Multiple Chemical Sensitivity: Baseline cytokine profiling and characterization of airway immunological response and gene expression profiling upon chemical exposure

Thomas Meinertz Dantoft

    Research output: Book/ReportPh.D. thesis

    Abstract

    Multiple chemical sensitivity (MCS) is a chronic disorder characterized by reports of symptoms from various organ systems attributed by the individuals to exposure to common odors and airborne
    chemicals in doses far below those known to induce toxic effects. There exists a general lack of knowledge about the mechanisms underpinning the disorder and no diagnostic tools or evidencebased
    treatment strategies are currently available. Little progress has been made in regards to clarifying the pathophysiology of MCS, and it remains a controversial topic with many opposing opinions. For further progress in the field, it is thus essential, that more evidence about the pathophysiological mechanisms is generated.
    The objectives of the thesis were thus to review the existing knowledge on immunology, genetics and metabolic abnormalities in MCS as presented in manuscript I and to investigate levels of primarily immunological biomarkers in MCS via three separate studies presented in manuscript IIIV. A complementary investigation of selected biomarkers associated with alternative modes of actions was likewise examined by gene expression measures, as part of manuscript IV.
    The study presented in Manuscript II compared blood plasma levels of 14 cytokines, chemokines and growth factors between a MCS group (N = 150) and a sex and age-matched healthy control group (N = 149). The study observed significantly increased levels of cytokines interleukin (IL)-1β, IL-2, IL-4 IL-6, tumor necrosis factor-α in the MCS group, significantly reduced levels of IL-13 in the MCS group and no group differences in the allergen specific IgE measures. The differences were independent of factors such as sex, age, Body Mass Index, asthma, smoking, depression, anxiety and allergen-specific IgE. In conclusion, the study identified a distinct systemic immune mediator profile suggestive of low-grade systemic inflammation, along with a deviating Th2- associated cytokine response not involving IgE-mediated mechanisms. The two studies presented in manuscript III and IV are both based on biological samples collected from MCS subjects and matched controls at baseline, immediately after and four hours after a controlled chemical (n-butanol) exposure, in an exposure chamber previously verified to induce symptom elicitation in MCS subjects.
    In manuscript III, mucosal lining fluid samples were collected and levels of 19 cytokines and chemokines were quantified and compared between MCS subjects and healthy controls. The investigation did not identify any group associated differences in mediator levels, either at baseline or upon the exposure session. However, time dependent changes were identified for four of the 19 mediators, with decreasing mediator levels observed over time in both MCS subjects and healthy controls. Overall, the findings suggest that the exposure session did not trigger a local inflammatory response and that symptom elicitation in MCS is not dependent or affected by secretion of immunological mediators from epithelial or immune cells in the upper airways.
    Manuscript IV presents an explorative study investigating the feasibility of using gene expression profiling as an analytical tool for biomarker discovery in MCS and to study the pathogenic mechanisms, based on differential gene expression regulation upon the symptom elicitation. Expression levels of 26 genes associated with MCS were quantified in white blood cells, nine genes showed low expression levels and were excluded while expression levels of the remaining genes were compared between the groups at each time of sampling. The study did not identify any significant group differences in gene expression levels of unexposed subjects or in the samples collected after the exposure session. As an effective measure of the longitudinal responses to the exposure session, an integrated area under the curve (AUC) value was computed for each gene and the AUC data revealed an increase in IL-6 expression in the MCS group and a tendency toward increased expression of in IL-10 and acid ceramidase. In general, the data revealed a non-significant overall increase in transcription rates associated with MCS and a larger intragroup variation among MCS subjects, indicative of a diversified physiological reaction to the exposure. Overall, the findings presented in this thesis support the hypothesis of abnormal regulation of the immune system in MCS subjects as a component in MCS pathophysiology, but were unable to reveal new correlations between symptom elicitation and gene transcription in MCS.
    Original languageEnglish
    PublisherDepartment of Systems Biology, Technical University of Denmark
    Number of pages205
    Publication statusPublished - 2015

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