted odds ratios for the first CNS demyelinating event within two months following an injection of HB vaccine were 1.8 (CI, 0.7-4.6) in the whole group. In cases with clinically definite multiple sclerosis (CDMS) or clinically probable multiple sclerosis (CPMS) only, the odds ratios were 2.0 (0.8-5.4) and 1.6 (0.4-5.6), respectively, thus ruling out any strong association between HB vaccine exposure and a subsequent demyelinating event.

Sadovnick (147) investigated MS in adolescents in British Columbia before and after an HB vaccination program was begun, finding no evidence of a link between HB vaccination and MS or other demyelinating disease. Monteyne (148) agreed that no scientific data supported a causal link between vaccination and MS and that the most plausible explanation for any observed temporal association between vaccination and MS is coincidence.

Such a conclusion is in line with that of numerous other studies, but using data from a British general practice database, Hernan et al. (149) detected a more than three-fold increase in MS incidence after three years following immunization. As pointed out by Naismith and Cross (150), the significance of this finding is made problematic by the fact that over 90% of the MS subjects in the database had never received the vaccine; by the possible selection of subjects for vaccination in the first place; by the winnowing process that led to only 11 of 713 original MS subjects being used to come to this conclusion; and by the absence of reports of MS following actual HB infection. The question has thus been re-opened, but the balance of evidence seems to be against any causal association.

Other

Exacerbations of MS in the context of a systemic infection lead to a more sustained damage than occur with other triggers, but there is no indication that it is due to enhanced opening of the blood-brain barrier (151).

MS-associated retrovirus (MSRV) is a component of the human endogenous retrovirus (HERV)-W family, with gliotoxic and superantigenic properties. In one study, MSRV was detected rarely in healthy blood donors, in most patients with inflammatory neurologic diseases, and in all MS patients. This agent may be a marker for inflammatory neurologic disease (152).

Respiratory tract infections may precipitate disease onset (151,153,154) and exacerbations of MS have been shown to be associated with significantly higher plasma levels of intracellular adhesion molecule 1, an inflammatory marker (151). Seven of nine upper respiratory tract infections URIs, due to picornaviruses, were associated with a subsequent MS attack during the at-risk period (155).

As summarized by Stuve et al. (156) no one candidate pathogen has been accepted as the causal agent of MS, but the supposition that neurotropic agents could disrupt the blood-brain barrier, allowing the release of CNS autoantigens into the blood compartment and leading to the creation of lymphocytes sensitized to myelin or axons is plausible and makes fewer assumptions than other current theories. Stuve et al. also discuss the concepts of molecular mimicry and the activation of CD4+ T-cells by infectious agents as alternative pathogenetic models.

Associations with Other Diseases

MS has been associated with other diseases, both directly and inversely. It has been stated that individuals with MS have a genetic predisposition to autoimmunity in general (157). Epidemiological studies of the co-occurrence of autoimmune diseases has aided the understanding of MS (158), and their co-occurrence may be biologically plausible if they are shown to share common etiologic pathways in immune system dysregulation. Moreover, other disease states may act as direct triggers for the induction of MS, or may induce relevant protective or provocative factors within the host. Unfortunately, factors such as the presence of circulating T-cells activated against myelin and the presence of gamma globulin in the CSF are not specific for MS, and even the passive transfer of antibodies to self-antigens does not induce as MS-like disease (102). It is problematic as to whether the manifestations suggesting an autoimmune basis to MS are primary rather than secondary to the neuronal damage resulting from some other mechanism.

In Table 2 we list some diseases that have been claimed to correlate with MS. One set of disorders that does appear to share commonality with the hypothesized autoimmune etiopathogenesis of MS is discussed further below (Fig. 5).

Thyroid Disease

Some studies have demonstrated a significant co-occurrence of both Graves disease and Hashimoto thyroiditis with MS (175). One hypothetical explanation is that MS is a disease characterized by activated T-cells that give off a milieu of cytokines, notably IFN-y. IFN-y has been hypothesized to induce the autoimmune process

Table 2 Co-occurrence of Multiple Sclerosis with Other Diseases

Disorder

Asthma

Eczema, dermatitis, rheumatoid arthritis, thyroid disorders, inflammatory bowel disease, type 1 diabetes Prior tonsillectomy Childhood infection with measles, rubella, mumps, varicella, pertussis, or scarlet fever Hyperandrogenism

Inflammatory bowel disease Type I diabetes

Autoimmune diseases (OR =

Vaccination against measles

Conclusion

Inverse correlation No association detected

No association No association

Significantly more common in MS

patients than in controls Increased expression in MS subjects Prevalence in people with MS 3 x that in their healthy siblings (P — 0.001) and 5x rate in general population (P < 0.0001) OR = 3.8; 95% CI, 2.0-7.1

References

Comment

Tremlett et al. (159,228) Retrospective matched case-control study

Tremlett et al. (159) But see comment on thyroid disease below

From the comprehensive Danish database

Falaschi et al. (162)

Small numbers

Zorzon et al. (165) Zorzon et al. (165) Zorzon et al. (165)

140 females, 131 controls only studied

140 females, 131 controls only studied

140 females, 131 controls only studied

HB vaccination

Vaccination

Thyroid disorders Autoimmune thyroid disease

(Graves' disease) Autoimmune thyroid disease

Presence of ANA and antithyroid autoantibodies (ATAbs)

Sjorgen syndrome (SS)

Young-adult-onset Hodgkin lymphoma Psoriasis

Acute poliomyelitis

No effect No effect 3x more common

Excess risk in first-degree relatives of probands with MS Higher prevalence of ATT in male MS patients (9.4%) than in controls (1.9%); P = 0.03 Frequency of ATAbs in opticospinal MS higher than that in non-OSMS (P = 0.007), but that of ANA similar in each group 3-16 x more common in subjects diagnosed with MS Familial clustering noted

Sievers (107) Offit and

Hackett (167) Kami et al. (81) Broadley et al. (168)

Niederweiser et al. (169)

Subgroup of patients with a first- or second- Annunziata et al. (173) degree relative with psoriasis had early MS onset

19 cases of MS found among 5652 polio Nielsen et al. (174) patients when compared with 11.0 expected [SIR = 1.73 (1.04-2.74)]

No need to modify vaccination regime See text

Females only studied

No significant differences in females, however

SS can mimic PPMS

Danish study; 149,364 years of follow-up, but small numbers of events

Abbreviations: MS, multiple sclerosis; HB, hepatitis B; PPMS, primary progressive multiple sclerosis.

Figure 5 Co-occurrence of multiple sclerosis with other diseases. Other disease processes, autoimmune or not, may share similar etiological processes, create environments or byproducts that initiate multiple sclerosis, or be instigated by multiple sclerosis.

observed in Hashimoto disease, so the increased availability of activated T-cells in MS may cause an increased frequency of Hashimoto disease in MS patients. MS, Hashimoto disease, and Graves disease may also share the dysregulation of apopto-sis during chronic inflammatory states through the induction of Fas expression on normal cells (220). Chronic inflammatory states may cause active T-cells to produce cytokines that may induce Fas expression in organs distal to the original inflammatory site.

Co-occurrence of MS with other defined autoimmune diseases has been suggested but not proven (Table 2) and no autoantigen specific to MS has been identified (156).

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