Pathogenesis Of Subacute Sclerosing Panencephalitis Research Articles

Antiviral microRNA Expression Signatures are Altered in Subacute Sclerosing Panencephalitis

Background: Subacute sclerosing panencephalitis (SSPE) is a chronic, progressive disease caused by a persistent infection of the measles virus. Despite extensive efforts, the exact neurodegeneration mechanism in SSPE remains unknown. MicroRNAs (miRNAs) have emerged as an essential part of cellular antiviral defense mechanisms and can be modulated by antiviral cytokines Such as interferon-beta (IFN-β). Aims and Objectives: In this study, we aimed to elucidate the role of antiviral miRNAs in the pathogenesis of SSPE and analyze the interaction between host antiviral miRNAs and virus genes. Materials and Methods: Thirty-seven patients who were followed with SSPE and age-matched healthy children were included in the study. Peripheral blood mononuclear cell levels of miR-196b, miR-296, miR-431, and miR-448 were analyzed using quantitative polymerase chain reaction. Target predictions and pathway constructions of deregulated miRNAs were assessed. Results: Here, we showed that IFN-β-modulated miR-196b, miR-296, and miR-431 were significantly upregulated in patients with SSPE compared with healthy controls. Besides, sequence complementarity analysis showed that miR-296 and miR-196b predicted binding regions in measles virus genomic RNA. Conclusion: Our findings suggest that antiviral miRNAs are upregulated in patients with SSPE, which could be a part of the host antiviral defense mechanism.

Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

Measles and SSPE: occurrence and pathogenesis

Measles is an acute febrile exanthematous condition that is usually a self-limiting disease, but it can be associated with several complications, one of which is subacute sclerosing panencephalitis (SSPE). It is a rare delayed complication of measles due topersistenceof the virus in the central nervous system. All of the genetic analyses of viral material derived from brain tissue of SSPE patients have revealed sequences of wild-type measles virus (MV). There is no evidence that measles vaccine can cause SSPE. Several mutations have been described in genes coding for proteins in SSPE strains of MV. Several host cell modifications, mechanisms of virus reactivation and immunopathology in pathogenesis of SSPE have been explained recently, broadening the understanding of this fatal disease.

A Correlative Study of FDG PET, MRI/CT, Electroencephalography, and Clinical Features in Subacute Sclerosing Panencephalitis

To describe F-18 fluorodeoxyglucose positron emission tomography (FDG PET) profile in patients with subacute sclerosing panencephalitis (SSPE) and to investigate its possible correlation with clinical, electroencephalography (EEG) or magnetic resonance imaging/computed tomography (MRI/CT) findings. EEG recording, MRI/CT and FDG PET imaging were performed in 16 patients with SSPE (1.9-15.6 years). FDG PET scans were assessed visually and in standardized uptake values. Finally, all the findings including clinical data were compared. MRI was abnormal in 10 patients. It was normal in 6 of 10 patients in earlier clinical stages. Nonspecific T2-weighted white matter findings were the most consistent MRI finding (10 patients). No thalamic lesion was detected in MRI/CT. FDG PET imaging was abnormal in 14 patients (8/10 patients in earlier stages). Glucose metabolism was decreased in thalamus, cerebellum or cerebral cortex in 12, 12, and 9 patients, respectively. Frontal cortex metabolism was preserved in earlier clinical stages. FDG PET imaging revealed putaminal hypermetabolism in 7 patients. However, MRI indicated striatal abnormality only in 2 patients with prolonged disease and later clinical stage. Three patients with putaminal hypermetabolism experienced a more rapid clinical deterioration. Onset age of SSPE, age of measles infection and EEG findings were not correlated with the imaging findings. Our findings suggest that FDG PET imaging can indicate affected brain regions in SSPE more confidently and earlier than MRI. FDG PET imaging would provide new insights into the pathogenesis of SSPE and help to develop new approaches to the patients with SSPE.

Rituximab in subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive, fatal neurological disorder of childhood and early adolescence. It is caused by a persistent measles virus infection of the brain without any available treatment to date. The physiopathology of the disease is largely unknown. Considering the potential role of humoral immunity in the pathogenesis of SSPE, one patient was given compassionate anti-CD20 antibodies. However, disease progression under treatment led to reconsider B cell involvement in this pathology. Nevertheless, we observed that carbamazepine was useful in improving life quality in our patient, and should be considered as a first-line drug. To date, measles vaccination remains the only solution to SSPE.

Hypothalamic digoxin-mediated model for subacute sclerosing panencephalitis.

The isoprenoid pathway including endogenous digoxin was assessed in subacute sclerosing panencephalitis (SSPE). This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The following parameters were measured in patients with SSPE and in individuals with right hemispheric, left hemispheric and bihemispheric dominance-(a) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (b) tryptophan/tyrosine catabolic patterns; (c) free-radical metabolism; (d) glycoconjugate metabolism; and (e) membrane composition and RBC membrane Na(+)-K(+) ATPase activity. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with SSPE and in those with right hemispheric dominance. In this group of patients: (a) the tryptophan catabolites were increased and the tyrosine catabolites reduced; (b) the dolichol and glycoconjugate levels were elevated; (c) lysosomal stability was reduced; (d) ubiquinone levels were low and free-radical levels increased; and (e) the membrane cholesterol:phospholipid ratios were increased and membrane glycoconjugates reduced. On the other hand, in patients with left hemispheric dominance the reverse patterns were obtained. The upregulated isoprenoid pathway and hypothalamic digoxin are involved in the pathogenesis of SSPE. SSPE occurs in right hemispheric chemically dominant individuals and a pathogenetic model for SSPE implicating hypothalamic digoxin is proposed.

Observations of subacute sclerosing panencephalitis in South Africa

Analysis of 75 cases of subacute sclerosing panencephalitis (SSPE) reported to the National Institute for Virology, South Africa, in 1984–1990 does not support the role of intensive exposure to measles virus in the pathogenesis of SSPE. The incidence of SSPE per million population was similar in Blacks and Whites, although that of reported measles is up to 10 times greater in Blacks. The age of SSPE follows the distribution of measles cases; thus, significantly more younger SSPE cases were found in Blacks than in Whites. The distribution between males and females was approximately equal. These data suggest SSPE to be a fortuitous complication of measles infection associated with as yet unidentified risk factors rather than a consequence of an excessive dose of infecting virus or immunological immaturity.

Immunocytochemical analysis of the cellular infiltrate in brain lesions in subacute sclerosing panencephalitis

We studied lymphocyte subsets and major histocompatibility complex (MHC) class II antigens in frozen brain tissues from three patients with subacute sclerosing panencephalitis (SSPE) using immunocytochemical techniques. Perivascular cuffs consisted predominantly of T cells and MHC class II-positive cells. In the parenchymal lesions, there were frequent B and CD4+ cells. MHC class II-positive cells were also diffusely distributed throughout the parenchyma. There were more CD4+ than CD8+ cells both in the parenchyma and in the perivascular cuffs. These findings suggest an overrepresentation of CD4+ cells in SSPE lesions and that CD4+ cells may be involved in the pathogenesis of SSPE.

Identification of interferon-resistant subpopulations in several strains of measles virus: positive selection by growth of the virus in brain tissue

Subacute sclerosing panencephalitis (SSPE) is a chronic and usually fatal central nervous system disease caused by a persistent infection with measles virus. The pathogenic mechanisms of the disease are poorly understood, but restricted expression of viral antigens within the infected tissue appears to be involved. We have previously proposed that interferon (IFN) plays a role in the pathogenesis of SSPE by interacting with viral subpopulations that are relatively resistant to IFN-mediated inhibition. Such IFN-resistant viral subpopulations have now been identified in six independent strains of measles virus, two derived from patients with measles and four derived from patients with SSPE. By means of a replicative-plating procedure, these IFN-resistant viruses were found to be heterogeneous with respect to their growth in the presence of high levels of IFN. One viral form replicates fully, with complete destruction of the infected-cell culture, whereas the other form induces a restricted, self-limited form of cytopathic effect, similar to that seen with cell-associated strains of measles virus isolated from SSPE patients. Passage of a virus stock containing both of these viral forms through the central nervous system tissue of newborn hamsters strongly selects for the viral form associated with the self-limiting type of cytopathic effect. The presence of this form of IFN-resistant virus coupled with chronic production of IFN within the central nervous system may account for viral persistence in SSPE patients.

Identification of a nonproductive, cell-associated form of measles virus by its resistance to inhibition by recombinant human interferon.

Subacute sclerosing panencephalitis (SSPE) is a fatal disease in children and young adults that is caused by persistent infection of the central nervous system (CNS) by a nonproductive, cell-associated form of measles virus. Using an experimental model for SSPE (LEC viral strain in newborn hamsters), we have shown previously that establishment of such CNS infections involves selective elimination from the CNS of productively infected cells by host defensive mechanisms, coupled with the selective sparing of cells carrying nonproductive viral forms. That interferon (IFN) may play a role in this process was suggested by the disappearance of productively infected cells from the CNS tissues prior to the appearance of antiviral antibodies and by the demonstration of cell-associated, IFN-resistant viral variants in the virus stocks that were used. Results of this study support these conclusions by showing that similar IFN-resistant viral variants are present in the HBS strain of SSPE-derived measles virus and that these variants, in the presence of IFN, have properties that are similar to those of naturally occurring cell-associated strains of SSPE viruses, e.g., DR, IP3, and Biken. These IFN-resistant forms of HBS virus were isolated and were shown to maintain their resistance to inhibition by IFN after cloning. However, on removal of IFN, they reverted to productive forms similar to the parental HBS virus. The potential role of such viral forms in the pathogenesis of SSPE is discussed.

Risk factors in subacute sclerosing panencephalitis: age- and sex-dependent host reactions or intensive exposure?

The central epidemiologic features of subacute sclerosing panencephalitis (SSPE)--young age of measles attack and overrepresentation or males--are usually explained as resulting from age- and sex-dependent host reactions. In this report, an alternative hypothesis is offered: intensive exposure, presumably due to the dose of infection, is a risk factor in the pathogenesis of SSPE. A hypothetical model of the influence of age and sex on the transmission of measles is suggested. According to this model, girls are exposed to measles more easily outside the home. Furthermore, small children are most likely to be exposed to measles at home. Consistent with this model is the fact that all studies indicate that female SSPE patients contract measles at a younger age than do male patients. Reports in the epidemiologic literature suggest that several characteristics of SSPE may result not from host reactions per se but from the distribution of intensive exposure to measles.

Partial C4 deficiency in subacute sclerosing panencephalitis.

In an immunogenetic study, 23 subacute sclerosing panencephalitis (SSPE) patients and their families were studied for the HLA region markers HLA-A, B, C, DR, BF, C2, C4A, C4B, GLO I, and PGM3. In addition, C3, C4, and factor B serum levels were determined. A highly significant association of C4A QO with SSPE was found. Furthermore, two rare haplotypes, C4A QOB QO, two C4ACh+ allotypes, and four Ch partial inhibitors were detected, which possibly impair the function of the C4 molecules. HLA-DR5 was increased. In addition, a number of rare HLA-A, C, B, DR haplotypes were observed. It is postulated that rare C4 molecular deficiency might be a predisposing factor in the pathogenesis of SSPE.

Immune Complexes in Subacute Sclerosing Panencephalitis

It has been observed that patients with Subacute Sclerosing Panencephalitis (SSPE) respond normally to skin test antigens, have normal isohemagglutinin titers, elevated serum IgG, IgA, and IgM levels, elevated cerebrospinal fluid (CSF) IgG levels and elevated serum and CSF measles antibody titers (MAT). It has also been observed that both serum and CSF IgG levels increase with progression of the disease, while the specific measles antibody titers remain at the same level. Findings have suggested that antigenic stimuli other than the measles virus may be involved in the disease. This chapter discusses the findings based on the studies conducted circulating immune complexes in patients with SSPE. The results indicate the presence of immune complexes (IC) in the circulation of patients suffering from SSPE and the presence of a specific blocking factor in the sera and CSF of SSPE patients. It is suggested that one of the sites at which IC can be deposited is the choroid plexus. This makes the supposition of the involvement of IC in the pathogenesis of SSPE more probable. Further studies are being conducted to elucidate the role of IC in the pathogenesis of SSPE.

Absence of M protein in a cell-associated subacute sclerosing panencephalitis virus.

Measles virus has been suggested to cause subacute sclerosing panencephalitis (SSPE), a slow central nervous system disease of children. However, several questions remain about the pathogenesis of SSPE. For example, it is not known whether alteration of the measles virus genome has a role in the initiation and persistence of the disease. Several studies have compared the RNA and protein composition of wild-type (wt) and SSPE strains of measles virus in a search for markers characteristic of the latter. All the studies used SSPE strains that had reverted to the budding, virion-producing form, similar to wt. We have shown, however, that only cell-associated non-budding strains of SSPE virus cause an SSPE-like persistent infection in young ferrets. Strong cell association and cell-fusing activity were essential for the virulence of measles virus in the brains of experimental animals and possibly humans. We have, therefore, compared the protein composition of virulent SSPE strains to that of the budding, non-virulent SSPE and wt strains. We report here that the M protein was not detectable in non-budding SSPE strains D.R., Biken and IP-3, and strain D.R. contained very little H protein.

Cell-mediated immunity in acute and chronic measles virus infections: 43

While the etiology of subacute sclerosing panencephalitis (SSPE) by a measles-like virus is now firmly established, the pathogenesis of SSPE is not understood. It has been suggested that the disease might be due to a specific unresponsiveness at the level of T cells (Burnet, Lancet ii,610,1968). To test this hypothesis specific T cell functions were measured by direct lymphocyte-mediated cytotoxicity in vitro using measles virus-infected lymphoblasts as target cells in 4- hr Cr-51 release assays. Results: Cells with the properties of cytotoxic T lymphocytes (CTL) were only present in children with acute measles and could be found among peripheral blood lymphocytes for up to 7 days after onset of measles rash. These cells were functionally restricted by the HLA system and belonged to the FcRy negative pool of lymphocytes. Such cells could neither be detected in measles convalescents nor in patients with SSPE. It is proposed that in order to assess specific T cell immunity in donors beyond the acute stage of measles, memory T cells must first be restimulated in vitro into secondary populations of CTL before testing direct lymphocyte-mediated cytotoxicity.

Measles and subacute sclerosing panencephalitis virus proteins: lack of antibodies to the M protein in patients with subacute sclerosing panencephalitis.

Studies on the immunoprecipitation of the proteins of several different measles and subacute sclerosing panencephalitis (SSPE) virus strains from lysates of infected cells have revealed a relative lack of antibodies to the nonglycosylated viral membrane protein (M) in the sera of patients with SSPE, in contrast to a high level of antibodies to other viral proteins. No evidence was found for the existence of a large number of antigenically unique M proteins. In contrast to SSPE sera, other hyperimmune human or rabbit sera precipitated M protein as well as the other viral proteins. The results suggest that in patients with SSPE there is either diminished synthesis of M, or it is not recognized normally by the immune system, and that an abnormality in M protein is involved in the pathogenesis of SSPE. Although differences in electrophoretic mobility of the M proteins and several other viral proteins were observed among different SSPE and measles strains, there was no pattern characteristic of SSPE strains, nor could these strains be distinguished by peptide mapping.

Serum thymic factor in subacute sclerosing panencephalitis patients

The activity of thymus-dependent serum factor (SF) was measured in 11 patients with subacute sclerosing panencephalitis (SSPE). A significantly decreased activity was found in 6 out of 11 patients, whereas the level of cyclic AMP in lymphocytes of the patients, a parameter for the maturation of peripheral blood lymphocytes, showed low values in 9 out of 11 patients. These findings were compared with the clinical stage of the disease and with some lymphocyte functions in vitro. No correlation was found between the SF levels and the amount of cyclic AMP in the lymphocytes or between these two parameters and the lymphocyte functions in vitro. It is concluded that a thymic humoral dysfunction is unlikely to play a role in the pathogenesis of SSPE; it appears that such a dysfunction is rather a secondary event in this disease.

Ultrastructural and histological studies of brains of ferrets inoculated with subacute sclerosing panencephalitis: similarities to human disease.

Similarities to human subacute sclerosing panencephalitis (SSPE) were revealed in a study of the brains of ferrets inoculated with a cell associated measles virus originally isolated from an SSPE patient. The similarities were greatest in animals that showed neurological signs 3-4 months after inoculation and had high titers of neutralizing antibodies against measles virus. These included dense core particles, nuclear bodies, alterations of basement membranes of small blood vessels, plasma cells, distorted myelin, and rod-like structures in some nuclei. Other abnormalities seen were Hirano bodies, tubular aggregates in cisternae of endoplasmic reticulum and clusters of cytoplasmic tubules. No cells containing viral inclusion bodies were observed by electron microscopy but cell cultures of the brains of these animals always yielded abundant measles virus nucleocapsids in typical SSPE multinucleated syncytia. These findings suggest that the ferret is a suitable animal model for the study of the pathogenesis of SSPE.