Tumor necrosis factor alpha and human Schwann cells: signalling and phenotype modulation without cell death.

The aim of the study was to evaluate the biological response of human Schwann cells (SC) to tumor necrosis factor alpha (TNFalpha) in vitro and to the inflammatory milieu of chronic inflammatory demyelinating polyradiculoneuritis (CIDP). By immunocytochemical and functional assays, we found that SC expressed TNF receptors and that TNFalpha promoted in SC cultures transient activation of transcription factors NFkappaB and c-jun in the absence of apoptosis. In addition, TNFalpha significantly increased the proportion of non-myelin-forming SC expressing the p75 nerve growth factor receptor. Such phenotypic effect was dose-dependent and partially mediated by NFkappaB, as assessed by functional blockage with acetylsalicylic acid. We then extended our study to a human disease in which SC are exposed to TNFalpha. Increased signals for NFkappaB, but not c-jun, molecules were observed by immunohistochemistry on SC nuclei in nerve biopsies from patients with CIDP, as compared with controls. Irrespective of the presence of nerve inflammation, SC showed no evidence of apoptosis. Taken together, our results suggested that SC are potential targets of TNFalpha and that this cytokine exerted no cytotoxic effects either in vivo or in vitro. Rather, TNFalpha may influence the fate of SC by activating transcriptional pathways and modulating their phenotype.

Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology.

Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-alpha, are known to generate survival signals through the activation of the transcription factors NF-kappaB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-kappaB complex and its inhibitor, IkappaB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-kappaB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IkappaB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.

Neuropsychological and neuroimaging correlates in corticobasal degeneration.

The aim of this study was to correlate neuropsychological and neuroimaging findings in corticobasal degeneration (CBD). Three patients with clinical criteria for CBD were examined by means of neuropsychological tests, brain magnetic resonance imaging (MRI), and flow and metabolism neuroimaging techniques. Neuropsychological assessment revealed impairment in executive functions, manual dexterity and motor programming with significant asymmetry between upper limbs. Ideomotor and oral apraxia were also detected, and memory deficits were observed in one patient. MRI revealed cortical dilation of the frontal and peri-rolandic regions, symmetrical in one case and asymmetrical in the other two cases. An increased T2 signal intensity in the posterolateral putamen and substantia nigra ipsilateral to the cortical atrophy was observed in one patient. Asymmetries of both frontal and parietal cortices and basal ganglia were detected in all three patients by 18-fluorodeoxyglucose positron emission tomography; temporal region hypometabolism was associated in one patient. These cortical and subcortical asymmetries were observed in two patients by single photon emission tomography with the tracer technetium Tc 99m hexamethyl propylenamine oxime; cortical asymmetry was observed in only one patient. The results showed that functional neuroimaging findings correlated well with neuropsychological aspects in CBD. Neuroimaging and neuropsychological correlations may contribute toward understanding anatomical and functional abnormalities associated with this neurodegenerative disorder.