| 1. |
- Hellberg, Sandra, 1986-
(författare)
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Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.
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| 2. |
- Håkansson, Irene, 1976-
(författare)
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Biomarkers and Disease Activity in Multiple Sclerosis : A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors.Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without.Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3).Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p≤0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters.Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.
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| 3. |
- Wickström, Anne, 1961-
(författare)
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Work ability in multiple sclerosis : the impact of immunomodulating treatments and adjusted working conditions
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease affecting the central nervous system (CNS) and is considered to be of autoimmune origin. The prevalence in Sweden is estimated to be about 1 in 500. The inflammation leads to demyelination as well as neurodegeneration and with time the patients often suffer from increasing neurological disability. The young age of onset makes MS one of the major causes of reduced ability to work in the Western society. Several factors in the disease affect the work ability. One important factor is ongoing inflammatory activity conferring risk to develop tissue damage and disability. Previous studies have indicated that fatigue, mobility and cognitive problems are the primary symptoms preventing individuals with MS to remain in employment. However, the possibility to adapt both tasks and the workplace, the possibility for sedentary work and flexible working hours also have great influence to keep the individual in employment.The purpose of the thesis was to investigate how factors in the disease, immunomodulating treatments and work requirements influence the ability to work and study in people with MS.Methods: A MS specific questionnaire was used in one retrospective and one prospective study to compare the work ability before and after start of the second-generation immunomodulating drug natalizumab. The number of working hours per week and the degree of sick leave before and after one year of treatment was calculated. The effect of disease-specific and workrelated factors on work ability was evaluated. The treatment effect on fatigue and walking ability was correlated to work ability. In addition, a healtheconomic calculation was performed to estimate the cost-benefit of the treatment. The degree of sickness absence was evaluated in a cross-sectional study of two MS-populations; one historical that never was exposed to immunomodulating drugs and the other consisted of individuals with MS that was diagnosed after the introduction of immunomodulating drugs. Furthermore, work ability was studied in two MS-populations, one southern and one northern cohort of Sweden, for the latter population more active immunomodulating treatment and work-promoting measures have been practiced. The data was collected using the instrument WAQ-MS. Results Paper I: After one year of treatment with natalizumab the average working hours per week had increased with 3.3 hours, corresponding to an economic value of 3216 euro per person per year. Paper II and III: After initiation of treatment with natalizumab, in an active phase of relapsing-remitting MS, the patients improved their working ability after one year from 31 % to 60 % (p<0.001) and reduced their sickness benefit correspondingly (p<0.001) in relation to their total employment rate. They also reported improved physical and cognitive ability in relation to their requirements. Short disease duration, younger age and lower Expanded Disability Status Scale (EDSS) grade at treatment onset predicted a positive effect on work ability and also improvement of walking ability correlated significantly with reduced sick leave. Paper IV: The proportion of individuals without any kind of sickness absence was higher in the MS population being exposed to disease modifying drugs compared to the unexposed population (66 % vs 38 %) (p<0.001). In addition, the proportion of patients with full-time sickness absence was higher in the unexposed compared to the exposed population (32 % vs 16 %) (p<0.001). The median EDSS was lower in the exposed compared to the unexposed MS population (p<0.001). Paper V: The proportion of MS patients who participated in the work force or studied was significantly higher in the northern cohort, where they had been exposed to more work promoting measures, compared with the southern cohort (p=0.022). MS patients in the northern cohort had significantly lower physical and cognitive requirements in their occupations, more adapted work conditions and could work more hours per week compared with the southern cohort. The EDSS level explained 12 % of the working ability in the northern cohort and 21 % in the southern cohort.Conclusion Our results indicate that patients in the inflammatory phase of the disease may retain their work ability several years after disease onset if they are subjected to effective anti-inflammatory treatment regimens from disease onset. Furthermore, work ability may be additionally improved by adjusted working conditions even in the progressive phase of the disease. It is obvious that these results have implications in a socioeconomic perspective as well as for the individual patients as improved quality of life due to retained work-life participation. Long-term follow-up of our data is required to determine whether these positive effects are durable over longer time-periods.
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| 4. |
- Danielsson, Olof, 1963-
(författare)
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The Clinical and Pathological Spectrum of Idiopathic Inflammatory Myopathies : Implications for pathogenesis, classification and diagnosis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of diseases with severe consequences for the life of affected patients. Dermatomyositis, polymyositis and inclusion body myositis (IBM) are the classical representatives of this group. The treatments given today often have limited effects, and are taken at the cost of side effects. Major obstacles in the search for more effective treatments are; (1) an incomplete understanding of the disease mechanisms, (2) difficulties to delineate homogeneous disease groups for clinical studies and (3) the sometimes challenging task to diagnose these diseases.Aims: We addressed a number of “loose ends” in the areas of pathogenesis, classification and diagnosis; mechanisms of muscle fiber degeneration in IIM, with a focus of programmed cell death (apoptosis) and invasion of muscle fibers by inflammatory cells (partial invasion); protecting and mediating factors present in muscle; the association of other diseases with IIM, in particular celiac disease ; the evaluation of two classification systems and laboratory methods for increased diagnostic performance.The studies: We included 106 patients, diagnosed at the Neuromuscular unit in Linköping, Sweden, with pathological muscle findings consistent with IIM. The incidence in the county of Östergötland (during 5 years) was 7.3 per million/year (3 patients each year). Of 88 patients with confirmed IIM 4 (4.5 %) had celiac disease, 33 (38%) had an associated systemic inflammatory disease and 5 (5.7 %) had a malignancy. Ninety-nine patients were included for a comparison of two classification systems using criteria of the European Neuromuscle Centre (Amato/ENMC), and the widely used Bohan and Peter classification, both with the addition of IBM according to Griggs et al. Using the Amato/ENMC criteria the most prevalent diagnostic group after IBM (30%) was nonspecific myositis (23%), followed by polymyositis (20%) and dermatomyositis 17%). A substantial number of patients meeting Bohan and Peter (or Griggs) criteria were excluded by Amato/ENMC criteria, most (21/23) due to lack of detectable muscle weakness. Extended muscle sectioning increased the sensitivity of a muscle biopsy by 15 % and the specificity by 22%, and showed an overlap between disease groups. Muscle biopsies from patients with IIM and controls were used to investigate pathological findings considered specific for disease groups, and for the presence of programmed cell death (apoptosis) and disease protecting and mediating factors in muscle. The presence of apoptotic muscle fiber nuclei was detected in muscle with partial invasion (however not in the invaded fibers) in the presence of granzyme B and CD8+ cytotoxic T cells. The major apoptosis inhibiting protein Bcl-2 was shown to be constitutionally expressed in healthy muscle but weakened in IIM.Conclusion: We present apoptosis as a possible disease mechanism in parallel with partial invasion of fibers. Furthermore, partial invasion may not be a suitable distinguishing feature in the pathogenesis, or for classification and diagnosis of IIM. We also introduce the anti-apoptotic Bcl-2 as a possible relevant muscle fiber protecting factor. A more extensive pathological work-up improves classification and diagnosis of IIM. The proposed Amato/ENMC creates a substantial portion of patients with non-specific or unclassified myositis. Associated diseases are common in IIM, and also include celiac disease.
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| 5. |
- Mellergård, Johan
(författare)
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Immunological Mechanisms and Natalizumab Treatment in Multiple Sclerosis : Studies on lymphocytes, inflammatory markers and magnetic resonance spectroscopy
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS), and a frequent cause of neurological disability among young adults. In addition to focal inflammatory demyelinated lesions, diffuse white matter pathology as well as a neurodegenerative component with accumulating axonal damage and gliosis have been demonstrated and contribute to MS disease characteristics. The inflammatory component is considered autoimmune and mediated by auto-reactive T lymphocytes together with other cell populations of the immune system and their respective products like cytokines and chemokines. Treatment with natalizumab, a monoclonal antibody directed against the α4β1-integrin (VLA-4), reduces migration of potential disease-promoting cells to the CNS. The efficacy of natalizumab in reducing relapses and MRI activity is evident, however associated effects on the immune response and the neurodegenerative component in MS are not clear.Methods: In total 72 MS patients were included, distributed among paper I-IV. We investigated effects associated with one-year natalizumab treatment in 31 MS patients regarding cytokine and chemokine levels in CSF and blood using multiplex bead assay analyses (paper I), as well as treatment effects on blood lymphocyte composition in 40 patients using flow cytometry, including functional assays of lymphocyte activation (paper II). Normal appearing white matter (NAWM) metabolite concentrations were assessed with proton magnetic resonance spectroscopy (1H-MRS) in 27 MS patients before and after one year of treatment (paper III). We also evaluated the balance between circulating T helper (Th) subsets in 33 MS patients using gene expression analyses of the CD4+ T cell related transcription factors in whole blood (paper IV).Results: One-year natalizumab treatment was associated with a marked decline in pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (CXCL8, CXCL9, CXCL10 and CXCL11) intrathecally. Circulating plasma levels of some cytokines (GM-CSF, TNF, IL-6 and IL-10) also decreased after treatment. Natalizumab treatment was further associated with an increase in lymphocyte numbers of major populations in blood (total lymphocytes, T cells, T helper cells, cytotoxic T cells, NK cells and B cells). In addition, T cell responsiveness to recall antigens and mitogens was restored after treatment. As to 1H-MRS metabolite concentrations in NAWM, no change in levels were detected post-to pretreatment on a group level. However, correlation analyses between one-year change in metabolite levels (total creatine and total choline) and levels of pro-inflammatory IL-1β and CXCL8 showed a pattern of high magnitude correlation coefficients (r=0.43-0.67). Gene expression analyses demonstrated a systemically reduced expression of transcription factors related to immunoregulatory T cell populations (regulatory T cells and Th2) in relapsing MS compared with controls.Conclusions: Our findings support that an important mode of action of natalizumab is reducing lymphocyte extravasation, although cell-signalling effects through VLA-4 also may be operative. Correlation analyses between changes 1H-MRS metabolite concentrations and inflammatory markers possibly point towards an association between intrathecal inflammation and gliosis development in NAWM. Finally, gene expression analyses indicate a systemic defect at the mRNA level in relapsing MS, involving downregulation of beneficial CD4+ phenotypes.
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| 6. |
- Samuelsson, Martin, 1965-
(författare)
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Taurine and Glutathione in cerebrospinal fluid and plasma from patients with psychiatric disorders and healthy controls
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A growing body of results indicate that immunological alterations and oxidative stress are of importance in various mental disorders. The inflammatory changes are possible to detect both in plasma and cerebrospinal fluid (CSF), and different psychiatric disorder exhibit similar changes indicating a common underlying mechanism. The antioxidants are of importance to regulate the redox balance and control the inflammatory processes but the causal relationship between psychiatric disorders and increased oxidative stress is however not fully clarified. Two important antioxidants; taurine and glutathione (GSH), have been suggested to have central nervous system (CNS)-protective properties. They have been found to fluctuate in several mental disorders including schizophrenia and depression but the clinical relevance need further studies.The general aim of this thesis was to increase the understanding of taurine and the GSH in depression and schizophrenia, two major mental disorders, in comparison to healthy controls.Correlations between glutathione and taurine levels in blood and CSF were analyzed in healthy male volunteers and we identified a complex pattern of associations showing that the CSF concentration was influenced by body mass index (BMI), age, intraspinal pressure, plasma concentrations the previous day and possible genetic factors. Electroconvulsive therapy (ECT) is used in the treatment of severely depressed patients. In blood collected before the first and after the third ECT, we found a significant decrease in plasma taurine in patients responding to the treatment, while total glutathione was unaltered. In a group of olanzapine treated patients with schizophrenia or schizoaffective disorders, we analysed taurine and glutathione in plasma and CSF and compared with healthy male and female volunteers. We observed increased plasma taurine levels in patients compared with controls, but no difference in CSF taurine and no alteration in glutathione.This thesis indicates that taurine might play a role in mental disorders such as depression and schizophrenia. Increased knowledge about the complex regulation of taurine and glutathione might provide new insights into the impact of redox balance in the pathophysiology of psychiatric disorder and contribute to a future personalization of the treatment.
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