More Than Effects in Skin: Ultraviolet Radiation-Induced Changes in Immune Cells in Human Blood.

Cells of the skin and circulation are in constant two-way communication. Following exposure of humans to sunlight or to phototherapy, there are alterations in the number, phenotype and function of circulating blood cells. In this review, only data obtained from human studies are considered, with changes induced by UV radiation (UVR) exposure described for phagocytic leukocytes and peripheral blood mononuclear cells plus their component T and B cells, natural killer cells and dendritic cells. These immune modulations illustrate the potential of UVR to have therapeutic effects beyond the skin, and that sunlight exposure is an important environmental influence on human health.

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

Melatonin mediates monochromatic light-induced proliferation of T/B lymphocytes in the spleen via the membrane receptor or nuclear receptor.

Our studies found that melatonin mediates the monochromatic light-induced lymphocyte proliferation in chickens. However, melatonin receptor subtypes contain membrane receptor (Mel1a/Mel1b/Mel1c) and nuclear receptor (Retinoic acid receptor-related orphan receptor [ROR] α/RORß/RORγ) and are characteristic with cell specificity. This study compared receptor pathway of melatonin, which mediated the monochromatic light-induced T/B lymphocyte proliferations in chickens. Newly hatched chicks were randomly divided into white light, red light, green light (GL), and blue light groups. Green light promoted the membrane receptor expression in the spleen but decreased the nuclear receptor level compared with that of red light. These changes were accompanied by increase of T/B lymphocyte proliferation and plasma melatonin level under GL. Pinealectomy reversed aforementioned changes and resulted in no differences among the light-treated groups. Supplementation of exogenous melatonin enhanced GL-induced T/B lymphocyte proliferation in the spleen but was reversed by Mel1c antagonist prazosin and RORα agonist SR1078 and enhanced by RORα antagonist SR3335. However, Mel1b antagonist 4P-PDOT and RORγ antagonist GSK increased the stimulation effect of melatonin on GL-induced T lymphocyte proliferation but no effect on the B-lymphocyte proliferation. These results indicate that melatonin promotes the GL-induced T lymphocyte proliferation through Mel1b, Mel1c, and RORα/RORγ; however, the Mel1a, Mel1c, and RORα may be involved in the B lymphocyte proliferation.

Microgravity versus Microgravity and Irradiation: Investigating the Change of Neuroendocrine-Immune System and the Antagonistic Effect of Traditional Chinese Medicine Formula.

During spaceflight, the homeostasis of the living body is threatened with cosmic environment including microgravity and irradiation. Traditional Chinese medicine could ameliorate the internal imbalance during spaceflight, but its mechanism is still unclear. In this article, we compared the difference of neuroendocrine-immune balance between simulated microgravity (S) and simulated microgravity and irradiation (SAI) environment. We also observed the antagonistic effect of SAI using a traditional Chinese medicine formula (TCMF). Wistar rats were, respectively, exposed under S using tail suspending and SAI using tail suspending and 60Co-gama irradiation exposure. The SAI rats were intervened with TCMF. The changes of hypothalamic-pituitary-adrenal (HPA) axis, splenic T-cell, celiac macrophages, and related cytokines were observed after 21 days. Compared with the normal group, the hyperfunction of HPA axis and celiac macrophages, as well as the hypofunction of splenic T-cells, was observed in both the S and SAI group. Compared with the S group, the levels of plasmatic corticotropin-releasing hormone (CRH), macrophage activity, and serous interleukin-6 (IL-6) in the SAI group were significantly reduced. The dysfunctional targets were mostly reversed in the TCMF group. Both S and SAI could lead to NEI imbalance. Irradiation could aggravate the negative feedback inhibition of HPA axis and macrophages caused by S. TCMF could ameliorate the NEI dysfunction caused by SAI.

The impact of irradiance on UVB-induced cutaneous immunosuppression: Implications on administering most efficient phototherapy.

BACKGROUND: Ultraviolet B (UVB) is commonly used for treating dermatologic conditions. Recently, high irradiance UVB (HIUVB) has been suggested to be more effective for treating skin conditions as compared to its low irradiance (LI) counterpart. The biological impact of UVB radiation emitted at different irradiance on cutaneous immunity remains obscure. OBJECTIVE: This study aimed to explore the impacts of UVB radiation administered at equivalent fluence (mJ/cm2) but different irradiance (mW/cm2) on cutaneous immune response. METHODS: Cultured bone marrow derived dendritic cell (BMDC) were treated with equivalent fluence of UVB radiation with HIUVB or LIUVB. The phenotypic and functional alterations of BMDCs were documented. Animal models were used to validate the in vitro results in vivo and explore the mechanisms involved. RESULTS: After equivalent fluence of UVB radiation, the HIUVB treated BMDC showed significantly lower MHCII and CD86 expressions, reduced capacity to stimulate T cell proliferation, and enhanced activation of aryl hydrocarbon receptor (AhR)-activated genes as compared to control while their LIUVB treated counterpart showed no significant change. Using animal model, the HIUVB induced significantly higher immune suppressive effect in mice as compared to their LIUVB counterpart after equivalent fluence of UVB treatment. The superior immune suppressive effect of HIUVB over LIUVB radiation was not observed when similar experiments were performed using AhR-deficient mice. CONCLUSION: We propose irradiance played an important role modulating UVB-induced cutaneous immune suppression. Future works on UVB phototherapy, both clinical and research, should incorporate this important parameter into consideration.

LED phototherapy in full-thickness burns induced by CO2 laser in rats skin.

Many studies have been conducted on the treatment of burns because they are important in morbidity and mortality. These studies are mainly focused on improving care and quality of life of patients. The aim of this study was evaluate the LED phototherapy effects in rats skin full-thickness burns induced by CO2 laser. The animals were divided in NT group that did not received any treatment and LED group that received LED irradiation at 685 nm, 220 mW, and 4.5 J/cm2 during 40 s by burned area. Biopsies were obtained after 7, 14, and 21 days of treatment and submitted to histological and immunohistochemical analysis. The LED phototherapy shows anti-inflammatory effects, improves angiogenesis, and stimulates the migration and proliferation of fibroblasts. The T CD8+ lymphocytes were more common in burned areas compared to T CD4+ lymphocytes since statistically significant differences were observed in the LED group compared to the NT group after 7 days of treatment. These results showed that LED phototherapy performs positive influence in full-thickness burns repair from the healing process modulated by cellular immune response. The obtained results allowed inferring that burns exhibit a characteristic cell immune response and this cannot be extrapolated to other wounds such as incision and wounds induced by punch, among others.

[PHYTOCORRECTION OF IMMUNOLOGICAL AND BIOCHEMICAL CHANGES IN THE COMBINED IMPACT OF COAL DUST AND HIGH DOSE OF RADIATION].

The objective of this researsh is to study the effects of Eminium Regelii phytopreparation (ERP) on immune status and free radical oxidation in the tissues of the adrenal glands and immunocompetent organs after combined exposure to 6 Gy dose of gamma irradiation and coal dust (remote period). The study was realized on 30 white laboratory male rats of the Wistar line, weighing 240±20g, that were divided into equal 3 groups: I group - intact, ІІ group - were exposured to combined effects of coal dust and gamma irradiation, III group - were exposured to combined effects and in parallel taking phytopreparation Eminium Regel. The animals of II and III groups were irradiated 90 days prior to the study at the TERAGAM 60Co radiotherapy unit ("ISOTREND spol. S.r.o.", Czech Republic) in dose of 6 Gy once. Experimental animals received phytopreparation of ER 2.5 mg/kg per day on calculate of body mass for 14 days. The results of the conducted studies showed that in the long-term period after the actions of the sublethal dose of gamma radiation and coal dust, significant changes were revealed that were characterized by a decrease in immunological reactivity, increased lipoperoxidation and inhibition of antioxidant defense activity of the organism. After exposure to ER, oxidative stress was alleviated, sufficient restoration of antioxidant protection and immune system indices, which were disrupted by the combined effects of a single high dose of radiation and a prolonged three-month inhalation of coal dust.

Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response.

Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.

Daily very low UV dose exposure enhances adaptive immunity, compared with a single high-dose exposure. Consequences for the control of a skin infection.

Ultraviolet radiation (UVr) promotes several well-known molecular changes, which may ultimately impact on health. Some of these effects are detrimental, like inflammation, carcinogenesis and immunosuppression. On the other hand, UVr also promotes vitamin D synthesis and other beneficial effects. We recently demonstrated that exposure to very low doses of UVr on four consecutive days [repetitive low UVd (rlUVd)] does not promote an inflammatory state, nor the recruitment of neutrophils or lymphocytes, as the exposure to a single high UV dose (shUVd) does. Moreover, rlUVd reinforce the epithelium by increasing antimicrobial peptides transcription and epidermal thickness. The aim of this study was to evaluate the adaptive immune response after shUVd and rlUVd, determining T-cell and B-cell responses. Finally, we challenged animals exposed to both irradiation procedures with Staphylococcus aureus to study the overall effects of both innate and adaptive immunity during a cutaneous infection. We observed, as expected, a marked suppression of T-cell and B-cell responses after exposure to an shUVd but a novel and significant increase in both specific responses after exposure to rlUVd. However, the control of the cutaneous S. aureus infection was defective in this last group, suggesting that responses against pathogens cannot be ruled out from isolated stimuli.

Current developments in phototherapy for psoriasis.

Phototherapy utilizes the beneficial effects of ultraviolet (UV) wavelengths to affect immunoregulatory functions. UV light phototherapy using narrowband UV-B (NB-UVB) and bath-psoralen UV-A (bath-PUVA) therapy are well-established treatments for psoriasis. Dual-action mechanisms of UV phototherapy have been identified: apoptosis and immune suppression. NB-UVB depletes pathogenic T cells by inducing apoptosis and regulatory T cells. Other wavelengths are also utilized for phototherapy, namely 308-nm excimer light and 312-nm flat-typed NB-UVB. Excimer light (308-nm) therapy effectively targets the affected skin without unduly exposing other areas and increases the levels of regulatory T cells. Phototherapy improves impaired resting regulatory T cells and increases activated regulatory T cells in patients with psoriasis. Intensive studies of phototherapy effects have led to several improvements in the design, protocols, and light sources, such as UV light-emitting diodes, thereby providing several options for patients with refractory skin disease, such as psoriasis.

Aging of lymphoid organs: Can photobiomodulation reverse age-associated thymic involution via stimulation of extrapineal melatonin synthesis and bone marrow stem cells?

Thymic atrophy and the subsequent reduction in T-cell production are the most noticeable age-related changes affecting lymphoid organs in the immune system. In fact, thymic involution has been described as "programmed aging." New therapeutic approaches, such as photobiomodulation (PBM), may reduce or reverse these changes. PBM (also known as low-level laser therapy) involves the delivery of non-thermal levels of red or near-infrared light that are absorbed by mitochondrial chromophores, in order to prevent tissue death and stimulate healing and regeneration. PBM may reverse or prevent thymic involution due to its ability to induce extrapineal melatonin biosynthesis via cyclic adenosine monophosphate (AMP) or NF-kB activation, or alternatively by stimulating bone marrow stem cells that can regenerate the thymus. This perspective puts forward a hypothesis that PBM can alter thymic involution, improve immune functioning in aged people and even extend lifespan.

Treatment of oral lichen planus using 308-nm excimer laser.

Oral lichen planus (OLP) is a chronic inflammatory disease, has prolonged courses, repeated attacks and resistance to treatment. The traditional narrow spectrum UVB treatment has an established efficacy on skin lichen planus, and high safety. However, most of ultraviolet phototherapy devices have a huge volume, thereby cannot be used in the treatment of OLP. Lymphocytic infiltration is evident in the lesions of lichen planus, and the direct irradiation of 308-nm excimer laser can induce apoptosis of the T lymphocytes in skin lesions, thereby has a unique therapeutic effect on the diseases involving T lymphocytes. This study aims to investigate the efficacy of 308-nm excimer laser in the treatment of OLP. A total of six OLP patients were enrolled into this study, and further pathological diagnosis was conducted, then 308-nm excimer laser was used in the treatment. The efficacy of 308-nm excimer laser in the treatment of OLP was satisfactory. The clinical symptoms of five patients were significantly improved. In two patients, the erosion surface based on congestion and the surrounding white spots completely disappeared, and clinical recovery was achieved. Three patients achieved partial remission, that is, the erosion surface healed, congestion and white spot area shrunk by more than 1/2 of the primary skin lesions. In the remaining one patient, the erosion surface had not completely healed after treatment, and congestion and white spot area shrunk by less than 1/2 of the primary skin lesions. Only one patients had developed mild pain during the treatment, and this symptom alleviated by itself. The 308-nm excimer laser therapy can serve as a safe and effective treatment for OLP.

Effect of phototherapy on B and T lymphocytes in Egyptian infants suffering from neonatal jaundice

BACKGROUND: Neonatal jaundice is one of the most common problems that affect newborn infants, and phototherapy is usually used for treatment. OBJECTIVES: Evaluation of the effect of phototherapy on neonatal immune system through measuring the percentage of B and T lymphocytes and determining the frequency of development of infections and need for hospitalisation during the first six months of life. METHODS: A prospective cohort study was conducted on 50 full term new-borns; 25 with indirect hyperbilirubinaemia and treated with conventional phototherapy and 25 healthy matched neonates as untreated controls. The percentages of CD19+, CD4+ and CD8+ lymphocytes were measured by flow cytometry before phototherapy and 72h after exposure. Follow-up of the study group for the occurrence of infections for a period of six months after phototherapy. RESULTS: The study showed a significant difference in CD19+ lymphocytes percentage between patients before phototherapy and controls (P value<0.01), also a significant correlation between serum levels of total bilirubin in patients and CD19+ lymphocytes percentage (P value<0.05). There was no significant difference between the percentages of CD19+, CD4+ and CD8+ lymphocytes in patients before or after 72h of exposure to phototherapy (P value>0.05). Also, there was no correlation between the percentages of CD19+, CD4+ and CD8+ lymphocytes after 72h of exposure to phototherapy and the occurrence of infections (Gastrointestinal tract and Respiratory tract infection) after six months of follow-up (P value>0.05). More studies are needed with larger number of patients to determine the effect of phototherapy on immune system

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The role of UVR and vitamin D on T cells and inflammatory bowel disease.

Vitamin D deficiency is associated with the development of inflammatory bowel disease (IBD). In experimental IBD the targets of vitamin D that result in protection from IBD include gut epithelial cells, innate immune cells, T cells, and the microbiota. Ultraviolet radiation (UVR) induces production of vitamin D in the skin and suppresses T cell responses in the host. There is limited data demonstrating an effect of UVR on experimental IBD but the mechanisms of UVR suppression in IBD have not been defined. There are several shared effects of vitamin D and UVR on T cells including inhibition of proliferation and suppression of IFN-γ and IL-17 producing T cells. Conversely UVR decreases and vitamin D increases IL-4 production from T cells. Together the data suggest that UVR suppression of T cells and potentially IBD are both vitamin D dependent and independent.

IMPACT OF LASER THERAPY ON THE PROLIFERATION OF VARIOUS CULTURED CELLS.

The purpose of our study was to establish the laser effects on the epithelial tissue and immune metabolism. The research was conducted on human leukemic mature T cells (Jurkat cells) (DSMZ-Deutshe Sammulung von Mikroorganismen und Zellkulturen (Germany)) and MDCK cell line (Lugar Laboratory, Tbilisi, Georgia). Cells were radiated by Laser device "ОПТОДАН"- АЛСТ-01 (power 5 W) 3 -7 days (4 minutes per day). With the aim to model oxidative stress-induced apoptosis, 30% hydrogen peroxide (H2O2) (Sigma) is added to Jurkat cells, in doses 25 and 50µM [4, 5]; and MDCK cells, in doses 400 and 800 µM [19] added to incubation suspension with subsequent incubation for 24, 48 and 72 hrs. Control group is represented by intact Jurkat and MDCK cells. MTT test was used to assess the cells' proliferation activity (viability). Statistical analyses of the obtained results were performed by SPSS (version 10.0) program package. Our research results show that effects of laser therapy on proliferation of cell cultures depend on the type of cells and incubation conditions. Laser irradiation revealed equal efficacy in both types of the intact cells and increased their viability in time-dependent manner. Jurkat cells turned out to be more susceptible to oxidative stress. Laser therapy only slightly improved their viability at moderate intensity of oxidative stress and proved to be ineffective in strong oxidative stress conditions. The MDCK cells appeared to be more sustainable to oxidative stress; significant changes in these cells viability were observed only when high doses of hydrogen peroxide were added to their incubation medium. Thus, laser therapy was effective for these cells incubated in both regimens of oxidative stress. Our research results prove the efficacy of laser therapy use during periodontitis with the aim to recover epithelium in the oral cavity and to modulate immune metabolism in the patient's body.

Changes in T-lymphocytes in lung cancer patients after hyperthermic intraperitoneal chemotherapy or radiotherapy.

We investigated dynamic changes in T-lymphocyte subsets after hyperthermic intraperitoneal chemotherapy (HIPEC) or radiotherapy using flow cytometry. A total of 1423 lung cancer patients admitted to our hospital between October 2012 and July 2015 were enrolled, and age-matched healthy individuals served as controls. Peripheral blood mononuclear cells (PBMCs) were purified using standard Ficoll density gradient centrifugation, based on which CD3+, CD4+, and CD8+ T-cells were isolated. A surface marker was identified by flow cytometry. Immunohistochemical analysis determined the distribution of the cells in the tumor mass or adjacent tissues. A total of 957 patients (male: 555; female: 402; median age: 49.3 years) with lung cancer who had received only HIPEC or radiotherapy were enrolled. The patients were followed-up until death. No statistical difference was noticed between the patients who had received chemotherapy compared with the baseline levels. A remarkable elevation was noticed in the CD3+ T-cells in the patients three months after radiotherapy (78.71 ± 9.36 vs 68.15 ± 9.65, P < 0.05). The level of CD8+ in the patients who had received chemotherapy or radiotherapy was remarkably elevated in the post-treatment period (P < 0.05). The CD3+ and CD8+ T-cells were mainly expressed in the cytoplasm rather than in the adjacent tissues. The expression of CD3+ and CD4+ was correlated to tumor infiltration and metastasis. Remarkable elevation was noticed in the CD3+ T-cells in the patients three months after radiotherapy. The expression of CD3+ and CD4+ was negatively correlated to tumor infiltration and metastasis in non-small-cell lung cancer patients.

Combination of ionising radiation with hyperthermia increases the immunogenic potential of B16-F10 melanoma cells in vitro and in vivo.

Mild hyperthermia (HT) (41.5 °C for 30-60 min) has been shown in various cell culture systems, preclinical and clinical models to be a very potent radiosensitiser. Recent research suggests that local HT application in combination with standard tumour therapies such as radiotherapy (RT) and/or chemotherapy may not only improve local tumour control but also lead to systemic and immune mediated anti-tumour responses. Melanoma has been proven to be rather radioresistant and mostly only the addition of immunotherapy is capable of inducing beneficial anti-melanoma responses. This work therefore focuses on whether HT increases the immunogenic potential of B16-F10 mouse melanoma cells in combination with RT. The in vitro experiments revealed that combination of RT with HT resulted in an increased percentage of apoptotic and necrotic melanoma cells and an increased release of the danger signal heat shock protein 70 (Hsp70) and high mobility group box protein 1 (HMGB1). HT alone was also capable of inducing this release. We set up local irradiation and heating procedures of B16-F10 tumour-bearing C57/BL6 mice and revealed that the tumour growth of tumours treated with RT plus HT was significantly retarded compared to tumours treated only with RT. This combined treatment generated a beneficial tumour microenvironment by enhancing the infiltration of CD11c + /MHCII + /CD86+ dendritic cells, CD8+ T cells, and NK cells, and decreasing that of regulatory T cells and myeloid-derived suppressor cells. We conclude that HT in combination with RT has an immune-stimulating potential that might result in anti-tumour immunity.

EMSA Eritin Drives Expansion of Regulatory T Cells and Promotes T Cells Differentiation in Irradiated Mice.

Sublethal irradiation therapy in cancer treatment causes generalized immunosuppression, which results in a range of DNA damage. We examined the significance of a polyherbal medicine called "EMSA Eritin" on immunological responses in sublethally irradiated mice focusing on the involvement of Treg, naïve T cell, and also the development and differentiation of T cells in thymus. Normal BALB/c mice were sublethally irradiated with dose of 600 rad. The irradiated mice were then orally administered by EMSA Eritin once a day at different doses: 1.04, 3.12, 9.37 mg/g body weight. The treatment was performed for 14 days. On day 15, immunological responses were observed by analyzing the status of Treg and differentiation of T cells in thymus. The administration of EMSA Eritin to irradiated mice resulted in a significant increase of pre T cells, Treg cells, and naïve T cells, which in general could maintain and normalize healthy condition in mice.

Carbon Ion Irradiated Neural Injury Induced the Peripheral Immune Effects in Vitro or in Vivo.

Carbon ion radiation is a promising treatment for brain cancer; however, the immune system involved long-term systemic effects evoke a concern of complementary and alternative therapies in clinical treatment. To clarify radiotherapy caused fundamental changes in peripheral immune system, examinations were performed based on established models in vitro and in vivo. We found that brain-localized carbon ion radiation of neural cells induced complex changes in the peripheral blood, thymus, and spleen at one, two, and three months after its application. Atrophy, apoptosis, and abnormal T-cell distributions were observed in rats receiving a single high dose of radiation. Radiation downregulated the expression of proteins involved in T-cell development at the transcriptional level and increased the proportion of CD3⁺CD4(-)CD8⁺ T-cells in the thymus and the proportion of CD3⁺CD4⁺CD8(-) T-cells in the spleen. These data show that brain irradiation severely affects the peripheral immune system, even at relatively long times after irradiation. In addition, they provide valuable information that will implement the design of biological-based strategies that will aid brain cancer patients suffering from the long-term side effects of radiation.