ReviewInfectious agents and multiple sclerosis—are Chlamydia pneumoniae and human herpes virus 6 involved?
Introduction
Multiple sclerosis (MS) is a demyelinating disease of white matter in the human central nervous system (CNS). The disease includes an autoimmune component, with self-reactive lymphocytes targeting constituents of the myelin sheath such as myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), among others. Patients with MS display significant variations in clinical course, but the disease occurs in two general forms: remitting-relapsing and chronic progressive, with the former more common (Paterson and Swanborg, 1988). Most patients with remitting-relapsing disease eventually progress to the latter form (secondary progressive), with consequent increase in motor dysfunction.
The etiology of MS remains unknown, but some evidence does indicate infectious involvement in disease genesis. For example, reasonably good data exist for seasonal variation in the incidence of new MS cases, and the disease is most prevalent in high northern latitudes Kurtzke, 1983, Granieri et al., 2001, Steiner et al., 2001. Other evidence for infectious involvement in MS derives from long-term studies in the Faroe Islands. Those data suggest that, about 1940, introduction of a new but unspecified microbial agent occurred in the islands and that this agent has since engendered pulses of new MS cases at approximately 13-year intervals (e.g., Kurtzke and Hyllested, 1988).
Involvement of an infectious agent in MS might explain some aspects of the autoimmune component of the disease. The idea that anti-myelin T cells or autoantibodies could be elicited by molecular mimicry has garnered much interest Fujinami and Oldstone, 1985, Wucherpfennig and Strominger, 1995, Ufret-Vincenty et al., 1998, Benoist and Mathis, 2001, Lang et al., 2002. Based on epidemiologic data and the mimicry hypothesis, many groups have searched for bacteria and viruses in clinical samples from MS patients. To date, about 20 organisms have been associated with the disease (Steiner et al., 2001). The screening techniques in these many studies varied from serology to polymerase chain reaction (PCR), and quality and numbers of controls examined varied widely. None of the organisms so far investigated for a role in MS has gained acceptance as the causal agent. Indeed, virtually all have been discarded due to the lack of confirmatory evidence from independent laboratories.
Recently, two new organisms were reported to be associated with MS in independent studies: the bacterial respiratory pathogen Chlamydia pneumoniae and human herpes virus 6 (HHV-6). Both have elicited significant controversy concerning their potential role in disease genesis (e.g., Gilden, 2001, Vastag, 2001). In this article, we review the available published evidence for and against involvement of C. pneumoniae and HHV-6 in the genesis and/or exacerbation of MS. On the basis of those highly inconsistent studies, as well as results from an important recent report regarding the neuropathology of this disease, we suggest directions for future study of these and other potential pathogens in relation MS.
Section snippets
C. pneumoniae and multiple sclerosis
C. pneumoniae is an obligate intracellular bacterial pathogen of the respiratory tract that is responsible for community-acquired pneumonia. The organism was first described as a unique chlamydial species in 1989 and is thought to be primarily a human pathogen. C. pneumoniae, like all members of this genus, infects mucosal surfaces, in this case the oral and nasal mucosa (Grayston et al., 1990, Hahn et al., 2002, Campbell, 2002 for reviews). Epidemiologic studies indicate that C. pneumoniae is
HHV-6 and multiple sclerosis
HHV-6 is a β-herpes virus isolated initially from peripheral blood mononuclear cells (PBMC) of infected AIDS patients; isolates since have been obtained from PBMC of children with undifferentiated acute febrile illness, from healthy adults and from immunocompromised individuals. Infection with HHV-6 has been linked to several diseases, including neonatal exanthum subitum, AIDS-associated encephalomyelitis and chronic fatigue syndrome (Challoner et al., 1995, Soldan et al., 1997 for review). The
APOE genotype and multiple sclerosis
Recent observations concerning possession of the APOE ε4 allele type on chromosome 19 appear to be relevant to the issue of whether C. pneumoniae, and possibly also HHV-6, are involved in MS (see Becker, 2001, Schmidt et al., 2002, Lucotte and French MS Consortium, 2002). In work unrelated to MS, one of us reported a relationship between possession of the ε4 allele type at APOE and the pathobiology of C. pneumoniae (Gérard et al., 1999). If this is the case, and if C. pneumoniae is involved in
Experimental problems in studies of infectious agents and multiple sclerosis
The inconsistency among published experimental data regarding the relationship between C. pneumoniae or HHV-6 and MS highlights critical technical issues concerning how any association between a microorganism and a particular disease is established. First, no standard PCR, immunohistochemical or other assay system targeting either C. pneumoniae or HHV-6 DNA or antigens, or those from any other organism for that matter, in any sample type has been agreed upon among researchers (e.g.,
Neuropathology in multiple sclerosis
Given the variation among MS patients in clinical course, responses to treatment, etc., large-scale comparative neuropathologic studies of MS clinical materials have been surprisingly rare. One recent report, however, has provided an important initial basis for understanding the heterogeneity in many aspects of MS. In a study involving multiple centers in the US and Europe, neuropathology was defined comparatively in materials from 83 patients with firm diagnoses of MS (Lucchinetti et al., 2000)
Summary
Epidemiologic data support the contention that an infectious agent or agents is/are involved in MS for at least some patients, although it is not clear whether that involvement operates at the level of etiology or disease exacerbation. Given the wildly divergent screening results currently available, and given recent information concerning the relationship between APOE genotype and onset/severity of MS, as well as that relating to neuropathology in the disease, we consider it to be impossible
Acknowledgements
The writing of this article was supported by NIH grants AR-42541 and AI-44055 (A.P.H.), NS-06985 (R.H.S.), and AI-44493 and AR-48331 (J.A.W.-H.), as well as grant RG1073 from the National Multiple Sclerosis Society (R.H.S.).
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Each author contributed equally to this article.