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- Edström, Måns, 1984-
(författare)
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Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsing-remitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4+ T cells have been shown to be of importance in disease pathology. A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4+ T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4+ T cells in vitro.We showed an imbalance in the mRNA expression of CD4+ T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated GATA3 and FOXP3 expression was decreased in RR-MS. Given the reciprocally inhibitory nature of TH subsets, this might imply not only diminished function of TH2 and TREG cells but also a permissive state of harmful TH1 and TH17 cells. The size of the peripheral TREG population was unaltered in RR-MS. When analysed in detail, activated and resting TREG were distinguished, showing clear differences in FOXP3 and CD39 expression. Furthermore, when investigating these subpopulations functionally, the ability of activated TREG to suppress proliferation of responder T cells was found to be decreased in RR-MS patients compared to controls. To further investigate this defect, the global gene expression of TREG was compared between patients and controls. Gene set enrichment analysis revealed an enrichment (over-expression) of chemokine receptor signalling genes in RR-MS TREG, possibly suggesting a role for chemokines in TREG function.A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. Furthermore, T cells from patients with MS displayed decreased responsiveness towards antigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.The importance of CD4+ T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4+ T cell differentiation were enriched for many, not only immunerelated, diseases. Furthermore, global CD4+ T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4+ T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.In conclusion, our results demonstrate an imbalance of peripheral CD4+ T cells in MS, along with a functional deficiency in the case of TREG. Taken together, these aberrations might result in differentiation and activation of harmful TH1 and TH17 cells, resulting in CNS tissue damage. The importance of CD4+ T cells was further demonstrated by the finding that genes associated with CD4+ T cell differentiation constitute a pleiotropic module common to a number of diseases. Investigation of natalizumab revealed drastic changes in the peripheral lymphocyte compartment caused by treatment. It also appears as treatment might influence the responsiveness of peripheral T cells to antigens. In addition, by using CD4+ T cell transcriptomics after in vitro drug exposure, prediction of treatment outcome may be possible.
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| 2. |
- Eriksson, Britt, 1967-
(författare)
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Metabolic, methodological and developmental aspects of body composition : Studies in women and children with special reference to early life mechanisms behind childhood obesity
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent decades the number of children with overweight has increased worldwide. To understand the mechanisms behind this development, knowledge regarding metabolism and physiology in relation to the nutritional situation in early life is of importance. In particular, information about body composition development during early childhood is relevant. This thesis presents three studies in this area. In the pregnancy study serum samples, collected from 23 women before, during and after pregnancy, were analysed for serum levels of leptin, adiponectin and resistin and used to assess insulin resistance (HOMA-IR) in relation to the total body fat (TBF) content of the women. TBF (%) and leptin were significantly correlated with HOMA-IR before and during pregnancy. When HOMA-IR was regressed on TBF (%) the slope of the regression line was 0.111 in gestational week 32 and significantly (p<0.05) higher than the value before pregnancy, 0.046, indicating that healthy pregnancy enhances the relationship between body fatness and insulin resistance. In the HF-study hydration of fat-free mass (hydration factor, HF) was assessed in 12 newborns using the doubly labelled water (DLW) method and air displacement plethysmography (PeaPod). HF was 80.9% with a low biological variability (0.81% of average HF). In the longitudinal study the body density of 108 healthy fullterm infants (53 girls, 55 boys) was measured at one and 12 weeks of age using PeaPod. Body composition was calculated using two models (Fomon’s and Butte’s). BMI values for the mothers of the infants were assessed before pregnancy. Body composition and total energy expenditure using the DLW-method were assessed in 20 of these children at the age of 1.5 years, when their sleeping metabolic rate was measured using indirect calorimetry and their resting energy metabolism was calculated using prediction equations. Butte´s model gave significantly (p<0.05) lower values for TBF than Fomon´s model, and invalid results for five newborns. Using Fomon´s model, at one week of age girls contained 13.4 ± 3.7 % and boys contained 12.5 ± 4.0 % TBF. The corresponding figures at 12 weeks were 26.3 ± 4.2 % and 26.4 ± 5.1 %. The mothers’ BMI values before pregnancy were correlated with the body weight but not with the TBF (g,%) or fat-free mass (g) of their infants at one week of age. At 1.5 years of age girls (n=9) contained 28.0±2.8 % and boys (n=11) 28.3±3.7 % TBF. Between one and 12 weeks of age all infants increased their TBF content, while 13 children increased and seven children decreased their TBF content between the ages of 12 weeks and 1.5 years. The results demonstrated that predicting rather than measuring resting energy metabolism involves a risk for spurious correlations between TBF and physical activity level. The level of physical activity (x), was negatively correlated with [TBF (%) at 1.5 years minus TBF (%) at 12 weeks] (y), r=-0.52, p=0.02. In conclusion, the results suggest that the body fat content of a woman has a stimulating effect on the growth, rather than on the fat retention, of her foetus. They also show that the Fomon model is the best available model when calculating the body composition of infants from body density. Finally, the results indicate that physical activity at the age of 1.5 years is important regarding the rate at which the high level of body fat, typical of infancy, decreases in early childhood.
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| 3. |
- Nilsing Strid, Emma, 1973-
(författare)
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The Sick Leave Process : Sick Leave Guidelines, Sickness Certificates, and Experiences of Professionals
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Decisions on entitlement to sickness benefits and return to work interventions have substantial impact on individuals’ lives and on society. In most Western European countries, such decisions are based on sickness certificates, which should provide information on how a disease or injury reduces the individual’s work ability. These are challenging and complex assessments. In 2008, guidelines for the management of sick leave were implemented in Sweden, emphasizing early assessments of work ability and return to work, and increasing the quality demands of sickness certificates by underscoring descriptions of activity limitations related to work. The overall aim of this thesis was to gain a deeper knowledge of the sick leave process with special emphasis on the content of sickness certificates and primary health care (PHC) professionals’ experiences with the process. Specific aims were to compare the quality of sickness certificates regarding descriptions of functioning by the use of WHO’s International Classification of Functioning, disability, and health (ICF), as well as the prescribed interventions before versus after implementation of the Swedish sick leave guidelines.The thesis comprises three studies. A cross-sectional design was used in studies I and II, which included 475 and 501 new sickness certificates consecutively collected in Östergötland County, Sweden, in 2007 and 2009, respectively. Text on functioning was analysed with a deductive content analysis using the ICF. Study III was an exploratory study using data from four semi-structured focus group discussions with a purposeful sample of PHC professionals (n=18) in Östergötland County. An inductive content analysis was used in this study.The thesis comprises three studies. A cross-sectional design was used in studies I and II, which included 475 and 501 new sickness certificates consecutively collected in Östergötland County, Sweden, in 2007 and 2009, respectively. Text on functioning was analysed with a deductive content analysis using the ICF. Study III was an exploratory study using data from four semi-structured focus group discussions with a purposeful sample of PHC professionals (n=18) in Östergötland County. An inductive content analysis was used in this study.An overall conclusion drawn from this thesis is that patient functioning and needs might not be adequately communicated in the sick leave process. Despite the implementation of sick leave guidelines, this information is limited in sickness certificates and the collaboration is poor among the involved stakeholders, i.e., health care, the social insurance office, the employer and the OHS. The basis for decisions on entitlement to sickness benefits could be improved by including a description of the patients’ activity limitations or participation restrictions related to work demands. One way to enhance the decision basis might be to use the available team competencies at the PHC.
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