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- Tjärnlund, Anna
(författare)
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Mucosal Immunity in Mycobacterial infections
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- More than a century after the identification of the tubercle bacillus and the first attempts at vaccination, tuberculosis (TB) still remains one of the world’s most serious infectious diseases. TB, caused by the bacterium Mycobacterium tuberculosis, is typically a disease of the lung, which serves both as port of entry and as the major site of disease manifestation. The currently used vaccine, BCG, is administered parenterally and induces a systemic immune response. However, it fails to protect against pulmonary TB, thereby raising the question whether vaccination targeting the mucosal immunity in the lungs could be favourable. The respiratory mucosal surfaces represent the first line of defence against a multitude of pathogens. Secretory IgA, in mucosal secretions has an important function by blocking entrance of pathogenic organisms and preventing infections. Additionally, a role for IgA in modulation of immune responses is currently being revealed. In this work, we investigated the relevance of mucosal IgA in protection against mycobacterial infections using mice deficient for IgA and the polymeric Ig receptor, the receptor responsible for mucosal secretions of IgA. Gene-targeted mice were more susceptible to mycobacterial infections in the respiratory tract and displayed reduced production of proinflammatory, and protective, factors such as IFN-γ and TNF-α in the lungs. The mechanisms explaining the defective proinflammatory responses in the lungs of deficient mice might involve impaired signalling through Fcα receptors, or homologous receptors, which could lead to inadequate activation of pulmonary macrophages. This could subsequently result in suboptimal induction and production of cytokines and chemokines important for attraction and migration of immune cells to the site of infection. Induction of optimal adaptive immune responses to combat mycobacterial infections requires prompt innate immune activation. Toll-like receptors (TLRs) are vital components of the innate branch of the immune system, ensuring early recognition of invading pathogens. Using TLR-deficient mice we demonstrated an important role for TLR2, and partly TLR4, in protection against mycobacterial infection in the respiratory tract. TLR2-deficient mice failed to induce proper proinflammatory responses at the site of infection, and macrophages derived from the knockout mice displayed impaired anti-mycobacterial activity. Experimental evidence has concluded that the immune response upon an infection can influence the outcome of succeeding infections with other pathogens. Concurrent infections might additionally interfere with responses to vaccinations and have deleterious effects. We developed an in vitro model to study the effect of a malaria infection on a successive M. tuberculosis infection. Our results demonstrate that a malaria blood-stage infection enhances the innate immune response to a subsequent M. tuberculosis infection with a Th1 prone profile. Reduced infectivity of malaria-exposed dendritic cells implies that a malaria infection could impose relative resistance to ensuing M. tuberculosis infection. However, a prolonged Th1 response may interfere with malaria parasite control. The outcome of this work emphasizes the importance of generating effective immune responses in the local mucosal environment upon respiratory mycobacterial infections. It furthermore puts new light on the immunological interaction between parasites and mycobacteria, which could have implications for future vaccine research.
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| 2. |
- Usman, Muhammad, 1980-
(författare)
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Impact of Ionizing Radiation on 4H-SiC Devices
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Electronic components, based on current semiconductor technologies and operating in radiation rich environments, suffer degradation of their performance as a result of radiation exposure. Silicon carbide (SiC) provides an alternate solution as a radiation hard material, because of its wide bandgap and higher atomic displacement energies, for devices intended for radiation environment applications. However, the radiation tolerance and reliability of SiC-based devices needs to be understood by testing devices under controlled radiation environments. These kinds of studies have been previously performed on diodes and MESFETs, but multilayer devices such as bipolar junction transistors (BJT) have not yet been studied. In this thesis, SiC material, BJTs fabricated from SiC, and various dielectrics for SiC passivation are studied by exposure to high energy ion beams with selected energies and fluences. The studies reveal that the implantation induced crystal damage in SiC material can be partly recovered at relatively low temperatures, for damag elevels much lower than needed for amorphization. The implantation experiments performed on BJTs in the bulk of devices show that the degradation in deviceperformance produced by low dose ion implantations can be recovered at 420 oC, however, higher doses produce more resistant damage. Ion induced damage at the interface of passivation layer and SiC in BJT has also been examined in this thesis. It is found that damaging of the interface by ionizing radiation reduces the current gain as well. However, for this type of damage, annealing at low temperatures further reduces the gain. Silicon dioxide (SiO2) is today the dielectric material most often used for gate dielectric or passivation layers, also for SiC. However, in this thesis several alternate passivation materials are investigated, such as, AlN, Al2O3 and Ta2O5. These materials are deposited by atomic layer deposition (ALD) both as single layers and in stacks, combining several different layers. Al2O3 is further investigated with respect to thermalstability and radiation hardness. It is observed that high temperature treatment of Al2O3 can substantially improve the performance of the dielectric film. A radiation hardness study furthermore reveals that Al2O3 is more resistant to ionizing radiation than currently used SiO2 and it is a suitable candidate for devices in radiation rich applications.
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| 3. |
- Widhe, Mona, 1971-
(författare)
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Immune responses in human lyme borreliosis : cytokines and IgG subclasses in relation to clinical outcome
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lyme borreliosis is a tick-borne infectious disease caused by the spirochete Borrelia burgdorferi sensu lato. The disease is characterised by several disease stages, where multiple organ systems might be affected, e.g. the skin, nervous system, heart or joints. The disease might lead to chronic symptoms of e.g. the nervous system, so called chronic neuroborreliosis (NB). The clinical features are often less severe in children, as compared to adults. The mechanisms responsible for the development of chronic symptoms are not fully established, but several factors might be involved. Probably the type of immune response elicited against the Borrelia spirochete during infection has implications on the clinical outcome, including development of chronic symptoms. Pro-inflammatory and type 1 responses are known to be efficient for elimination of pathogens, but may also be disease generating, whereas anti-inflammatory and type 2 responses are believed to regulate inflammation and possible tissue-harm, and have been reported in relation to resolution of symptoms in inflammatory diseases. In human Lyme borreliosis, mostly pro-inflammatory and type 1 responses have been reported previously.Aim: To examine selected aspects of the immune response- i.e. type 1/type 2 responses and pro-/anti-inflammatory responses - during the course of human Lyme borreliosis in patients with chronic and non-chronic manifestations, and in children vs. adults with NB, and to relate the type of immune response to the clinical outcome.Material and methods: Adult patients with the non-chronic manifestations erythema migrans and non-chronic NB or the chronic manifestations chronic NB and acrodermatitis chronica atrophicans (ACA), and children with NB were included in the study. Some of the adult patients were followed during the course of the disease. The Borrelia-specific cytokine production of interferon (IFN)-γ and interleukin (IL)-4 and the Borrelia-specific IgG subclass distribution were analysed as a measure of type 1 and type 2 responses, and the cytokinelevels of tumour necrosis factor (TNF)-α, IL-6 and transforming growth factor (TGF)-ß1 were analysed as a measure of the pro- and anti-inflammatory responses. IFN-γ and IL-4 were measured as number of cytokine secreting cells, using the sensitive method ELISPOT. Mononuclear cells were separated from blood and cerebrospinal fluid (CSF) and stimulated with a Borrelia antigen containing outer surface protein (Osp)A and OspB. Borrelia-specific IgG subclasses were measured in serum and CSF by ELISA using a flagellin-containing antigen. Levels of TNF-α, IL-6 and total TGF-ß1 were measured in serum and CSF by ELISA.Results: Adult patients with non-chronic NB showed a strong initial TNF-α and IFN-γ response in the CSF with production of the complement-activating and opsonizing IgG1 and IgG3. Subsequently, this inflammatory response seemed to be down-regulated by an upregulation of IL-4. TGF-ß1 was expressed during the entire follow-up period. Patients with EM showed the same pattern, with an early IFN-γ response, elevated levels of TGF-ß1 and a late up-regulation of IL-4. In addition, the children with early stage NB had elevated production of both IFN-γ and IL-4. The chronic NB patients, however, lacked early TNF-α in CSF and the subsequent up-regulation of IL-4, but showed persistent expression of IFN-γ. Furthermore, they did not show IgG3 or early TGF-ß1 in serum. Furthermore, ACA patients showed elevated IFN-γ late in disease.Conclusions: Altogether, the results suggest that good prognosis of human Lyme borreliosis is associated with a strong initial pro-inflammatory type 1 response, effective for elimination of Borrelia spirochetes, which is subsequently down-regulated by up-regulation of a type-2 response, and whose possible harmful effects might also be limited by TGF-ß1. Chronic manifestations, on the contrary, seem to be associated with lack of early pro-inflammatory responses, plausibly limiting their ability to eradicate the pathogen, followed by persistent inflammatory type 1 response, which might be self-destructive and disease-generating. In addition, the relative absence of type-2 responses in chronic manifestations may reduce the ability to limit the possibly harmful effects generated by long-standing IFN-γ. The results may have implications on future development of immuomodulatory treatments of chronic Lyme neuroborreliosis.
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