The direct infection hypothesis implies that the virus persists in the brain or perhaps in other organs, periodically seeding the brain. There are many examples of persistent infections or viral latency in the nervous system. In the former category are measles virus (SSPE), HIV, HTLV-1, papovavirus, and rubella virus encephalopathies. Herpes simplex, herpes zoster, EBV, certain retroviruses, and human herpes virus 6 (HHV-6) are examples of common viruses that persist in neural or other tissue, usually in a latent form. In these models, chronic low grade infection, periodic reactivation of latent virus, or seeding of the brain through a hematogenous route could cause direct injury to glial cells or neurons. Alternatively, the agent could initiate an autoimmune response secondary to release or alteration of previously sequestered self-antigens with epitope spread or through molecular mimicry (36,37). In addition, the infectious agent could prime macrophages and lymphocytes, so that subsequently non-encephalitogenic activated T- or B-cells could enter the CNS and release cytokines or antibodies causing demyelination by a bystander effect (37). Lastly, the agent could act as a super-antigen, directly stimulating encephalitogenic T-cell clones (38). Through any of these mechanisms, demyelination and axonal injury could arise.
If the agent does persist in the host, it should ultimately be identifiable, particularly early in the course of the disease using appropriate techniques, including the exquisitely sensitive polymerase chain reaction (PCR) or newer molecular techniques for identifying exogenous genes or proteins. Further, if an infectious agent persists in the patient, it might be possible to show a serological association between pathogen and disease. Antibody to the agent might be extremely elevated when compared with controls, even though the controls had been infected transiently by the same virus. For example, SSPE is a persistent measles virus infection of the brain, leading to very high serum and CSF measles antibody titers to most but not all measles virus proteins. However, even with persistent infection, viral antibody titers are not always elevated. For example, in progressive canine distemper encephalitis, viral antibody titers are often lower in animals with fulminant disease, perhaps related to virus-induced lymphopenia and immunosuppression (1,14).
Although discouraging, the failure to reproducibly culture an organism from or identify viral genome or antigens in MS tissues cannot be considered as proof that an infectious agent is not present (1,9,14). Nevertheless, the negative results to date indicate the need to consider alternative mechanisms for CNS lesion genesis in MS.
The second mechanism that can be considered for infection-induced lesion genesis in MS is the transient infection or "hit-and-run" hypothesis (1,35). In this scenario, the pathogen is present only briefly in the host, but this is sufficient for a persistent organ-specific autoimmune process to be established (37). The virus acts as a triggering agent only and may be undetectable when clinical symptoms develop. Demyeli-nation could then be induced in several possible ways. As discussed previously, the infectious agent might contain structural sequences identical with a brain protein or other antigen (molecular mimicry). An immune response to the agent then cross-reacts with the corresponding brain antigen, resulting in a chronic, self-perpetuating inflammatory disease. Streptococcus-induced rheumatic heart disease may be an example of this type of autoimmune organ-specific disorder, where an antigenic similarity between bacterial M protein and cardiac myosin leads to cardiac valvular damage (1,14,39). Consistent with this mechanism, many bacterial and viral deca-peptides have been identified with amino acid or structural profiles similar to myelin proteins (18). These include hepatitis B virus, EBV, Escherichia coli, adenovirus, influenza, measles, and CDV. Using a different approach, Wucherpfennig and
Strominger screened a large number of peptides for degeneracy of amino acid side chains required for major histocompatibility complex (MHC) class II binding and activation of myelin basic protein (MBP)-responsive T-cells (40). A panel of 129 peptides satisfying these criteria was identified, of which herpes simplex virus, EBV, adenovirus type 12, influenza type A, and Pseudomonas aeruginosa peptides gave the greatest activation of MBP-specific T-cell clones derived from MS patients. Collectively, these studies support the concept that multiple common infectious agents have the potential for triggering MS by a molecular mimicry mechanism. An alternative possibility for tissue injury might also involve molecular mimicry between infectious agent and host protein, but instead of a myelin protein, a regulatory protein in the immune system or a critical host enzyme might be the target, resulting in altered immune function, disruption of the blood-brain barrier, or interference with myelin metabolism. This could lead to a less direct but equally devastating immunopathology. Additionally, transient CNS inflammation in a genetically susceptible host could also prime the hosts CNS, leading to periodic bystander demyelination when the systemic immune response is activated (37). Another indirect mechanism for myelin injury could be through the effect of exogenous super-antigens. In this scenario, infectious agents can activate T-cells, including auto-reactive T-cells, by interacting directly with the T-cell receptor resulting in a self-perpetuating autoimmune disease even after the agent is eliminated. Lastly, the agent could infect lymphocytes or other immunocompetent cells, altering delicately balanced control mechanisms, and thereby allowing the emergence of aggressive autoimmune T- or B-cell clones (1,14). Measles and CDV are examples of viruses that produce transient profound immunosuppression and neurological illness in which MBP responsive T-cells can be found in peripheral blood (1,9,14,41,42).
If a virus triggers MS, but is no longer present in the host when neurological disease is manifest, it will be extremely difficult to prove causation (1,14). In such a situation, it will be necessary to have persuasive epidemiological and other laboratory as well as clinical evidence linking the virus to MS. However, several problems exist in attempting to use serology to link a virus to MS. If MS is caused by multiple viruses, there may be considerable variability in viral titers geographically and temporally. For example, CMV-induced GBS may occur in epidemics, with few GBS patients demonstrating positive CMV serology in the interepidemic period (43). Second, because MS is a chronic disorder with a variable, often long latent period before onset of neurological symptoms, one would not expect to see a fourfold rise or fall in antibody titers to the agent or a predominantly IgM antibody response, as usually occurs with an acute infectious process (44). Furthermore, if MS is an uncommon complication of a common infection and the agent does not persist, both MS patients and controls may have similar antibody titers to the agent in CSF and serum with no increase in the CSF to serum antibody index (1,14). For example, it may be difficult to conclude whether an individual had early adult infectious mononucleosis or an asymptomatic childhood EBV infection, or paralytic or nonparalytic poliomyelitis, by measuring IgG antibody titers later in adult life. In addition, one would need to show some specificity of the antibody response by demonstrating no similar increase in antibody titers to other viral or nonviral antigens in MS patients. Similarly, antibody titers should not be solely related to an increase in serum or CSF IgG. In contrast, if MS is caused by an agent that does not usually infect humans, it might be easier to demonstrate higher antibody titers to the agent in patients than in normal individuals (1). An example of this type of serological response is found with human rabies. In this type of situation, there should be fewer MS patients with low and more with higher antibody titers to the original as compared to controls. Last, the presence of low antibody titers cannot be taken as proof that an individual has not been previously infected by the agent in question, because after many infections, antibody titers fall over time.
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