Multiple sclerosis: basic concepts and hypothesis

Multiple sclerosis, an inflammatory disease of the central nervous system, is characterized by primary destruction of myelin. This review covers recent advances in neuropathology, immunogenetics, neuroimmunology, and neurovirology that have provided insights regarding its pathogenesis. Three hypotheses are discussed: (1) autoimmunity, (2) "bystander" demyelination, and (3) immune destruction of persistently infected oligodendrocytes. A paradigm for induction of primary demyelination is proposed in which immune cells recognize "foreign" antigens on the surface of oligodendrocytes in the context of major histocompatibility complex gene products. The final result of this scheme may be "dying-back gliopathy," the alteration being noted first in the most distal extension of the oligodendrocyte--that is, the myelin sheaths.     

Therapeutic criteria in hydrocephalic children

The xanthine, hypoxanthine, and total oxypurine levels were determined in the CSF of 28 hydrocephalic patients (age from newborn to 2 years) and 8 healthy controls using HPLC. The Evans' index, the mean weekly increase in cranial circumference, and the intracranial pressure were also measured. Of the hydrocephalic patients 13 were self-compensated and the other 15 had a shunt implanted during the course of the study. The mean xanthine, hypoxanthine, and total oxypurine levels in the normal children were 5.20, 5.94, and 11.29 mol/l, respectively. In the self-compensated hydrocephalics these levels were 5.17, 5.71, and 10.79 mol/l, respectively. In the noncompensated hydrocephalics, they were 9.90, 9.91, and 19.82 mol/l. The differences between the latter group and the first two are statistically significant (P<0.001). The mean Evans' index and the mean weakly increase in cranial circumference in the self-compensated hydrocephalics were 0.35 and 0.25 cm, respectively. In the noncompensated hydrocephalics, they were 0.55 and 0.95 cm. The differences between the two groups are statistically significant (P<0.001). Two weeks after implantation of shunts in the noncompensated cases, the mean xanthine, hypoxanthine, and total oxypurine levels fell to 4.22, 4.57, and 8.80 mol/l, respectively. These changes are statistically significant (P<0.001). We think that the two criteria (clinical and biochemical) are equally useful for the prediction of self-compensation in hydrocephalic children and that the oxypurine values after shunt implantation can be used to monitor progress in noncompensated cases.     

Microtiter solid-phase radioimmunoassay for detection of Escherichia coli heat-labile enterotoxin.

The development of a microtiter solid-phase radioimmunoassay for the detection of Vibrio cholerae enterotoxin and heat-labile Escherichia coli enterotoxin is described. The test is based on the immunological similarity between V. cholerae toxin and E. coli heat-labile toxin. The assay is easy to perform, quantitative, and at least as sensitive and specific as the Y-1 adrenal cell system.     

Virus persists in beta cells of islets of Langerhans and infection is associated with chemical manifestations of diabetes. II. Morphologic observations.

Persistence of lymphocytic choriomeningitis (LCM) virus in the islets of Langerhans was associated with mild hyperglycemia and abnormal glucose tolerance test results. Early histopathologic events consisted of occasional perivascular inflammatory mononuclear cells around both islet and acinar cells. Morphometric studies showed an increase in the size of islets from virus-infected mice. By electron microscopy, LCM virions were found within infected beta cells. Cytolytic injury of beta cells was minimal and did not account for the abnormalities of glucose metabolism. In contrast to the findings in islets, ultrastructural studies of acinar cells revealed LCM virions in abundance, vacuolar degeneration, and intracytoplasmic inclusions. This study extends the previous observation that LCM virus infection may persist in beta cells of the islets of Langerhans without causing structural injury but be associated with abnormalities resembling the chemical and histopathologic features of the early stage of Type II (adult-onset) human diabetes mellitus.     

Isolation and purification of two immunodominant antigens from Nocardia brasiliensis.

Two immunogenic proteins from a crude extract of Nocardia brasiliensis were purified to homogeneity. A 61-kDa protein (P61) was isolated from a 50% ammonium sulfate precipitate in two steps. Initially, P61 was obtained by electroelution in a 10% nondenatured preparative polyacrylamide gel electrophoresis (PAGE). In a second step, the eluate from the nondenatured gel was run in a 12% sodium dodecyl sulfate (SDS) preparative polyacrylamide gel. After elution, a single band was demonstrated by SDS-PAGE and Western blot (immunoblot). Also, a 24-kDa immunogenic protein (P24) was isolated by gel filtration in a Sephadex G-100 column and then by electroelution in a 12% nondenatured polyacrylamide gel. In a previous paper, we showed by Western blot assays that these proteins are recognized by the sera of mycetoma patients and not by sera from mycobacterial-infected or healthy individuals. We consider these proteins to be good candidates for the study of the host-parasite relationship in nocardial infections. The possible clinical application of these purified antigens in a serological diagnosis is discussed.     

Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease.

Platelet-derived growth factor (PDGF) isoforms and PDGF receptor-alpha are upregulated in fibroproliferative lesions in response to asbestos exposure. To examine the functional role of PDGF in asbestos-induced lung disease, we have evaluated the impact of PDGF-B overexpression in the lung on the development of pulmonary fibrosis induced by asbestos inhalation. Transgenic mice expressing PDGF-B from the surfactant protein C promoter and wild-type C57BL/6 mice were exposed to aerosolized chrysotile asbestos fibers via three different exposure regimens: 3 consecutive days to 9 mg/m(3), once a week for 5 weeks to 12 mg/m(3), or once a week for 8 weeks to 11 mg/m(3). The 3-day exposure did not produce fibroproliferative lesions in SPC-PDGFB or wild-type mice, indicating that PDGF expression did not increase susceptibility to a subthreshold dose of asbestos. Transgenic and wild-type mice subjected to the 5-week exposure protocol exhibited similar fibrogenic lesions histologically 48 hours and 8 weeks postexposure, but lungs from transgenic mice had elevated lung hydroxyproline content 8 weeks postexposure relative to wild-type mice. In addition, SPC-PDGFB transgenic mice developed pronounced thickening of arterioles following the 5-week exposure regimen. Mice exposed to asbestos for 8 weeks and examined 10 months later showed pronounced, diffuse fibrotic lesions of terminal bronchioles and alveolar ducts, but no histological differences between transgenic and nontransgenic mice were observed. These results indicated that PDGF-B overexpression can stimulate increased collagen deposition and vascular smooth muscle hyperplasia following asbestos inhalation and that a limited exposure (8 times) to chrysotile aerosol can produce long-lasting fibrotic lesions. The 8-week exposure regimen provides an animal model that encompasses an important aspect of human asbestosis-i.e., persistence of fibrosis for long periods after cessation of asbestos exposure.     

Modulation of mechanosensory responses by motoneurons that regulate skin surface topology in the leech

Central regulation of somatosensory signals has been extensively studied, but little is known about their regulation in the periphery. Given the widespread exposure of the skin sensory terminals to the environment, it is of interest to explore how somatosensory sensitivity is affected by changes in properties of the skin. In the leech, the annuli that subdivide the skin can be erected under the control of the annulus erector (AE) motoneurons. To analyze whether this surface change influences mechanosensory sensitivity, we studied the responses of low threshold mechanosensory T cells to mechanical stimulation of the skin as AE motoneurons were activated. In segments of the body wall connected to the corresponding ganglion and submerged in an aqueous environment, T cells responded to localized bubbling on the skin and to water flow parallel to its surface. Excitation of AE motoneurons diminished these responses in a way that depended on the motoneuron firing frequency. Video recordings established that the range of AE firing frequencies that produced effective annulus erection coincided with that influencing T cell responses. In isolated ganglia, AE firing had no effect on T cell excitability, suggesting that annulus erection diminished T cell responsiveness to mechanical input. Counteracting this effect, mechanosensory inputs inhibited AE motoneurons. However, because depolarization of AE cells caused a decrease in their input resistance, the more active the motoneuron, the less sensitive it became to inhibitory signals. Thus when brought to fire, AE motoneurons would stay "committed" to a high activity level, and this would limit sensory responsiveness to incoming mechanical signals.     

4E-binding protein phosphorylation and eukaryotic initiation factor-4E release are required for airway smooth muscle hypertrophy

The molecular mechanisms of airway smooth muscle hypertrophy, a feature of severe asthma, are poorly understood. We previously established a conditionally immortalized human bronchial smooth muscle cell line with a temperature-sensitive SV40 large T antigen. Temperature shift and loss of large T cause G1-phase cell cycle arrest that is accompanied by increased airway smooth muscle cell size. In the present study, we hypothesized that phosphorylation of eukaryotic initiation factor-4E (eIF4E)-binding protein (4E-BP), which subsequently releases eIF4E and initiates cap-dependent mRNA translation, was required for airway smooth muscle hypertrophy. Treatment of cells with chemical inhibitors of PI 3-kinase and mammalian target of rapamycin blocked protein synthesis and cell growth while decreasing the phosphorylation of 4E-BP and increasing the binding of 4E-BP to eIF4E, consistent with the notion that 4E-BP1 phosphorylation and eIF4E function are required for hypertrophy. To test this directly, we infected cells with a retrovirus encoding a phosphorylation site mutant of 4E-BP1 (AA-4E-BP-1) that dominantly inhibits eIF4E. Upon temperature shift, cells infected with AA-4E-BP-1, but not empty vector, failed to undergo hypertrophic growth. We conclude that phosphorylation of 4E-BP, eIF4E release, and cap-dependent protein synthesis are required for hypertrophy of human airway smooth muscle cells.