Table 2.
Overview of studies describing immunological changes in people exposed to different scenarios of irradiation.
| Citation | Population/Site | Collective & Numbers | Dose | Endpoints | Remarks & Conclusions |
|---|---|---|---|---|---|
|
| |||||
| Acute and chronic exposure | |||||
| (Ito et al., 2017) | A-bomb survivors | Cohort, 165 human tissue blocks from RERF archive | no (<5 mGy), low (5–200 mGy), moderate-to-high (<200 mGy) exposure; 11 unexposed controls | Immunohistology of thymus from pathology archive | Low dose is sufficient to result in decreased thymic function many years after exposure (years from exposure 9–41), accelerated thymus aging (involution) |
| (Kusunoki et al., 1998) | A-bomb survivors | Cohort, 159 exposed, 234 controls (<0.05 Gy) | 1) <5 mGy; 2) >5 mGy to >1.5 Gy | PBMCs by flow cytometry, subsets of T, B, NK cells | A-bomb radiation might have triggered dominant Th2-cell responses, stimulating B-cell lymphopoiesis for a long period. |
| (Kusunoki et al., 2003) | A-bomb survivors | Cohort, 1280 individuals | 2 groups: <5 mGy and >5 mGy | Subsets of CD4+ T cells | Memory CD4+ T-cells of individuals who received significant radiation doses in adulthood may have become dependent on a much less TCR Vβ families than unexposed |
| (Kusunoki et al., 2010) | A-bomb survivors | Cohort, 1035 individuals between 2006 and 2008 | dose categories: <5 mGy, 5 mGy–0.5 Gy, 0.5 Gy–1.0 Gy, 1.0 Gy–4.0 Gy | PBMCs by flow cytometry, plasma TNF-alpha level (only a subgroup) | A-bomb survivors may have induced T-cell immunosenescence resulting in attenuation of T-cell-mediated immunity. |
| (Kyoizumi et al., 1992) | A-bomb survivors | 203 A-bomb survivors, 6 Thorotrast patients, 18 thyroid disease patients; one Chernobyl person with high accidental exposure | A-bomb survivors: 1) <5 mGy (n = 125); 2) >1.5 Gy (n=78) | Mutation frequency of T-cell receptor (TCR) in PBMCs: flow cytometry with CD3 and CD4 antibodies assuming that mutant CD4+ T cells have only a small fraction of CD3 expression | No significant dose effects in A-bomb survivors. |
| (Kyoizumi et al., 2010) | A-bomb survivors | Cohort, 916 individuals | dose categories: <5 mGy, 5 mGy–0.5 Gy, 0.5 Gy–1.0 Gy, 1.0 Gy–4.0 Gy | PBMCs characterized by flow cytometry: subsets of memory T-cells by CD43 level | The steady state of the T-cell memory, which is regulated by cell activation and/or cell survival processes in subsets may have been perturbed by prior radiation exposure. |
| (Lustig et al., 2016) | A-bomb survivors | Cohort, 415 individuals, 2 time points: 55 and 66 years after exposure | 3 exposure groups: 157 with no dose (<5 mGy), 123 with low (5 mGy–700 mGy), 135 with high (>700 mGy) dose | T cell counts, telomere length; serum cytokines, c-reactive protein (CRP) | Radiation damage drives changes in telomere length that persist in the progeny over half a century and therefore likely derived from the initial lesion. Radiation damage seems more severe in the young than the old. Telomere shortening likely cause functional defects that in the case of lymphocytes would lead to less T cell immunity and less myeloid function (less inflammatory cytokines). |
| (Yoshida et al., 2016) | A-bomb survivors | Cohort, 620 participants | dose range 0–1.736 Gy | PBMCs: telomere length of naïve and memory CD4+ T cells, total CD8+ T cells; metabolic status | Radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals. |
| (Yoshida et al., 2019) | A-bomb survivors | Cohort, 14,349 participants | 3 dose groups; <1 Gy (n = 1616), >1 Gy (n = 9393), control (not-in-town, n = 3340) | Longitudinal statistical analysis of blood cell counts | Radiation exposure might accelerate aging-associated clonal haematopoiesis, which could result in a long-lasting elevation of circulating monocytes. |
| (Ilienko et al., 2018) | Chernobyl | 235 Chernobyl accident male clean-up workers exposed in 1986–1987; 45 matched non-exposed controls | Mean dose ± SD: 419.48 mSv ± 654.60; range 0.10–3,500 mSv | Lymphoctes: gene expression of candidate genes: BCL2, CDKN2A, CLSTN2, GSTM1, IFNG, IL1B, MCF2L, SERPINB9, STAT3, TERF1, TERF2,TERT, TNF, TP53, CCND1; relative telomere length; immune cell subsets, γ-H2AX and CyclinD1. | Cellular immunity, gene expression, telomere length, intracellular protein parameters are shown to be among perspective biological markers at a late period after radiation exposure. |
| (Kuzmenok et al., 2003) | Chernobyl | Chernobyl healthy clean up workers from Belarus: 134 workers and 89 matched controls | Dose estimation: 150 mGy–500mGy | PBMCs; isolated T-cells; mitogen stimulation | An approach to a more accurate analysis of the immunological disorders found after exposure to radiation from Chernobyl-related activities. |
| (Oradovskaia et al., 2011a) | Chernobyl | Liquidators, comparison of different time points (1986, 1987) and working conditions | Differences by time and timing of liquidation work | PBMC subpopulations; immunoglobulins | Specific features of changes in the immune system depend on dose of external gamma-irradiation. However, distinctions in the age dynamics of the immune system in liquidators in the presence and in the absence of cancer manifested themselves in a stable level of CD3+, CD4+, CD8(+)-T-lymphocytes, immune regulation index, CD95+, serum IgA at the age between 40 and 70 years. |
| (Saenko et al., 2000) | Chernobyl | 57 liquidators, 21 controls | Physical dosimetry from official records; Chernobyl liquidators <0.25 Gy | erythrocyte variant cells bearing a mutated glycophorin A (GPA) surface marker | In Chernobyl clean-up workers the TCR mutant frequency was significantly higher than in control non-irradiated individuals. |
| (Chang et al., 1999a) | Home environment, Taiwan | 196 exposed residents with 2–13 years of exposure in their homes; 55 close relatives non-exposed | Protracted gamma-radiation, mean excess cumulative dose: 169 +/− 272 mSv; mean annual excess dose 24+/− 29.9 mSv | blood: lymphocyte subpopulations | Significant immunological effects were observed in those who received chronic low-dose radiation exposure. |
| (Jain and Das, 2017) | Kerala, India | Cohort, 36 healthy male individuals, age 28–52 living in different level natural background radiation areas | 5 dose groups based on annual background dose received; I (control): <1.5 mGy/year; II: 1.51–5.0 mGy/year; III: 5.01–15.0 mGy/year; IV: >15 mGy/year; individual dosimetry | Gene expression in PBMCs, gene ontology, pathway analysis | Individuals exposed to background doses of >5 mGy/year showed alterations in the expression of genes involved in immune system-related pathways. |
| (Takahashi et al., 1999) | Marshall Islands | Cohort, 4766 individuals aged to be at risk from exposure of radioactive fallout by the US nuclear testing programme on Bikini and Eniertah atoll (1946 and 1958) | No dose estimation provided | Thyroid examination by ultrasound, thyroid hormone determination, anti-thyroid antibodies, questionnaire, iodine status (urine samples) | Dietary intake of iodine needs to be taken into account when looking at the link between radiation exposure and thyroid nodules. |
| (Attar et al., 2007) | Ramsar, Iran | 100 individuals from villages with high level natural background radiation (HLNBR) and villages with low background radiation | 13 times higher than normal in HLNBR area | PBMCs for functional assays, cytokines IL-2, IL-4, IL-10, IFN-gamma | Immune system adaptation in individuals living in high natural radiation background areas |
| (Borzoueisileh et al., 2013) | Ramsar, Iran | 50 individuals aged 25–35 years, exposure duration 10–35 years, different level natural background radiation areas | estimated dose of 10.2–260 mSv/year in Ramsar area | Flow cytometry of PBMC subpopulations: CD4+/CD45+ (T-helper-cells), CD8+ (cytotoxic T-cells), NK cells and CD107a-cells | Multiple immune system alterations |
| (Ghiassi-nejad et al., 2002) | Ramsar, Iran | Individuals from HLNBR areas vs normal background radiation area | Annual radiation absorbed dose from background radiation up to 260 mSv/year | chromosome aberrations after in vitro challenge dose with 1.5 Gy | An adative response in terms of chromosomal aberrations induced by chronic low dose exposure |
| (Ghiassi-Nejad et al., 2004) | Ramsar, Iran | 50 exposed individuals from HLNBR area aged 40+/−16 years; 30 matched controls | Estimated annual effective dose: 1.6–42 mSv/year; 2.3 mSv/year for controls | Immunoglobulins IgM, IgG, IgA, IgE, complement (C3, C4, C1-inactivator), rheumatoid factor, CRP; flow cytometry of PHA stimulated and unstimulated PBMCs with CD3, CD4, CD5, CD69 markers; cytogenetic analysis | Stimulation of Th2 response is discussed |
| (Molaie et al., 2012) | Ramsar, Iran | Subjects from high and low level natural background radiation areas | high and low natural background radiation | Neutrophil chemotaxis, Nitro-Blue Tetrazolium (NBT), antioxidant effects, cytokines (IL-2, IL-4) levels | The level of IL-4 increased in individuals who lived in area with high levels of natural radiation, which could lead to Th2 pattern of immune response |
| (Akleyev et al., 2019) | Techa River, Mayak area | Cohort, 66 residents of the Techa River basin contaminated due to release of liquid radioactive waste from the Mayak Production Association (Plutonium) in 1952; groups: 29 people with vs 37 people without increased TCR-mutations | Dose estimation according to the Techa River Dosimetry system 2009 (TRDS-2009): main group (TCR-mutations): dose rate to bone marrow 0.21+/− 0.02 Gy/year 1951, absorbed dose = 0.89+/−0.09 Gy (individual 0.09–1.96 Gy) comparison group: dose rate to BM 0.25+/−0.02 Gy/year 1951; absorbed dose = 1.03 +/− 0.07 Gy (range 0.03–2.34 Gy) | Number of CD19+, CD3+, CD3+CD4+, CD3+CD8+, CD3+CD4+/CD3+CD8+ cell ratio, immunglobulins (IgA, IgM, IgG); number of neutrophils, monocytes and their phagocytotic, lysosomal activity and intensity of intracellular oxygen-dependent metabolism; eosinophils, basophils, CD16+CD56+ and CD3+CD16+CD56+ lymphocytes; cytokines; colony stimulating factors: GM-CSF, G-CSF, TNF-alpha; IFN-alpha, IFN-gamma lymphocyte subsets; 30 cytokines | Low dose exposure induced long term changes of the innate immune system; immune system seems to react to DNA damage driving innate immune cell activation in an effort to eliminate TCR-mutated lymphocytes other than by apoptosis |
| (Li et al., 2019) | Yangjiang district, China | 100 women exposed to HLNBR, 100 matched controls | estimated cumulative dose in exposed group: 58.5–249.13 mSv | Immune function was found to be affected in humans exposed to long-term low dose radiation: increase in CD8+ T-cell numbers and upregulated inflammatory biomarkers like IFN-gamma, MCP-1, sIL6R, EGFR, CRP | |
| (Gyuleva et al., 2015a) | Nuclear power plant workers | Nuclear Power Plant (NPP) ‘Kozloduy”, Bulgaria. 438 persons working in NPP; 10 year survey | Cumulative doses between 0.06 mSv and 766.36 mSv and a control group with 65 persons | Flow cytometry of lymphocyte subpopulations, serum levels of IgG, IgA, IgM | Assumption that while the adaptation processes are dominated with low prevalence of T-helper 1 (Th1) immune response to cumulative doses <100 mSv, a switch to TH-2 response occured at doses >100 mSv. |
| (Gyuleva et al., 2015b) | Nuclear power plant workers | NPP “Kozloduy”, Bulgaria. 438 persons working in NPP; 10 year survey | Cumulative doses between 0.06 mSv and 766.36 mSv and a control group with 65 persons; | Flow cytometry measurements of T, B, natural killer (NK) and natural killer T (NKT) cells | Some of the studied parameters could be interpreted in terms of adaptation processes at low doses. At doses above 100–200 mSv, compensatory mechanisms might be involved to balance deviations in lymphocyte subsets. Some observed variations in some cases on the immune system might be due to other unknown factors. |
| (Gyuleva et al., 2018) | Nuclear power plant workers | NPP “Kozloduy”, Bulgaria. 105 employees | control, 4 dose groups: <25 mSv; <100 mSv; <200 mSv; > 200 mSv | lymphocyte subpopulations; serum IgG, IgM, IgA; IL-2, IL-4, IFN-gamma | The observed even slight trends in some lymphocyte populations and in cytokines profile allow to assume a possibility of a gradual polarization of Th1 to Th2 immune response at dose range 100 to 200 mSv. |
| (Rees et al., 2004) | NPP workers | British Nuclear Fuels, Sellafield: 194 male radiation workers >200 mSv (mean 331.5 mSv); 131 workers <27.5 mSv (mean 13.9 mSv) | Film badge dosimetry over 30.6 years vs 23.9 years; cumulative exposure >200 mSv vs <27.5 mSv | PBMCs: T cell and B cell subsets | No significant immunological effects in male radiation workers at >200 mSv compared to <27.5 mSv; smoking is an important confounding variable. |
| (Ahmad et al., 2016) | Radiology workers | 60 healthy individuals working in different medical diagnostic units: 20 exposed, 40 matched controls | mean dose: 2.03 mSv/year; duration of radiation exposure: 16 years | Superoxide, DNA oxidation, cytokines | The data suggest a pro-inflammatory response at doses above 17 mSv. A threshold and non-linearity is discussed. |
| (Godekmerdan et al., 2004) | Radiology workers | 50 radiology workers vs 35 age-matched healthy controls, mean age 30.1 +/− 7 vs 31.5 +/−5.8 years; 48% vs 0% smokers; | <3.5 mSv/year for 86%; the rest received above that; exposure time >5 years in 48% | Subgroups of PBMCs; serum complement and Igs | T helper cell and humoral immune components are compromised. |
| (Karimi et al., 2017) | Radiology workers | 30 radiology workers vs 20 control laboratory workers | Exposure <50 mSv | PBMCs, PHA stimulation assay; serum cytokines | No dose response tested. A shift towards Th1 responses by low dose radiation is discussed. |
| (Klucinski et al., 2014) | Radiology workers | X-ray diagnostics units: 47 workers (14 men, 33 women); control group 38 (10 men, 28 women) non-exposed | Period of employment: 1–33 years with annual effective dose < 1 mSv | Flow cytometry of B-cell subsets: B-cells (CD19 +), B1-cells (CD5+ CD19+), memory B-cells (CD27+ CD19+) | Association of suppressive influence of low level ionizing radiation on B and memory B-cells is discussed. |
| (Rybkina et al., 2014) | Mayak production workers | Mayak Production Association workers cohort; 91 workers and 43 controls | 14 workers exposed to external gamma-rays (total dose 05–3.0 Gy), 77 workers with combined exposure (external gamma-rays and internal alpha radiation from incorporated plutonium) | Cytokines: TGF-beta1, TNF-alpha, IFN-gamma, IL-1beta, IL-8; immunoglobulins: IgM, IgG, IgA, IgE; p53, HSP70, MMP-9; lymphocyte subsets | Chronic occupational IR exposure of workers induced a depletion of immune cells in peripheral blood |
| (Zakeri et al., 2010) | Interventional cardiologists | 37 interventional cardiologist vs 37 control; | 8.14 mSv/year (range 1.2–27.8) for 12.1 +/− 6.6 years and an accumulated dose over the last 5 years of 30.5 +/− 24.3 mSv | serum cytokines and Igs; cytokine release from activated lymphocytes, PBMC phenotypes | No dose response observed due to low case numbers |
| Studies on radiation-exposed children | |||||
| (Imaizumi et al., 2008) | A-bomb survivors | A-bomb survivors exposed in utero; 328 persons (mean age 55.2 year; 162 male); examination 55–58 year after exposure in utero | mean maternal uterine radiation dose 0.256 Gy; <5 mGy, 5 mGy–0.1 Gy, 0.1–0.5 Gy, 0.5–1 Gy, > 1 Gy | Thyroid: solid thyroid nodules and cysts; blood: antithyroid antibodies (ATAs): antithyroperoxidase (TPO-Ab) and antithyroglobuline (TgAb) | Antithyroid antibodies were not associated with dose or gestational week at exposure. No significant dose–response relationship for autoimmune thyroid disease in the in utero-exposed subjects (similar to exposed children). |
| (Chang et al., 1999) | Home environment, Taiwan | 289 children exposed at kindergarden in 1983–92 to continuous low dose Co-60 gamma irradiation vs 751 aged- and sex-matched exposed to lower dose, studied 5–7 years later | High dose group estimated 21–85 mSv in total (200–800 chest X-rays) compared to low dose group 2–5 mSv (20–50 chest X-rays) | Blood draw for basic differential blood counts | Persistent changes in haematopoietic system following chronic low dose expsoures in the observed children. |
| (Agate et al., 2008) | Chernobyl | Cohort, 1433 sera from adolescents 13–17 years (born 1982–1986); additional 1441 control sera from aged-matched and sex-matched children in Denmark and Sardinia | Contaminated areas included Klintsy (Russia), Korosten (Ukraine) and Lelchitsky (Belarus) at 555–1480 kBq/m2; iodine deficiency prevalent in both contaminated and non-contamined areas; | ATAs: TPO-Ab, TgAb; thyroid function based on circulating levels of thyroid-stimulating hormone (TSH) and free triiodothyronine (FT3) and thyroxine (FT4) | TPO-AB prevalence in adolescents exposed to radioactive fallout was still increased in Belarus 13–15 years but a lot less than at 6–8 years after the Chernobyl accident but normal thyorid function possibly suggests a transient radiation-induced autoimmune reaction without triggering clinical thyorid autoimmune disease. |
| (Chernyshov et al., 1997) | Chernobyl | 120 children aged 6–13 years from 15 radiation-contaminated areas in North Ukraine after Chernobyl accident with/withour recurrent respiratory disease (RRDC); 87 children from non-contaminated areas with/without RRDC | Exposed children from areas within a 40–75 km radius from the reactor; estimated dose of Cs-137 and Sr-90 of 0.57–3.09 mSv over 3 years; two groups < or >1 mSv | Major lymphocyte subsets analysed in whole blood by flow cytometry | Long-time exposure to low radiation doses may affect the immune balance, especially in vulnerable populations. |
| (Kasatkina et al., 1997) | Chernobyl | 89 children from Uritzky region (416 km north of Chernobyl); 116 non-contaminated Kolpnyansky area; 2 age groups: age at exposure in utero (n = 89 and n = 100 controls) or 8–9 years (n = 81 and n = 97 controls) | Average Cs-137 soil contamination 1.71 Ci/km2 (range 0.18–3.97) | Thyroid dimension by clinical exam and ultrasound; thyroid function (hormones); autoantibodies; fine needle aspiration | Autoimmune thyroid disease markedly increased in children with poor iodine nutrition who were exposed to low level radiation. Low level radiation may induce thyroid gland changes in children who had inadequate iodine intake. |
| (Pacini et al., 1998) | Chernobyl | 472 patients with thyroid carcinoma from Belarus diagnosed at <21 year compared to aged-matched controls with thyroid carcinoma from Italy and France: a) <14 year children (n = 372); b) adolescent 14–21 year (n = 100); | Radioactive contamination I-131 in Belarus: ranging from 185 to 37,000 kBq/m2 | Thyroid immunity and function: T4, T3, TSH, thyroid ATAs: TPO-Ab, TgAb | Young children (<5 year) are especially vulnerable to radiation-induced thyroid cancer that tend to be more aggressive in nature and associated with signs of thyroid autoimmunity |
| (Sheikh Sajjadieh et al., 2012) | Chernobyl | Chernobyl area: children aged 4–18 years with/without diagnosed irritable bowel disease | Internal whole body radioactivity due to Cs-137; group1 (21 children aged 4–9): 1.9 Bq, group2 (26 children aged 10–13): 1.85 Bq, group3 (28 children aged 14–18): 2.01 Bq, group4 (21 healthy childen aged 5–15): 1.8 Bq | Lymphocyte subsets, cytokines: IL-4, IFN-gamma | Children with irritable bowel disease had less CD4+ T-cells, a higher level of IL-4 and a lower level of IFN gamma, suggesting a stronger polarization toward a Th2 phenotype. There was no difference with age, suggesting that there was no radiation-dose effect. |
| (Vykhovanets et al., 2000) | Chernobyl | 6–14 year old children in radiation-contaminated areas in North Ukraine after Chernobyl accident (n = 78; 5 years after accident) and 141 different children (8–10 years after accident); children with recurrent respiratory disease (RRDC, mean age 8.3 years) vs non-RRDC in contaminated areas; n = 61 (1991) and n = 87 aged-matched controls from non-contaminated areas | Low doses of radiation to the whole body from Cs-137 ranging from 1.79 to 53.7 mSv (1991) and 2.17–29.33 mSv (1994–96) and various doses of radiation to the thyroid from I-131 as fallout | Major lymphocyte subsets analysed in whole blood by flow cytometry | Possibility that long-term exposure to low doses of Cs-137 may have altered the immune balance in especially vulnerable children. The shifts in circulating lymphocyte subsets between healthy children and those with RRDC may be attributed to long-term low-dose exposure of the whole body to radiation from Cs-137 and exposure of the thyroid to radiation from I-131. |