Browsing by Author "Adams, Rozanne Charlene McChary"

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    In utero exposure to maternal chronic inflammation transfers a pro-inflammatory profile to generation F2 via sex-specific mechanisms
    (Frontiers Media, 2020) Adams, Rozanne Charlene McChary; Smith, Carine
    Generational transfer of maladaptations in offspring have been reported to persist for multiple generations in conditions of chronic inflammation, metabolic and psychological stress. Thus, the current study aimed to expand our understanding of the nature, potential sex specificity, and transgenerational plasticity of inflammatory maladaptations resulting from maternal chronic inflammation. Briefly, F1 and F2 generations of offspring from C57/BL/6 dams exposed to a modified maternal periconception systemic inflammation (MSPI) protocol were profiled in terms of leukocyte and splenocyte counts and cytokine responses, as well as glucocorticoid sensitivity. Overall, F1 male and female LPS groups presented with glucocorticoid hypersensitivity (with elevated corticosterone and increased leukocyte glucocorticoid receptor levels) along with a pro-inflammatory phenotype, which carried over to the F2 generation. The transfer of inflammatory and glucocorticoid responsiveness from F1 to F2 is evident, with heritability of this phenotype in F2. The findings suggest that maternal (F0) perinatal chronic inflammation resulted in glucocorticoid dysregulation and a resultant pro-inflammatory phenotype, which is transferred in the maternal lineage but seems to affect male offspring to a greater extent. Of further interest, upregulation of IL-1β cytokine responses is reported in female offspring only. The cumulative maladaptation reported in F2 offspring when both F1 parents were affected by maternal LPS exposure is suggestive of immune senescence. Given the potential impact of current results and the lack of sex-specific investigations, more research in this context is urgently required.
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    Influence of maternal inflammation on immune modulation
    (Stellenbosch : Stellenbosch University, 2020-03) Adams, Rozanne Charlene McChary; Smith, Carine; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Perturbations within intrauterine microenvironment, due to maternal stressors such as chronic inflammation, metabolic dysfunction and psychological stress, can result in lifelong detrimental consequences in affected offspring. Given the substantial contribution of noncommunicable diseases to the global morbidity and mortality rate, the potential impact of maternal prenatal chronic disease on foetal development is of increasing concern. Additionally, inheritance of these developmental defects, such as behavioural, neurological, glucocorticoid and immune maladaptations, can persist for multiple generations in offspring. Although inflammation that forms part of the aetiology of chronic diseases, very few studies have reported on the immunological and glucocorticoid maladaptations in offspring exposed to maternal inflammation. Moreover, even less is known about the extent of this generational transfer, the sex-specific inheritance or the transgenerational plasticity of these maladaptations in the F1 and F2 generations. Thus, we aimed to delineate the immune functionality and glucocorticoid sensitivity in leukocytes in two generations of offspring in a mouse model of chronic induced maternal inflammation. Pregnant C57/BL/6 (F0) dams were exposed to either 10µg/kg lipopolysaccharide (LPS) or 0.9% saline (control) every seven days for the duration of gestation, with no further intervention after gestation. At 8 weeks of age, the F1 offspring were crossed with either a wild-type untreated C57/BL/6 mate or F1 LPS-affected non-sibling mate to create the second generation of offspring, F2. For experimental analyses, F0, F1 and F2 mice were profiled to assess the changes in differential splenic and circulatory leukocyte populations, corticosterone concentrations, splenic leukocyte glucocorticoid sensitivity and ex vivo cytokine responses. LPS-treated F0 dams displayed augmented glucocorticoid receptor expression in splenic leukocytes, which transferred to both F1 and F2 offspring, as well as elevated inflammatory cytokine responses in LPS-stimulated splenocytes. Both male and female F1 offspring displayed glucocorticoid hypersensitivity, indicated by elevated corticosterone and leukocyte glucocorticoid receptor levels, as well as a heightened inflammatory phenotype, which was transferred to F2. However, no sex-specific traits were observed. Interestingly, F1 LPS-affected offspring displayed sex-specific transfer of inflammatory effects to F2. The glucocorticoid dysregulation and the resultant pro-inflammatory phenotype appeared to be transferred in the F1 maternal lineage to her F2 offspring, affecting the male offspring to a greater extent. In contrast, F1 LPS males only transferred a pro-inflammatory phenotype to their offspring. The cumulative inheritance of maladaptation in F2 offspring, from F1 maternal and paternal lineages being LPS-affected, displayed blunted functional immune responses, and dampened glucocorticoid levels, but unchanged leukocyte numbers and may be suggestive of immune senescence. This study contributes to the knowledge of inheritance of susceptibility to noncommunicable chronic diseases. Our findings illustrate that parental chronic inflammation may cause lifelong reprogramming to a maladapted pro-inflammatory phenotype, persisting to at least two subsequent generations of offspring. Moreover, divergent adverse outcomes are seen in F2 offspring, in terms of sex-differences and cumulative inheritance of inflammatory effects. Given the potential impact of these findings, more focussed research in this context is required to confirm and further characterise the mechanisms underlying this paradigm, to facilitate the development of future interventions.
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    Ontogeny of the innate immune response in healthy South African infants
    (Stellenbosch : Stellenbosch University, 2012-12) Adams, Rozanne Charlene McChary; Esser, Monika Maria; Kollmann, Tobias; Bouic, Patrick J. D.; De Beer, Corena; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.
    ENGLISH ABSTRACT: Infection is a major cause of morbidity and mortality in infants within the first few months of life. Susceptibility to infectious disease in this vulnerable population is more prevalent in resource-limited regions, with a higher disease burden. Due to certain deficiencies in their adaptive immune system, neonates rely predominantly on their innate immune system for protection against infection, a vital component in the early host defence against pathogens. Several studies have described differences in neonatal innate toll-like receptor-mediated responses compared to adult counterparts, though very little is known about these receptor responses within resource-limited settings. To address this issue, we assessed the longitudinal development of cytokine-specific responses of TLR4 and TLR7/8 in monocytes, myeloid dendritic cells and plasmacytoid dendritic cells in infants from a resource-limited setting, South Africa, within the first 12 months of life and compared it to adults. Contrary to previously published literature, we observed heightened production of TH-1 cytokines: we showed increased responsiveness to TLR4 and TLR7/8 stimulation in infants at two and six weeks of age, which may be due to vaccination administered at birth. Unexpectedly, the hyper-inflammatory response persisted at six months in response to the LPS (TLR4) stimulus. This increased response at six months may be attributed to decreased passive immunity through infant weaning as well as increased exposure to microbial pathogens in this setting. Maturation of most cytokine responses was reached at twelve months for the TLR4 receptor, and at six months for the TLR7/8 receptor. The first year of life represents a critical period for maturation of the immune response. Data from this study point towards an elevated response within the first six months of life. This heightened response reflects both an ability to mount a sufficient TH-1 response in infancy, but more likely, the increased exposure to microbial stimuli in the environment. Thus, we speculate that these age-specific inflammatory responses may influence the outcome of immune responses to various vaccines administered, which may result in altered responsiveness to immunisation in infancy.