Low dose ionizing radiation and the immune response: what is the role of non-targeted effects?

This review aims to trace the historical narrative surrounding the low dose effects of radiation on the immune system and how our understanding has changed from the beginning of the 20th century to now. The particular focus is on the non-targeted effects (NTEs) of low dose ionizing radiation (LDIR) which are effects that occur when irradiated cells emit signals that cause effects in the nearby or distant non-irradiated cells known as radiation induced bystander effect (RIBE). Moreover, radiation induced genomic instability (RIGI) and abscopal effect (AE) also regarded as NTE. This was prompted by our recent discovery that ultraviolet A (UVA) photons are emitted by the irradiated cells and that these photons can trigger NTE such as the RIBE in unirradiated recipients of these photons. Given the well-known association between UV radiation and the immune response, where these biophotons may pose as bystander signals potentiating processes in deep tissues as a consequence of LDIR, it is timely to review the field with a fresh lens. Various pathways and immune components that contribute to the beneficial and adverse types of modulation induced by LDR will also be revisited.There is limited evidence for LDIR induced immune effects by way of a non-targeted mechanism in biological tissue. The literature examining low to medium dose effects of ionizing radiation on the immune system and its components is complex and controversial. Early work was compromised by lack of good dosimetry while later work mainly looks at the involvement of immune response in radiotherapy. There is a lack of research in the LDIR/NTE field focusing on immune response although bone marrow stem cells and lineages were critical in the identification and characterization of NTE where effects like RIGI and RIBE were heavily researched. 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.