An infectious etiology to MS ?

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The possibilities of an infectious etiology to MS has been discussed for long and remains a controversy. Before going further into this, the reader is asked to consider the following alternatives:

1. Systemic infection may aggravate MS of whatever etiology.
2. CNS-infection may directly cause MS in some (genetically disposed) persons.
3. CNS-infection (but also other disorders) may cause exposition of otherwise undetectable proteins behind the blood-brain barrier, in turn leading to autoantingenic response in genetically disposed persons.
4. Cross-reactivity (molecular mimicry) between the antigen response towards infectious agents and myelin components triggers an initial reaction, kept upright through continued damage of myelinshealts.
5. An infection alters the lymphocytic response towards autoantigeneity.

Failure to distinguish between these alternatives leads to considerable confusion among the studies cited. The MS-patient may hope for alternative 1 (and is stimulated in this hope by various reports), simply because it would offer another therapeutic aspect. The second alternative is almost trivially true but may explain some of the results. In effect, it is impossible to distinguish between alternatives 3 and 4, whether the infection would be directly or indirectly responsible and anyhow no longer active. At best, this possibility would carry prophylactic aspects, or it may simply explain how some clinical MS-cases develop without yielding any possibility to alter anything. Finally, alterations induced may have the lymphocytes as their primary target and only secondarily affect the brain.

The idea that infection might play a role was stimulated early by the sudden appearance of MS-cases after the British occupation of the Faroe Islands in the 1940ies, and also other "MS-epidemies" have been described. It is well established from Israel that the incidence of MS depends of the age at the time of immigration, so that people who are 14 years or older have the same incidence of MS as found in the countries they are coming from (generally higher in the Nordic countries), whereas younger children tend to have the same incidence as found in Israel.

The present page attempts to review the newer literature to the theme. At first, it deserves attention that some drugs, which are interesting for treatment of MS, have both anti-infectious and immunomodulatory effects: beta-interferon was originally tested against MS for its general effect against viruses; tetracyclines, recommended against chlamydia infection, are MMP-9 antagonists (see MMP-Inhibitors); and d-penicillamine has been connected to both properties (see Mercury Clearence and d-Penicillamin).

General quotations in favor of an infectious genesis:

Martyn [1] mentioned the possibility that not only MS, but also Parkinson's disease and other neurological disorders may be a consequence of childhood infection, but presently no single pathogenic virus has been identified. Gronning et al. [2] found in a Norwegian case-control study (among less clear differences) that MS-cases had more frequently experienced bronchitis and/or pneumonia in the age group 11-15 years and also tonsillectomies were reported more frequently. They judged the results to be "consistent with the idea of MS as an age-dependent, host-immune response to infection during childhood or adolescence." Evaluating 90 MS paients, Korting et al. [3] found that frequent and severe upper airway infections in childhood and youth were couples with a severe course of the disease. They hypothesized a disturbed regulation of infection and immunity as essential in the genesis.
Barnett et al.[4] demonstrated in an animal study that virus infection may be a means to modulated immune responsiveness to CNS disease. Svenninsson et al. [5] found a different lymphocyte population among MS patients and hypothesized that activated B lymphocytes expressing high levels of B7-1 may be of pathogenic importance in the development and maintenance of the disease.
Restricting consideration to current disease activity in MS patients, Giovannoni et al. [6] found infection to be a potent inducer of symptomatic and asymptomatic disease activity in mutiple sclerosis. Moreover, measuring urinary neopterin (a marker of IFN-gamma) this observation was understood to provide support of a pivotal role for IFN-gamma in the pathogenesis of mutiple sclerosis.

Special infections in the possible ethiology

Most attention is given to various herpes viruses [Table 1], anyhow frequently infecting humans and mostly without causing symptoms of encephalitis.

alpha:     Herpes simplex virus type 1        (aciclovir, valaciclovir, famciclovir, foscarnet)
alpha:     Herpes simplex virus type 2        (aciclovir, valaciclovir, famciclovir, foscarnet)
alpha:     Varicella-zoster virus                 (aciclovir, valaciclovir, famciclovir)
beta:       Cytomegalovirus                       (Ganciclovir, foscarnet, cidofovir)
beta:       Human herpesvirus 6                 (none registered)
beta:       Human herpesvirus 7                 (none registered)
gamma:  Epstein-Barr virus                      (none registered)
gamma:  Human herpesvirus 8                 (none registered)

Table 1: Distinction of herpes viruses and (in brackets) current registered therapeutic agents, after Bergström [35]. Virus detection in CSF/CNS has been reported for all subtypes.

The Epstein-Barr virus [EBV] (instantly responsible for infectious mononucleosis) has been given particular attention in newer studies. Opersalsky et al. [7] found in a case-control study a strong positive association for history of this disease. In an epidemiological study, Hernon et al. [46] found that individuals who suffered from infectious mononucleosis, a marker of late infection with the Epstein-Barr virus, have an increased risk of multiple sclerosis. Vaughan et al. [8] found elevated antibodies to EBV among Norwegian MS patients. Utilizing a very complex methodology (and perhaps not quite understood by me), Rand et al. [9] found a similarity between the oligoclonal bands produced during active phases in the CSF of MS patients and the antigenic response to an EBV infection. They also wrote that "other studies have suggested a relation between RBV infection and MS, including nearly 100% EBV seropositivity among patients with MS and increased concentrations of antibody to EBV in CSF of patients with multiple sclerosis."

Several new publications are dealing with herpes virus infections. Friedman et al. [28] found 36% of the brains from patients with MS demonstrated antibodies against herpes viruses against only 13.5% of controls. Moreover, MS patients demonstrated unusually high immune reactivity towards these viruses. Clerica et al. [32] found immune responses to retroviruses particular prominent among MS-patients. Using another technique, Christensen et al. [36] found that B-lymphocytoblastoid cell lines from MS patients produced both EBV and retrovirus-like particles. Ongradi et al. [29] suggested that intrathecal chronic active or primary human herpes virus type 6 [HHV-6] -B infection might contribute to MS progression, while other herpex virus types seemed to be less important. Also Xu et al. [49] have detected the gene of HHV-6 in oligodendrocytes of MS patients. On the contrary, Enborn et al. [33] did not find IgM response towards herpes virus more frequent in MS patients as compared to controls but did, in the light of previous studies, suggest a role for the virus in a subset of patients. Enbom [48] reviewed possible mechanisms for virally induced demyelinization and autoimmunity and summarized the conflicting evidence for and against a role for HHV-6 in MS.

Perron et al. [10] found indications that a novel (currently unidentified) retrovirus was responsible - they even baptized it the "multiple sclerosis-associated retrovirus" (MSRV). This concept was further supported by Tuke et al. [11]. Also Christensen et al. [47] found indication for the hypothesis that activation of normally replicatively quiescent retroviruses may be causally involved in MS. Dybwas et al. [12] analyzed the cerebrospinal fluid antibody specificities within one oligoclonal band. They found antibodies to other viruses such as herpes simplex virus, human cytomegalovirus and human papillomavirus, raising the question of the involvement of multiple pathogens in MS. Svenningsson et al. [13] found a reduction of about 20% in the incidence of MS in Gothenborg. They related this to the vaccination for measles, which has been carried out on a large scale since 1971, practically eradicating this disease in their area. Nevertheless, the children who might profit from this had hardly reached the age where MS is seen.

Ending up the consideration of viruses, the spectacular (though not very strong) effect of the antiviral drug acyclovir against MS [14] deserves attention. The pro-drug valacyclovir offers a better bioavailability of the substance, still another multicenter study [57] failed to yield evidence for success, except for a subgroup of very active disease.

Cross-reactivity towards the autoimmune response to herpes virus infection and oligodendrocytic products have been focused by other authors. Espositio et al. [31] demonstrated cross reactivity of autoantibodies binding to transaldolase, which is expressed in the brain selectively by oligodendrocytes, with EBV and herpex simplex virus. Bronstein et al. [34] found cross reaction of antibodies to an oligodendrocyte specific protein and several common viral peptides. Finally, van Sechel et al. [37] suggested that infection with common viruses such as EBV and human herpesvirus-6 infections can trigger myelin-directed autoimmunity in a way that is unique for humans.

Also chlamydia pneumonia has been associated with MS, but in addition with other neuropathogenic diseases such as Mb. Alzheimer. An intracellular form would require a prolonged (2-3 months) antibiotic therapy. Again, this possibility is vigorously discussed [15-18,50-56].

Using an animal model of infectious encephalitis, Burt et al. [30] found it difficult to understand any effect of autologous hematopoietic transplantation in patients with MS if this had a virus etiology, particularly if the graft is aggressively depleted of lymphocytes.


Analyzing plaque-periplaque areas from MS brain tissue and utilizing a technique, which was otherwise successful in determining other viruses, Gilden et al. [19] failed to detect any latent enveloped viruses. From an epidemiological study, v. Buuren et al. [20] deduced that perinatal infections were unlikely to be a major factor in determining MS susceptibility. Considering only cases of parainfectious transverse myelitis, Jeffery et al. [21] found that parainfectious cases were easily distinguishable from MS. DeCarli et al. [22] found that that the immune response was predominantly IgG-kappa in MS and IgG-lambda in infections. In a limited number of MS patients, Spitler and Dau [23] found reactivity to three viral antigens to be lower than that in normal subjects, as measured by lymphocyte stimulation. No evidence was found for human spumaretrovirus, oncovirus or human T-cell lymphotropic virus type 1 in three swedish publications [24,25,26].

The methodology for analyzing this question was investigated by Joseph et al. [27]. I am currently not aware of their conclusion.

Molecular Mimicry

Increased serum and cerebrospinal fluid antibody titers to numerous viruses have been reported; however, there have been no confirmed studies detecting viral RNA or antigen in MS brain tissue. Instead, structural similarity between viral T cell epitopes and self-peptides could lead to an indirect induction of an autoaggressive T cell response (mimicry), in turn aggravated by genetical and environmental factors, a possibility mentioned by several newer publications concerning specific viruses cited above. Myelin basic protein (MBP) and some viral proteins shows similarities in the amino-acid sequences. Wucherpfennig & Strominger [38] tested 129 proteins maching molecular mimicry on seven MBP-specific T cell clones from multiple sclerosis patients. Seven viral and one bacterial peptide efficiently activated three of these clones. A single T cell receptor can thus recognize quite distinct but structurally related peptides from multiple pathogens. Shaw et al. [39] found that these similarities are even stronger what myelin proteolipid is concerned. At least what envelope proteins of viruses suspected of inducing demyelinating processes and MBP was concerned, Rubio and Cuesta [40] could not detect any cross-reaction. Banki et al. [41] suggested as  a result of their study molecular mimicry between viral core proteins and the human transaldolase gene which, among others, has the function to maintain glutathione at a reduced state and, consequently, to protect sulfhydryl groups and cellular integrity from oxygen radicals. Talbot et al. [42] demonstrated possible molecular mimicry between a human coronavirus and MBP in MS-patients (29% of T-cell lines) but not in normal subjects (1.3%). Bronstein et al. [43] found antibodies to an oligodendrocyte-specific protein, cross-reacting to several common viral peptides, in 80% of the samples from MS-patients but not in those from the normal subjects; and Cortese et al. [44] found that the surface glycoprotein gB of HSV-1 was recognized by oligoclonal immunoglbulins. In an experimental study, Ufret-Vincenty et al. [45] incriminated both the human papillomavirus and Epstein-Barr virus for triggering an autoimmune disease (EAE) after transferral of the viral antigens to mice.

In Summary ...

Many viruses may induce an antigen response to many antigens. I cannot help speculating what would be found when other antigens, not relating to MS, were tested. Moreover, as mentioned under environmental factors, mimicry is not restricted to microbal antibodies, also a cow milk protein has been identified. At the present stage, the mechanism is well possible but the findings reviewed are not very helpful for defining a certain direction. There may well be an infectious genesis adding to other influences on producing MS, but it is hardly alone responsible for the majority of cases. There are not much indications of an ongoing infection and therefore hardly any therapeutical consequences for patients already hit by this disease, although some prophylactic consequences might follow, of interest for the children of MS-patients. Currently, no recommendations can be given in this direction.



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Revised May 21, 2004

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