Experimental allergic encephalitis (EAE) is considered by many to be a model for human multiple sclerosis. Intraperitoneal inoculation of mice with Chlamydia pneumoniae, after immunization with neural antigens, increased the severity of EAE. Accentuation of EAE required live infectious C. pneumoniae, and the severity of the disease was attenuated with antiinfective therapy. After immunization with neural antigens, systemic infection with C. pneumoniae led to the dissemination of the organism into the central nervous system (CNS) in mice with accentuated EAE. Inoculation with Chlamydia trachomatis did not worsen EAE and infectious organisms were not seen in the CNS. These observations suggest that dissemination of C. pneumoniae results in localized infection in CNS tissues in animals with EAE. We propose that infection of the CNS by C. pneumoniae can amplify the autoreactive pool of lymphocytes and regulate the expression of an autoimmune disease.

To examine a possible relationship between Chlamydia pneumoniae infection and multiple sclerosis (MS), we undertook an immunohistochemical (IHC), molecular, and ultrastructural comparison of central nervous system (CNS) tissue and cerebrospinal fluid (CSF) sediment from patients with MS and control individuals with other neurological diseases (ONDs). In 7 of 20 MS cases, IHC staining was seen in association with ependymal surfaces and periventricular regions of formalin-fixed brain tissue, by use of 3 different antichlamydial antibodies. There was no staining with any of the 3 antichlamydial antibodies in formalin-fixed brain tissue from OND controls (n=17). With available frozen CNS tissue, polymerase chain reaction (PCR) studies for the presence of C. pneumoniae genes were performed. The presence of a PCR signal was confirmed in 5 of 8 MS cases and in 3 of 18 OND controls. In an examination of CSF sediment by electron microscopy, we observed electron-dense structures resembling chlamydial organisms in CSF sediments from 11 of 20 MS cases and 2 of 12 OND controls. The presence of immunogold-labeled electron-dense bodies was correlated with the presence of a PCR signal in 10 of 11 MS cases. Results of studies using these different approaches support our suspicion of the presence of chlamydial organisms in the CNS, in a subset of patients with MS.

There are currently four known isoforms of nitric oxide synthase (NOS). Of these, neuronal NOS (nNOS) is known to be present exclusively in neurons, endothelial NOS (eNOS) in vascular endothelium, while the inducible form of NOS (iNOS) is known to be activated in oligodendrocytes, astrocytes and microglia. The fourth isoform, mitochondrial NOS (mtNOS), represents a post translational modification of nNOS. Using western blotting and real time-PCR, we show induction and activation of nNOS following culture of oligodendrocyte progenitor cells (OPC) with lipopolysaccharide (LPS). Activation of nNOS results in accumulation of peroxynitrite and tyrosine nitration of proteins in oligodendrocytes resulting in reduced cell viability. Injection of LPS in vivo into the corpus callosum of rats leads to the development of extensive demyelination of the white matter tracts. Immunostaining of regions close to the injection site shows the presence of nNOS, but not iNOS, in oligodendrocytes. Neither iNOS nor nNOS was seen in astrocytes in areas of demyelination. These studies suggest that activation of nNOS in oligodendrocytes leads to oligodendrocyte injury resulting in demyelination.

Defective elimination of autoreactive cells is thought to play a role in the development of autoimmune diseases including multiple sclerosis (MS). We examined the activation of the ATM-CHK2-p53 pathway in MS patients after subjecting their peripheral blood mononuclear cells to gamma-irradiation. We found that peripheral blood mononuclear cells from a subset of MS patients show resistance to cell death induced by irradiation. This defect is due to impaired constitutive expression and activation of ATM (ataxia telangiectasia mutated), resulting in impaired stabilization of p53. We predict that these fundamental defects likely alter the regulation of the immune population of cells in MS and may contribute to the development or progression of the disease.

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