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- Båve, Ullvi
(författare)
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Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.
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| 2. |
- Cristea, Alexander, 1966-
(författare)
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Effects of Ageing and Physical Activity on Regulation of Muscle Contraction
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this study were to investigate the mechanisms underlying (1) the ageing-related motor handicap at the whole muscle, cellular, contractile protein and myonuclear levels; and (2) ageing-related differences in muscle adaptability.In vivo muscles function was studied in the knee extensors. Decreases were observed in isokinetic and isometric torque outputs in old age in the sedentary men and women and elite master sprinters. A 20-week long specific sprint and resistance training successfully improved the maximal isometric force and rate of force development in a subgroup of master sprinters.In vitro measurements were performed in muscle biopsies from the vastus lateralis muscle. Immunocytochemical and contractile measurements in single membrane permeabilized muscle fibres demonstrated ageing- and gender-related changes at the myofibrillar level. In sedentary subjects, data showed a preferential decrease in the size of muscle fibres expressing type IIa MyHC in men, lower force generating capacity in muscle fibres expressing the type I MyHC isoform in both men and women and lower maximum velocity of unloaded shortening (V0) in fibres expressing types I and IIa MyHC isoforms in both men and women. The master sprinters also experienced the typical ageing-related reduction in the size of fast-twitch fibres, a shift toward a slower MyHC isoform profile and a lower V0 of type I MyHC fibres, which played a role in the decline in explosive force production capacity. The fast-twitch fibre area increased after the resistance training period. A model combining single muscle fibre confocal microscopy with a novel algorithm for 3D imaging of myonuclei in single muscle fibre segments was introduced to study the spatial organisation of myonuclei and the size of individual myonuclear domains (MNDs). Significant changes in the MND size variability and myonuclear organization were observed in old age, irrespective gender and fibre type. Those changes may influence the local quantity of specific proteins per muscle fibre volume by decreased and/or local cooperativity of myonuclei in a gender and muscle fibre specific manner.In conclusion, the ageing-related impairments in in vivo muscle function were related to significant changes in morphology, contractile protein expression and regulation at the muscle fibre level. It is suggested that the altered myonuclear organisation observed in old age impacts on muscle fibre protein synthesis and degradation with consequences for the ageing-related changes in skeletal muscle structure and function. However, the improved muscle function in response to a 20-week intense physical training regime in highly motivated physically active old subjects demonstrates that all ageing-related in muscle function are not immutable.
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| 3. |
- Lundberg, Stina
(författare)
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Examining Female Resilience to Early Environmental Influences : Short- and long-term consequences on behaviour, HPA axis activity and alcohol intake after prolonged maternal separation
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Early-life experiences are an important factor influencing further development of the individual. Adverse experiences early in life, such as various kinds of abuse or neglect, are types of early-life stress that can adversely affect an individuals health, as well as contribute to the development of an array of disorders later in life. Most prominent is the increased risk for psychiatric disorders, primarily depression, anxiety-related and substance use disorders. Many of the implicated disorders also exhibit sex-dependent differences in prevalence and severity. Thus, it is important to consider sex-dependent effects when modeling early-life stress and its consequences. A common animal model for early-life stress is prolonged maternal separation (MS). MS is an umbrella term for different manipulations of the early environment of rodent pups. In this thesis, a prolonged MS condition with separation of rat litters from their dams for six hours per day during the first three weeks of life (MS360) was used. In male offspring MS360 have been associated with early-life stress and negative effects apparent during both adolescence and adulthood. The literature regarding female offspring is not as substantial as for the males, but it seems that females’ exhibit less pronounced or no effect after prolonged MS independent of separation time. In addition, the studies that have examined female offspring have done so in adulthood and thus, short-term consequences of prolonged MS possibly present during adolescence have not been investigated. The aim of this thesis is to provide a broad investigation into the consequences of prolonged MS in female offspring, in both adolescence and adulthood. As stated above, MS360 was used as the adverse rearing condition in this thesis. As control, daily short MS (15 min; MS15) was used; this ensured that all animals were handled equally, except for the length of separation. Any detected differences are thus due to the length of separation only. Three categories of assessments were used to evaluate short- and long-term consequences: 1) hypothalamus-pituitary-adrenal (HPA) axis assessments, 2) behavioral assessments and 3) assessment of voluntary alcohol consumption. HPA axis reactivity was assessed in adolescent and adult offspring by blood sampling before and after challenge. HPA activity was also evaluated after long-term alcohol consumption by measurement of the fecal corticosterone content. Behavior was assessed in adolescence by registration of social play behavior and in adulthood by generation of behavioral profiles in the multivariate concentric square fieldTM (MCSF). Alcohol consumption was evaluated using the modified intermittent alcohol access schedule with the two- (20% alcohol) and three- bottle (5% and 20% alcohol) free-choice paradigms. Female offspring did not differ depending on rearing condition in HPA reactivity in adolescence or adulthood. However, after the long-term alcohol intake, MS360 females had increased levels of corticosterone in their feces compared to MS15 females. No difference was detected in adolescent social play among female offspring and only a minor alteration was detected in the adult behavioral profile, where MS360 females had increased risk assessment compared to MS15 females. No effect of rearing condition was seen during the two-bottle choice paradigm of alcohol intake, while whole- group differences over time were discovered. Alcohol intake and preference were highest the first week of access and directly after a two-week deprivation period, apart from those time-points, intake and preference were maintained on a stable level. In the three-bottle choice, an interaction with rearing condition was revealed for the total alcohol preference, however this only translated to a minor group-dependent difference. In conclusion, females reared under a prolonged MS paradigm exhibited no or only minor basal changes in HPA axis reactivity, behavior and alcohol consumption. However, after long-term alcohol intake females subjected to prolonged MS had increased corticosterone excretion into feces. That differences only emerge after long-term perturbation can be a sign that females have higher buffering capabilities than males after early-life adversity, as modeled through prolonged MS, and thus require additional challenges before consequences become apparent. This thesis highlights the importance of considering sex when studying the impact of early-life stress, and that the choice of animal model needs to be considered carefully in relation to the research question posed.
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