Multiple Sclerosis: Studies of the Interferon system and search for infectious agents

Abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by focal inflammatory lesions with demyelination and axonal loss. It is believed that MS is an immune-mediated disorder with both genetic and environmental contributions to the pathogenesis. Interferons (IFNs) are naturally occurring proteins known to have antiviral, antiproliferative and immunoregulatory effects. Treatment with IFN beta has a favourable effect in MS while IFN gamma was found to precipitate exacerbations. We have investigated whether polymorphisms in the IFN system influenced susceptibility to MS, but found no linkage between any of the investigated loci and MS. Approximately 70% of monozygotic twins are discordant for MS indicating that environmental factors contribute to the development of the disease. We investigated, in 3 pairs of monozygotic twins discordant for MS, serological differences that could be important for the development of MS. Two MS affected twins had serological evidence of a previous infection with Borrelia burgdorferi respective Toxoplasma gondii. In general the serum titers were strikingly similar in the twins, indicating no major disturbances of the humoral immune system in MS. Many types of viruses induce IFN production, but it is unclear whether IFN is produced in MS lesions. We searched for the expression of MxA, a cytoplasmic protein induced by IFNA/B, with the capability to inhibit the replication of several viruses. No anti-MxA staining was found in MS brain tissue indicating that MxA, and consequently IFNA/B, probably is not produced in these lesions. Oligoclonal bands (OCBs) are detected in the CSF in majority of patients with MS. They are believed to result from continuous immunization against unknown antigens. We investigated if antibodies in CSF from MS patients bound to structures in MS brain lesions and control brain tissue and found that brain lesions from secondary progressive MS patients contain a unique structure that binds IgG antibodies from the patients. Preincubation of brain sections with CSF from MS patients enhanced the IgG staining. Direct fluorescence labelled CSF antibodies from an MS patient showed similar binding pattern as with anti-IgG in MS lesions. No binding of fluorescence labelled antibodies was detected in control brain tissue. This indicates that the antigens/target structures are absent from normal brain. Double staining showed that the IgG was bound to the axons and was observed both in myelinated axons and in totally or partially demyelinated axons suggesting that the antibody binding may be an early event in myelin and axon destruction.