Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from first page of PDF file (viewed on June 11, 2009). Includes bibliographical references.

This thesis explores the meaning and experience of the bodily states associated with the condition referred to as myalgic encephalomyelitis (ME). It uses as a theoretical point of departure an understanding of the body as a socially constructed phenomenon and, in so dOing, offers an interpretation of illness that is seen to differ markedly from those offered by the medical and behavioural sciences. Using descriptive narrative research analysis, the thesis attempts to elicit personal trajectories of illness experience. In contrast to biomedical and social trajectories of illness, in which the interpretation and meaning given to the condition are imposed externally, personal trajectories are seen to provide unique subjective accounts of illness experience. And the value of using narrative accounts of illness is seen to lie in their ability to bring to light these individualised versions of illness experience. It is shown, in addition, that these narrative accounts of illness are also valuable in exposing the culturally shared knowledge that is employed in the process of assigning meaning to illness experiences. The aim of the thesis, then, in employing the descriptive narrative research method is to describe these shared cultural schemas. It is suggested that this approach leads to an interpretation of illness experience which sheds light on important links between the body, self and society. It is argued, more specifically, that Western capitalist society is associated with the creation of an "unnatural" environment and social context which is perceived to be inherently damaging and threatening to the well·being of those living in it; and that this assumption is pivotal to the interpretation of the illness experiences narrated and analysed for the thesis. This sociological reading of embodiment provides a basis for understanding the experience of illness, as not one simply embedded in the body or mind of the individual, but as one laden with personal meaning assimilated from, and hence revealing of, the social context in which the illness is experienced. As such, an attempt is made to provide an account of illness experience distinct from the dominant biomedical and behavioural accounts of ME.

No description available.

Infections in the central nervous system pose a considerable challenge to the host. On one hand, a quick and rapid immune response is important to control the infection, while on the other hand, too robust a response can damage the CNS, which has poor regenerative properties. Therefore, nowhere else in the body is such a balance between pro- and anti-inflammatory mediators as important. Mice infected with the coronavirus, mouse hepatitis virus strain J2.2-V-1, are a useful model for understanding the two sides of the immune system. In this neurotropic viral infection, demyelination occurs secondary to the immune response's control of the viral infection. Thus, J2.2-V-1 infection also functions as an infectious animal model for multiple sclerosis (MS). Many arms of the pro-inflammatory immune system have been studied during J2.2-V-1 infection but the anti-inflammatory immune response has not been thoroughly investigated prior to this study. The data demonstrated here represent an in-depth look into the role of regulatory T cells and IL-10 during J2.2-V-1 infection. Specifically, by adoptive transfer of Tregs, I show that there is a relative paucity of Tregs during J2.2-V-1 infection in C57BL/6 mice and their addition decreases clinical scores, demyelination and the T cell response during infection without affecting viral clearance. A RAG1-/- adoptive transfer model demonstrates clinical results consistent with results obtained in B6 mice, while further demonstrating that Tregs function in the draining cervical lymph node by dampening dendritic cell activation and pro-inflammatory chemokine and cytokine release. There is also a relative decrease in T cell proliferation. Thus, Tregs are protective in J2.2-V-1-induced encephalomyelitis and their enhancement is a potential therapy for MS. Additionally, IL-10 is an important anti-inflammatory component of the immune response, as its absence causes increased immunopathology with increased demyelination in J2.2-V-1-infected B6 mice. Through the development of a recombinant J2.2-V-1 virus that produces IL-10, I also demonstrate that increasing the level of IL-10 at the site of infection is protective early in the immune response. Antigen-specific IFN-γ+ CD4 and CD8 T cells produce IL-10 at the height of the inflammation. CD8 T cells require a high level of antigen stimulation and the most recently activated CD69+CD8 T cells express high levels of IL-10. Additionally, this IL-10 expression is transient in both CD4 and CD8 T cells, presumably only by the recently stimulated cells. Through microarray analysis, protein expression and cytolytic assay, I show that IL-10+CD8 T cells are more activated than IL-10-CD8 T cells. Nonetheless, the IL-10 produced is anti-inflammatory and its production in CD8 T cells is protective in J2.2-V-1-infected mice. Thus, the most activated and cytotoxic CD8 T cells self-regulate the immune response through the production of IL-10. Overall, these studies show that the anti-inflammatory component of the immune system is vital to protecting the host from the immunopathology that occurs during J2.2-V-1 virus clearance. Specifically, the addition of Tregs and IL-10 helps ameliorate clinical disease and demyelination. These studies suggest that increasing Tregs and/or increasing the cytokine IL-10 in patients with MS may have therapeutic potential.

No description available.

Multiple Sclerosis (MS) and its corresponding animal model Experimental Autoimmune Encephalomyelitis (EAE) are autoimmune diseases of the central nervous system (CNS). Besides CD4+ T cells specific for myelin-derived antigens CD8+ T cells additionally contribute to the pathogenesis of that disease. However, the role of CD8+ T cells during the induction phase of the disease outside the CNS has not been clarified so far. Thus the contribution of CD8+ T cells to the immunopathogenesis of EAE in the Lewis rat was investigated in this work. For that purpose active EAE was induced in normal Lewis rats and animals that were deficient for CD8+ T cells due to the application of CD8-specific monoclonal antibodies. The CD8-depleted animals showed diminished disease activity in comparison to control rats. Equally, CD8-knockout rats, characterized by the absence of functional CD8+ T cells, developed clearly reduced symptoms of the disease in comparison to wild type littermates. Reduced disease activity of the CD8-deficient animals was accompanied by reduced infiltration of T cells and macrophages into the CNS. In the draining lymph nodes activated gpMBP-specific CD4+ T cells could be detected in the absence of CD8+ T cells, but they produced less amounts of proinflammatory cytokines like interferon-gamma than CD4+ T cells of normal rats. Obviously in the active EAE, myelin-specific CD4+ T cells are not able to differentiate completely into effector cells and invade the CNS upon absence of CD8+ T cells. In contrast fully differentiated encephalitogenic CD4+ effector cells equally potently induced EAE upon transfer into either normal or CD8-deficient rats. Hence, the pathogenic potential of completely differentiated CD4+ effector cells does not depend on the presence of CD8+ T cells. With the help of a rat-IFN-gamma ELISpot interferon-gamma-producing gpMBP-specific CD8+ T cells were detected in animals immunized with gpMBP. To directly detect gpMBP-specific CD8+ T cells, RT1.Al-Ig dimeres were generated and loaded with different gpMBP-derived peptides. Indeed, CD8+ T cells specifically recognizing RT1.Al-Ig dimeres loaded with gpMBP125-133 could be detected in the draining lymph nodes of rats, immunized with gpMBP in CFA. The results of this work allow the conclusion that in the EAE of the Lewis rat interferon--producing CD8+ T cells interact with myelin-specific CD4+ T cells, thus licensing these cells to differentiate into CNS invading effector cells. / Die Multiple Sklerose (MS) und ihr Tiermodell, die Experimentelle Autoimmune Enzephalomyelitis (EAE), sind Autoimmunerkrankungen des Zentralen Nervensystems (ZNS). Neben myelinspezifischen CD4+ T-Zellen tragen auch CD8+ T-Zellen zur Pathogenese dieser Erkrankungen bei. Allerdings ist die Rolle der CD8+ T-Zellen während der Induktionsphase der Erkrankung außerhalb des ZNS noch unklar. In dieser Arbeit wurde daher der Beitrag der CD8+ T-Zellen in der EAE der Lewis-Ratte näher untersucht. Dazu wurde die Krankheitsaktivität der aktiven EAE in normalen Lewis-Ratten mit Tieren verglichen, in denen die CD8+ T-Zellen durch CD8-spezifische monoklonale Antikörper depletiert wurden. Die CD8-depletierten Tiere zeigten dabei eine verminderte Krankheitsaktivität im Vergleich zu den Kontrolltieren. Ebenso entwickelten CD8 knockout Ratten, die durch die Abwesenheit funktionsfähiger CD8+ T-Zellen gekennzeichnet sind, deutlich reduzierte Krankheitssymptome im Vergleich zu wildtypischen Tieren. Die reduzierte Krankheitsaktivität in den CD8-defizienten Tieren war von einer verminderten Infiltration von T-Zellen und Makrophagen in das ZNS begleitet. Zwar konnten aktivierte gpMBP-spezifische CD4+ T-Zellen in den drainierenden Lymphknoten von CD8-depletierten Ratten detektiert werden, diese produzierten jedoch in deutlich reduziertem Umfang pro-inflammatorische Zytokine wie beispielsweise Interferon-. Offensichtlich können in der aktiven EAE myelinspezifische CD4+ T-Zellen in Abwesenheit von CD8+ T-Zellen nicht vollständig zu Effektorzellen differenzieren und infolgedessen das ZNS nicht infiltrieren. Umgekehrt konnten nach adoptivem Transfer von voll ausdifferenzierten enzephalitogenen CD4+ Effektorzellen sowohl in normalen als auch CD8-defizienten Empfängertieren gleich starke Symptome einer AT-EAE beobachtet werden. Die Entfaltung des pathogenen Potentials voll ausgereifter CD4+ Effektorzellen scheint somit nicht von der Präsenz von CD8+ T-Zellen abzuhängen. Mit Hilfe eines Ratten-IFN- ELISpots gelang erstmals die Detektion Interferon--produzierender gpMBP-spezifischer CD8+ T-Zellen in Tieren, die zuvor mit gpMBP immunisiert wurden. Zum direkten Nachweis von gpMBP-spezifischen CD8+ T-Zellen wurden RT1.Al-Ig Dimere generiert und mit verschiedenen gpMBP-Peptiden beladen. Tatsächlich konnten in den drainierenden Lymphknotenzellen von Ratten, die zuvor mit gpMBP in CFA immunisiert wurden, CD8+ T-Zellen detektiert werden, die gpMBP125-133-beladene RT1.Al-Ig Dimere erkennen. Die Ergebnisse dieser Arbeit legen insgesamt den Schluss nahe, dass bei der EAE der Lewis-Ratte Interferon--produzierende CD8+ T-Zellen in der Peripherie mit myelinspezifischen CD4+ T-Zellen interagieren und damit deren Differenzierung zu ZNS-infiltrierenden Effektorzellen ermöglichen.

Chronic Fatigue Syndrome (CFS) is a contested condition that generates scepticism and occupies a marginalised position within medical and social contexts. The thesis examines the illness experiences, and specifically the experiences of self, for people affected with CFS. Using qualitative inquiry, a substantive theory related to the process of self-renewal and adaptation associated with CFS is explicated. The theory encompasses the trajectory of CFS from onset to chronicity, and in exceptional instances, recovery. Illness narratives were derived from in-depth, semi-structured interviews of 19 adults, including 16 people affected with, and 3 people recovered from, CFS. Data was coded and analysed using a grounded theory approach. Analysis generated two parallel narratives that defined the illness experience of CFS: the narrative of the illness biographies and the narrative of self, specifically the struggling and diminished self seeking renewal. The illness biographies encompassed the stories of symptoms and their explanations, the encounters that ensued and their contentious milieu. The narrative of self was the primary narrative. It articulated the negative consequences to self and personhood associated with CFS, named the Violation of Self, and the consequent efforts of participants to decrease the struggle and violation by use of the Guardian Response and the Reconstructing Response. The Guardian Response provided protection and self-reclamation. The Reconstructing Response fostered self-renewal and meaning. The two narratives were bridged by the threats of CFS. That is, the illness biographies were accompanied by threats of disruption related to chronic illness, and by threats of invalidation that arose from CFS as a contested condition. In turn, these threats provided the catalyst to the violation and responses as described in the narrative of self. Under different conditions the relative strengths of violation, guardianship or reconstruction fluctuated, and it was these fluctuations that presented the participants with the ongoing struggle of CFS.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized by widespread focal areas of inflammation and demyelination. Although the exact cause of the disease is still not known, myelin-reactive T cells that enter the CNS trigger the disease and lead to the recruitment and activation of macrophages and other immune cells. One set of candidates that could serve to mediate these CNS changes is the family of phospholipase A2 (PLA2) enzymes, which consist of secreted (sPLA2) and cytosolic (cPLA2) forms. These enzymes hydrolyze membrane phospholipids to release free fatty acids (arachidonic acid) that can stimulate complex inflammatory cascades, and lysophospholipids that can induce myelin breakdown and demyelination, the two pathological hallmarks of MS. / For my Ph.D. research I studied the expression and role of different members of the PLA2 family in 'experimental autoimmune encephalomyelitis' (EAE), a widely used animal model of MS. I first generated a relapsing-remitting form of EAE in the C57BL/6 mouse strain that lacks a major form of sPLA2. I showed that cPLA2 is expressed by immune cells in the EAE lesions in the CNS. Furthermore blocking the activity of cPLA2 with a broad-spectrum chemical inhibitor starting at the time of EAE induction reduced the incidence and severity of disease, reduced lesion burden as well as reduced the expression of a number of chemokines and cytokines. Treating mice in the remission phase also prevented further clinical episodes. This showed that some or all members of the cPLA2 family play an important role in the onset and progression of EAE in a strain of mice lacking sPLA2. / I next carried out studies to assess the expression of all 14 members of the sPLA2 and cPLA2 families at the onset, peak and remission stages of EAE in the SJL/J mouse strain that expresses all forms of PLA2. The mRNA expression of only 4 of these PLA2s was increased. These include sPLA2 (groups IIA and V) and cPLA 2 (groups IVA and VIA). The expression of these PLA2s in the CNS was also characterized by double-immunofluorescence. The role of these PLA2s was assessed using selective inhibitors and analysed by monitoring the clinical disability scores, chemokine/cytokine protein arrays, lipomics lipid profiling, and histological analysis. Surprisingly, the sPLA2 inhibitor prevented disease remission and worsened the clinical outcome. This was accompanied by an increase in several pro-inflammatory chemokines. Selective inhibitors of cPLA2 group IVA and the calcium independent foam group VIA (iPLA2) reduced severity of EAE when given starting before onset of disease. The cPLA2 inhibitor treatment was effective only while administered, while iPLA2 inhibitor treatment was effective even after treatment was stopped. Furthermore, only delayed treatment with the iPLA2 inhibitor was effective, suggesting that cPLA2 group IVA only plays a role in the initiation of disease, while iPLA 2 plays a role in both disease onset and progression. These effects were also associated with concomitant reduction in chemokine/cytokine expression, reduction of inflammatory lipid mediators, and increase in protective lipids e.g., omega 3 fatty acids. / This work has allowed us to dissect out the expression and role of different members of the PLA2 family and has revealed the importance of selectively inhibiting some but not others in EAE. These findings may therefore have important implications for the treatment of MS.

Thesis (MEd (Distance Education))--Deakin University/University of South Australia, 1993