No description available.

No description available.

No description available.

To examine the pathophysiological consequences of autoimmunity to TAG-1, CD4⁺ T cells and autoantibodies specific for TAG-1 were generated and their potential to induce EAE was investigated in a rat model. An adoptive transfer of T cells specific for the first two immunoglobulin domains of TAG-1 initiates an intense inflammatory response in both the cortex and spinal cord in the Dark Agouti and Lewis rats. This is particularly interesting as conventional models of EAE are of little help in investigating the pathomechanisms responsible for cortical tissue damage, as the cortex is only rarely targeted by myelin-specific autoimmune responses in this animal model of Multiple Sclerosis (MS). Moreover, when a demyelinating antibody like Z2 (anti-MOG) antibody was co-transferred with TAG-1-specific T cells it resulted in demyelination not only in the spinal cord white matter but also the grey matter and triggered demyelination coupled with macrophage infiltration in the perivascular areas of the cortex. This new model of cortical demyelination is exciting as it bears some resemblance with chronic progressive MS. However, two different monoclonal antibodies (4D7/TAG1) and 3.1C12) specific to TAG-1, when co-transferred with TAG-1 specific T cells, failed to mediate tissue damage in the CNS. Although the role of TAG-1-specific antibodies in EAE remained inconclusive from the preliminary experiments, this study clearly demonstrates TAG-1-specific T cells as a new tool to mediate EAE highlighting cortical pathology which can be exploited further to investigate the factors that control regional differences in the pathogenesis of inflammatory demyelinating lesions in the CNS. This new model might provide novel insights into the development of cortical pathology in MS patients and will ultimately guide to design therapeutic approaches in MS.

Background: Multiple sclerosis (MS) is a common, disabling neuro-inflammatory disorder, whose prevalence seems to be increasing. Objectives: The main aims of this thesis were to: (i) systematically review good quality MS prevalence studies and assess heterogeneity in prevalence rates; (ii) conduct a new prevalence study in Aberdeen, Orkney and Shetland to assess temporal trends, compare rates to other areas and describe demographic, clinical and disability data in prevalent MS patients. Methods: The systematic review used defined search strategies to identify references that satisfied inclusion criteria. The influence of time, latitude, diagnostic criteria, quality of case ascertainment and methods of classifying patients on age-gender standardised prevalence rates and sex ratios were analysed by uni- and multivariate regression. The new prevalence study identified all MS patients alive on 24/9/09 from defined general practices through multiple sources. Primary and secondary care records were used to confirm the diagnosis. Prevalence rates were standardised to 2009 Scottish population. A postal questionnaire survey was conducted to gain additional data, which allowed a randomised factorial trial of the effect of envelope colour/address labelling on response rates to be performed. Results: The review identified marked heterogeneity (I2 99.7%) in prevalence rates, partially explained by latitude (p<0.0001), prevalence date (p=0.009) and number of ascertainment sources (p=0.04). High and rising prevalence was recorded in Orkney [402/100,000 (95% CI 319-500)], the highest worldwide, Shetland [295/100,000 (95%CI 229-375)] and Aberdeen city [229/100,000 (95%CI 208-250)]. Male-to-female ratio was 1:2.55 (95%CI 2.26-2.89). Postal response rates to brown/white envelopes were not different [OR 1.17 (95% CI 0.81 to 1.68)] but hand-written address labels had a higher response than computer-generated labels [OR 1.22 (95% CI 1.06-1.40)]. Conclusions: This research showed that MS prevalence remains very high in northern Scotland and confirmed international observations of rising prevalence. Explanations include increased survival, improved diagnosis and probably increasing incidence.

An endophenotype is a concept that allows the description of complex diseases with genetic and environmental contributions,enabling the identification of an at risk population. I aim to describe an endophenotypic gradient between healthy controls, siblings of people with MS and people with MS. Siblings of people with MS are at increased risk of developing MS; this is thought to be a result of genetic and environmental contributions. Epidemiological studies have identified a number of factors contributing to MS risk including smoking,vitamin D,infection with Epstein Barr virus and HLAZDRB1*1501. A genome wide association study in 2011 gave information regarding the contribution of HLAZtype and nonZHLA"SNPs to MS risk. I set out to integrate these into an endophenotypic risk score for MS. When the genetic contribution from HLAZDRB1*1501 alone was used,the mean MS risk score was significantly higher for people with MS than siblings or controls. Siblings had a higher MS risk score than controls. The differences between the three groups become more apparent when all genetic information was used in the MS risk score. I used MRI and biomarker studies to validate the MS risk score generated. Preliminary studies enabled an evaluation of the potential association between selected biomarkers and CSF oligoclonal bands. The analyses performed demonstrate the potential clinical utility of such a score in describing MS risk. Siblings have a risk score intermediate to people with MS and controls, confirming their “at"risk” position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with environmental factors potentially providing the trigger for clinically apparent disease. The findings of this research have the potential to enrich future prevention studies with individuals at high risk of developing MS,enabling such studies to be performed within a realistic timeframe.

No description available.

Multiple sclerosis, (MS), presents affected individuals with an uncertain future, and has broad physical and psychosocial implications for their daily functioning. This study aimed to investigate the psychological well-being of people with MS with an emphasis on positive psychological functioning. It also aimed to extend previous research that suggested reporting perceived benefits during adversity may be indicative of cognitive adaptation. Disease-related variables (mobility, fatigue) and psychosocial factors (optimism, coping) were examined to ascertain the effects of living with MS upon well-being. Well-being was determined using two general measures (The Profile of Mood States (POMS), Shacham, 1983; and the Ryff Psychological Well-being Scale (PWB), Ryff & Keyes, 1995), and Mohr et al.�s (1999) MS psychosocial factors (Demoralization, Deteriorated Relationships, Benefit Finding). Participants were 154 people with MS who were recruited through the MS Societies of Victoria and Tasmania. Results showed participants reported both negative and positive consequences from their MS experiences. Higher levels of Demoralization and Deteriorated Relationships were related to decreased well-being. However, no association was found between Benefit Finding and psychological well-being. Benefit Finding was also unrelated to optimism, and the disease-related variables (mobility, fatigue). Only positive reappraisal coping was predictive of reporting of benefits which lends support to the notion that it is a coping strategy. To examine the effects of mobility the sample was divided into three groups: normal gait, mild gait problems but not using aids and those who require aids for mobility. Significant differences between the mobility groups were found on Demoralization and fatigue levels. As participants� difficulties with mobilisation increased so too did their levels of demoralisation. However, those with mild gait problems reported fatigue levels comparable with those experiencing more complex gait difficulties. No differences were found between the groups on the general psychological measures, which may indicate some form of resilience or psychological adaptation occurring. More generally, results showed that participants who were more optimistic, less fatigued, and used less of particular coping strategies (either less avoidant coping or less blaming self or others) to deal with their MS problems reported higher well-being (less demoralisation, less psychological distress and higher positive functioning). In conclusion, the use of multi-dimensional outcomes enabled a comprehensive examination of well-being and highlighted the effects of specific illness-related factors and coping strategies. As demonstrated in this study, despite the adversity of living with MS, people are able to maintain a healthy sense of self and their relationships, and report benefits from their experiences.

Multiple sclerosis (MS) is the most common primary demyelinating disease of the central nervous system in humans. Type I interferons are most frequently used to treat MS. However, their main mechanism of action remains elusive. Various biomarkers have been investigated for their ability to assess treatment efficacy, but results are often confounding due to differences in experimental design and variation in individual physiology. In fact, not all MS patients respond to IFN therapy and a significant number suffer severe negative side effects and must cease treatment. Thus, alternative therapeutics that offer less cytotoxicity and greater efficacy are a major objective of research. This dissertation evaluated a novel type I interferon, interferon-tau (IFNT), and its ability to attenuate Theiler’s virus-induced-demyelinating disease (TVID), a mouse model of MS. In this model, viral infection with the BeAn strain of Theiler’s murine encephalomyelitis virus (TMEV) is the initiating factor leading to demyelination of the CNS. It was hypothesized that IFNT would: 1) provide therapeutic benefit as witnessed by a stabilization of clinical score, a decrease in CNS inflammation, and a decrease in CNS demyelination, and 2) shift the immune profile from a Th1 to a Th2 response. Once mice developed chronic disability, IFNT treatment began. This novel IFN was delivered in an innovative way: encapsulation (eIFNT) in an alginate polymer, which allowed for slow and sustained release. eIFNT was delivered by a 100 μl intraperitoneal injection (i.p.) containing 1.4M U of IFNT once every two weeks for 8 weeks. Mice were clinically scored weekly and BeAn-eIFNT mice demonstrated a decrease in clinical score. Bright field microscopy was used to evaluate CNS tissues where a decrease in demyelination and inflammation was noted in BeAn-eIFNT-treated mice. Ex vivo stimulation of virus-specific lymphocytes revealed an increase in both T helper 1 (Th1) and T helper 2 (Th2) cytokine production. Specifically, TNFA was produced at very high levels by splenocytes from BeAneIFNT mice in response to UV-inactivated BeAn alone and in the presence of IFNT when compared to BeAn-eMOPS mice under the same conditions. IFNG was produced at elevated levels from the splenocytes of BeAn-eIFNT mice versus BeAn-eMOPS mice when stimulated in vitro with UV-inactivated Bean and with BeAn in the presence of IFNT. IL-2 was produced at moderately elevated levels from the splenocytes of BeAn-eIFNT mice versus BeAn-eMOPS mice when stimulated in vitro with UV-inactivated Bean. Il-2 was elevated to a statistically significant level (p<0.05) from BeAn-eIFNT mouse splenocytes when stimulated with BeAn in the presence of IFNT when compared to BeAn-eMOPS mice and IL-10 was produced at elevated levels by splenocytes from BeAn-eIFNT mice versus that produced from BeAn-eMOPS mouse splenocytes in response to UV-inactivated BeAn alone and in the presence of IFNT. Quantification of T regulatory (Treg) cells in the spleen of eIFNT vs. eMOPS mice and blood of eIFNT vs. eMOPS mice revealed no difference between the two groups. There was no statistical difference in virus-specific serum antibodies at the pretreatment time point noted in the OD readings of eIFNT mice at a dilution of 1/200 compared to the eMOPS mice. A modest decrease in the OD values at the 1/200 dilution were noted in the eIFNT mice compared to the eMOPS mice, but this difference was not significant. Antibody secreting cells (ASCs) from eIFNT mice versus eMOPS mice were slightly lower in the spleen and brains whereas there was a slight increase in ASCs from the spinal cord of eIFNT mice when compared to those from eMOPS mice. Altogether, the results support efficacy of the eIFNT treatment in the mice with TVID. Actual mechanisms of disease attenuation remain elusive at this time as mice exhibited an increase in certain Th1 and Th2 cytokines rather than the hypothesized shift from a Th1 to a Th2 immune profile. Likewise, mice exhibited a modest decrease in virus specific antibodies as well as the number virus-specific ASCs which also refute the hypothesized increase in these values. A remarkable finding was the fact that immune cells derived from eIFNT treated mice appeared to be divided into two distinct types of biological responders although all of the mice responded to the in vivo treatment with a decrease in disease severity. It is hypothesized that this difference is a reflection of individual genetic variability in response to immune modulation which is surprising owing to the fact that the animals used for these studies are in-bred and considered to be as identical genetically as is feasible in a population of animals. Obviously, immune modulation can proceed through different mechanisms and still provide the desired result of a decrease in disease severity. However, this reality creates an added level of difficulty when one is trying to interpret biological data in order to determine whether a therapeutic regimen is efficacious within a patient population.

Thesis (M. Sp. Path.)--University of Queensland, 2002. / Includes bibliographical references.