The historical narrative and our understanding about the low dose effects of radiation on the immune system has changed drastically from the beginning of the 20th century to now. A paradigm shift from the DNA target hit model to the one that also considers non-targeted effects (NTE) has attracted a lot of interest recently. Investigations to delineate mechanisms of NTE in the biological tissue have been carried out by various research groups where radiation induced genomic instability (RIGI), bystander effect (RIBE) and abscopal effect (AE) are the effects with most evidence available. This thesis addresses the question of whether low dose ionizing radiation (LDIR) stimulates or suppresses the immune system and how NTEs contribute to this immune modulation by adopting a two-pronged approach where first a narrative review constituting the introduction and literature review was performed followed by a systematic review using PRISMA guidelines to synthesize existing LDIR literature. This was prompted by our recent discovery that UVA photons are emitted by the irradiated cells and that these photons can trigger bystander effects in unirradiated recipients of these photons. Given the well-known association between UV radiation and the immune response, where these biphotons may pose as bystander signals potentiating processes in deep tissues as a consequence of ionising radiation, it is timely to revisit the field with a fresh lens. After reviewing various pathways and immune components that contribute to the beneficial and adverse effects induced by LDIR, it was found that these modulations can occur by way of NTE. However, the exact mechanistic underpinnings are still unclear and the literature examining low to medium dose effects of ionising radiation on the immune system is complex and controversial. Early work was compromised by lack of good dosimetry while later work mainly focuses on the involvement of immune responses in radiotherapy which typically uses high dose radiation. There is a lack of research in the LDIR/NTE field focussing on immune responses although bone marrow stem cells and lineages were critical in the identification and characterisation of NTE. This may be in part, a result of the difficulty of isolating NTE in whole organisms which are essential for good immune response studies. Models involving inter organism transmission of NTE are a promising route to overcome these issues. It is concluded that the simple question of whether LDIR stimulates or suppress the immune system is not as simple as initially hypothesized. An attempt was made to analyze if LDIR shifts the balance to immune suppression or enhancement via systematic review but, due to too many differences in the experimental methods in the current radiation and immune studies, a cookie-cutter answer was not possible. However, this thesis did point out the areas of concern such as lack of standardised tools in the field of radiobiological experimental research and quality of methods used which requires urgent attention. / Thesis / Master of Science (MSc)

Fifty percent of solid cancers are treated with radiation therapy (RT). The dose used in RT is adjusted to the most sensitive individuals so that not more than 5% of the patients will have severe adverse healthy tissue effects. As a consequence, the majority of the patients will receive a suboptimal dose, as they would have tolerated a higher total dose and received a better tumor control. Thus, if RT could be individualized based on radiation sensitivity (RS), more patients would be cured and the most severe adverse reactions could be avoided. At present the mechanisms behind RS are not known. The long term aim of this thesis was to develop diagnostic tools to assess the individual RS of breast cancer patients and to better understand the mechanisms behind the RS and radiation effects after low dose exposures. The approach was based on the hypothesis that biomarkers of individual RS, in terms of acute adverse skin reactions after breast cancer RT, can be found in whole blood that has been stressed by low doses of ionizing radiation (IR).  To reach this goal two different approaches to identify biomarkers of RS have been investigated. A protocol for the analysis of differential protein expression in response to low dose in vitro irradiated whole blood was developed (paper I). This protocol was then used to investigate the proteomic profile of radiation sensitive and normo-sensitive patients, using isotope-coded protein labeled proteomics (ICPL). The results from the ICPL study (paper III) show that the two patient groups have different protein expression profiles both at the basal level and after IR. In paper II the potential biomarker 8-oxo-dG was investigated in serum after IR. The relative levels of IR induced 8-oxo-dG from radiation sensitive patients differ significantly from normo-sensitive patients. This indicates that the sensitive patients differ in their cellular response to IR and that 8-oxo-dG is a potential biomarker for RS. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p>