Thesis (Ph.D.(Physiology))--University of the Witwatersrand, Faculty of Health Sciences, 2012. / The acute phase response is implemented by infected hosts in response to exposure to pathogens, including bacteria and viruses. Acute phase responses comprise physiological and behavioural changes, such as fever and a range of “sickness behaviours”, including lethargy and anorexia as well as impairment in learning and memory. Similar to other sickness behaviours, the effect of infection on learning and memory processes has been attributed to the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6). However, the exact role of IL-1β and IL-6 in mediating infection-induced cognitive impairment is not clear. Unlike fever, anorexia and lethargy, which may benefit an infected host, the physiological benefit of cognitive impairment during illness is doubtful. To initiate an acute phase response experimentally, moieties of typical bacteria (Gramnegative and Gram-positive) and viruses frequently are employed. Moieties from the atypical Mycoplasmas seldom have been used. Consequently, there is a dearth of information on the physiological mechanisms that underlie acute phase responses following Mycoplasma infection, despite the prevalence of the disease in the general population. Mycoplasma pneumoniae frequently causes community-acquired pneumonia, which may have serious extra-pulmonary complications, including cognitive deficits. Therefore, I investigated fever and sickness behaviours as well as cytokine responses in simulated, atypical Mycoplasma infection. I implemented an animal model of simulated Mycoplasma infection and characterised fever and sickness behaviours, including lethargy and anorexia as well as impairment in learning and memory during acute and recurrent acute simulated infection. I also characterized the response in the periphery and in the brain of individual pro-inflammatory cytokines, IL-1β and IL-6, to administration of fibroblast-stimulating lipopeptide-1 (FSL-1), which simulates Mycoplasma infection. Using rats, I recorded fever and lethargy with biotelemetry and assessed effects of simulated Mycoplasma infection on learning and memory using a Morris Water Maze. In addition, I examined the histology of tissue from the hippocampus, a key brain area involved in spatial learning and memory, to assess residual effects of simulated Mycoplasma infection on learning and memory. I showed that bolus administration of a pyrogenic moiety from Mycoplasma, fibroblaststimulating lipopeptide-1 (FSL-1), dose-dependently induced fever, lethargy, anorexia and body mass stunting in rats. However, FSL-1 administration did not induce concomitant impairment in spatial learning and memory. Importantly, at the time of testing in the Maze, I found the concentrations of IL-1β to be up-regulated in both the hypothalamus and the hippocampus, while the concentrations of IL-6 were unaffected. I also showed that recurrent acute injections of FSL-1, at 10 d intervals, induced recurrent fevers, lethargy and anorexia without the development of pyrogenic tolerance to any of the sickness responses measured. However, there was no residual body mass stunting in rats and also no growth retardation, despite the recurrent simulated infection. Equally importantly, there were neither lasting detrimental effects on spatial learning and memory nor any residual histological damage to the hippocampus of rats. My findings in simulated Mycoplasma infection are important, firstly because Mycoplasma infection is prevalent in both developing and developed countries and frequently causes outbreaks, and secondly because Mycoplasma infection affects children and adolescents of school-going age. My findings also are encouraging: although lasting detrimental effects, including impairment in learning and memory as well as body mass stunting may occur in other infections, these appear not to be inevitable outcomes in Mycoplasma infection.

Thesis (M.Sc. in Microbiology) -- Mahidol University, 1976.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 5 uppsatser.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on July 1, 2010). Includes bibliographical references.

The overall objective of this thesis work was to develop new insights into the etiology of scleroderma, a human systemic autoimmune disease, by analyzing the autoantibodies to centrosome antigens that develop during the disease. Centrosomes are perinuclear organelles that form microtubule arrays, including mitotic spindles that ensure the faithful segregation of chromosomes during mitosis. These studies used a novel methodology to determine the prevalence of anti-centrosome autoantibodies in patients with scleroderma. Recombinant centrosome antigens were used to determine the antigenic specificity of anti-centrosome antibody subsets by immunoblotting. Centrosome marker antibodies were used in indirect immunofluorescence assays to distinguish centrosomes within the polymorphic staining pattern frequently given by scleroderma sera. We found that 43% of patients are autoreactive to centrosomes, a prevalence higher than has been reported for any other scleroderma autoantigen. Half of the centrosome-positive patients also had autoantibodies against other antigens used in scleroderma diagnosis. However, in the remaining half of these patients, anti-centrosome antibodies represented the sole class of autoantibodies that was detectable. Anti-centrosome antibodies were detected in only a small percentage of normal individuals and patients with other connective tissue diseases. These data suggest that anti-centrosome autoantibodies may represent a new diagnostic tool in scleroderma. Upon examination of anti-centrosome autoantibody development in an animal model, it appeared that this autoantibody specificity may develop in mice as a consequence of an infection. An infectious agent was isolated by plaque-formation from carrier mice. Further characterization of the infectious agent was undertaken to obtain information on its physical, morphological and cytopathological properties. The infectious agent was identified by sequence and unique antigenic properties to be homologous to the pig pathogen Mycoplasma hyorhinis. When reintroduced into naive mice, the murine mycoplasma triggered anti-centrosome autoantibody development. While anti-centrosome autoantibodies of IgM isotype are part of the repertoire of naive unimmunized mice, mycoplasma infection specifically triggered the development of anti-centrosome IgG. Moreover, centrosome autoreactivity was prevented by antibiotic treatment. The autoantibody response evolved to recruit additional specificities, having IgM isotypes, reactive to endoplasmic reticulum-associated autoantigens.