Irradiation Attenuates Systemic Lupus Erythematosus-Like Morbidity in NZBWF1 Mice: Focusing on CD180-Negative Cells.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can induce systemic inflammation. Ultraviolet-A and X-ray irradiation have been reported to have therapeutic effects in patients with SLE. We previously demonstrated that CD180-negative cells, these are radiosensitive, contribute to the development of SLE-like morbidity in NZBWF1 mice. In this study, the effects of irradiation on SLE-like morbidity manifestations in NZBWF1 mice and on CD180-negative cells were investigated. Whole-body irradiation, excluding the head, attenuated SLE-like morbidity in vivo, as indicated by the prevention of the renal lesion development, inhibition of anti-dsDNA antibody production, reduction of urinary protein levels, and prolongation of the lifespan. Irradiation also reduced the proportion of CD180-negative cells in the spleen. Although other immune cells or molecules may be triggered because of the whole-body irradiation treatment, previous research, and the current results suggest a strong relationship between the radiation-induced decrease in CD180-negative cells and the amelioration of SLE-like morbidities. Clinical trials assessing CD180-negative cells as a therapeutic target for SLE have been hampered by the lack of validated cell markers; nonetheless, the present findings suggest that radiotherapy may be a new therapeutic strategy for managing SLE symptoms.

Ultraviolet-A1 irradiation therapy for systemic lupus erythematosus.

Systemic lupus erythematosus (lupus, SLE) is a chronic autoimmune disease characterized by the production of autoantibodies, which bind to antigens and are deposited within tissues to fix complement, resulting in widespread systemic inflammation. The studies presented herein are consistent with hyperpolarized, adenosine triphosphate (ATP)-deficient mitochondria being central to the disease process. These hyperpolarized mitochondria resist the depolarization required for activation-induced apoptosis. The mitochondrial ATP deficits add to this resistance to apoptosis and also reduce the macrophage energy that is needed to clear apoptotic bodies. In both cases, necrosis, the alternative pathway of cell death, results. Intracellular constituents spill into the blood and tissues, eliciting inflammatory responses directed at their removal. What results is "autoimmunity." Ultraviolet (UV)-A1 photons have the capacity to remediate this aberrancy. Exogenous exposure to low-dose, full-body, UV-A1 radiation generates singlet oxygen. Singlet oxygen has two major palliative actions in patients with lupus and the UV-A1 photons themselves have several more. Singlet oxygen depolarizes the hyperpolarized mitochondrion, triggering non-ATP-dependent apoptosis that deters necrosis. Next, singlet oxygen activates the gene encoding heme oxygenase (HO-1), a major governor of systemic homeostasis. HO-1 catalyzes the degradation of the oxidant heme into biliverdin (converted to bilirubin), Fe, and carbon monoxide (CO), the first three of these exerting powerful antioxidant effects, and in conjunction with a fourth, CO, protecting against injury to the coronary arteries, the central nervous system, and the lungs. The UV-A1 photons themselves directly attenuate disease in lupus by reducing B cell activity, preventing the suppression of cell-mediated immunity, slowing an epigenetic progression toward SLE, and ameliorating discoid and subacute cutaneous lupus. Finally, a combination of these mechanisms reduces levels of anticardiolipin antibodies and protects during lupus pregnancy. Capping all of this is that UV-A1 irradiation is an essentially innocuous, highly manageable, and comfortable therapeutic agency.

DNA methylation modulates HERV-E expression in CD4+ T cells from systemic lupus erythematosus patients.

BACKGROUND: Previous studies have reported that the DNA of T cells from systemic lupus erythematosus (SLE) patients contains global hypomethylation that may contribute to the development of SLE. Human endogenous retroviruses (HERVs) are encoded within the genomes of all higher eukaryotes and are of special interest where autoimmune disorders are concerned. Until recently, minimal effort has been made to identify specific HERVs associated with SLE and to explore their precise mechanism of expression. OBJECTIVE: To examine the expression of HERVs associated with SLE and elucidate the effect of ultraviolet B (UVB) exposure on SLE-associated HERV expression in CD4+ T cells from patients with SLE. METHODS: Fifteen patients with SLE and 10 healthy controls were enrolled in the study. The mRNA expression of selected HERVs and the methylation status of the long terminal repeats (LTRs) in SLE-related HERVs in CD4+ T cells were investigated. Furthermore, CD4+ T cells treated with 5-aza-deoxycytidine (5-aza C) and UVB were analyzed. Reverse-transcription PCR (RT-PCR), quantitative real-time PCR (qRT-PCR) and bisulfite sequencing analysis were employed. RESULTS: HERV-E mRNA expression was higher in lupus CD4+ T cells than in cells from healthy controls, whereas the mRNA expression levels of HERV-K, HERV-K10 and HERV-W were comparable in SLE patients and healthy controls. Additionally, the HERV-E mRNA expression level was positively correlated with SLE disease activity. Furthermore, the HERV-E LTR methylation level was decreased and was negatively correlated to the HERV-E mRNA expression level in lupus CD4+ T cells. Finally, lupus CD4+ T cells showed markedly decreased HERV-E LTR2C methylation levels and increased HERV-E mRNA expression after treatment with 5-aza C or UVB. CONCLUSION: HERV-E is involved in the development of SLE. HERV-E transcription may be activated via inhibition of LTR methylation in lupus CD4+ T cells.

La radiación UVA-1: un nuevo aporte en la fototerapia dermatológica / Ultraviolet radiation A1 (UVA-1): therapeutic use in dermatology

La radiación ultravioleta ha sido usada durante décadas para el tratamiento de diversas enfermedades cutáneas. La radiación ultravioleta A1 (UVA-1) que tiene una longitud de onda entre los 340nm y 400 nm está disponible desde el año 1981, pero recién en las últimas dos décadas se ha estudiado, publicado y reportado su potencial uso terapéutico en la dermatología. Los primeros beneficios de su uso se reportaron en la dermatitis atópica donde se utilizaron dosis altas de UVA-1 para tratar las exacerbaciones severas de esta condición. Luego, nuevas indicaciones terapéuticas de su uso se fueron expandiendo a otras enfermedades cutáneas tales como: morfea, liquen escleroso, queratosis liquenoide, linfomacutáneo de células T y otras dermatopatías. La radiación UVA-1 al tener una longitud de onda más larga penetra a las capas más profundas de la dermis, lo que le permite una acción en la modificación de la respuesta inflamatoria, la respuesta inmunológica y los mecanismos de reparación cutánea.

Ultraviolet light radiation has been used for decades for the treatment of several cutaneous diseases. The ultraviolet radiation A1 (UVA-1) with a wave length between 340 nm-400 nm has been available since 1981, but only in the last two decades it has been studied and published for therapeutic use in dermatology. The first reported benefits of its use were reported in atopic dermatitis in which high doses of UVA-1were used to treat severe exacerbations of this condition. Thereafter, new therapeutic indications expanded its use for other cutaneous diseases like: morphea, lichen sclerosus, lichenoid keratosis, cutaneous T cell lymphoma and other skin conditions. The UVA-1 radiation has a long wavelength that make possible to reach the deep dermis and to modify the inflammatory response, immunological response and the cutaneous repair mechanisms.

Avoidance of radiotherapy-related, gastrointestinal complications in a patient with systemic lupus erythematosus: a case report and review of literature.

Systemic lupus erythematosus (SLE) is associated with major gastrointestinal complications due to radiotherapy. A patient with active SLE and grade 4 nephropathy presented with inoperable advanced cancer of the cervix which proved to be contraindicated for chemotherapy. The patient was treated with intensity-modulated radiotherapy technique (IMRT). The patient, however, did not experience severe radiotherapy-related complications as expected with conventional techniques of radiotherapy. The tolerance of SLE patients to radiotherapy can thus be achieved by proper delivery of radiation and the sparing of normal tissues by IMRT although further confirmatory studies are required.

The protective effects of ultraviolet A1 irradiation on spontaneous lupus erythematosus-like skin lesions in MRL/lpr mice.

We investigated the effects of ultraviolet A1 (UVA1) irradiation on spontaneous lupus erythematosus- (LE-) like skin lesions of MRL/lpr mice, using a disease prevention model. UVA1 irradiation significantly inhibited the development of LE-like skin lesions, without obvious changes of the disease including renal disease and serum antinuclear antibody levels. Besides the massive infiltration of mast cells in the LE-like skin lesions, in the nonlesional skins, more mast cells infiltrated in the UVA1-irradiated group compared with the nonirradiated group. Although apoptotic cells were remarkably seen in the dermis of UVA1-irradiated mice, those cells were hardly detectable in the dermis of the nonirradiated mice without skin lesions. Further analysis showed that some of those apoptotic cells were mast cells. Thus, UVA1 might exert its effects, at least in part, through the induction of the apoptosis of pathogenic mast cells. Our results supported the clinical efficacy of UVA1 irradiation for skin lesions of lupus patients.

Systemic lupus erythematosus, radiotherapy, and the risk of acute and chronic toxicity: the Mayo Clinic Experience.

PURPOSE: To determine the acute and chronic toxic effects of radiotherapy in patients with systemic lupus erythematosus (SLE). METHODS AND MATERIALS: Medical records of 21 consecutive patients with SLE, who had received 34 courses of external beam radiotherapy and one low-dose-rate prostate implant, were retrospectively reviewed. Patients with discoid lupus erythematosus were excluded. RESULTS: Median survival was 2.3 years and median follow-up 5.6 years. Eight (42%) of 19 patients evaluable for acute toxicity during radiotherapy experienced acute toxicity of Grade 1 or greater, and 4 (21%) had acute toxicity of Grade 3 or greater. The 5- and 10-year incidence of chronic toxicity of Grade 1 or greater was 45% (95% confidence interval [CI], 22-72%) and 56% (95% CI, 28-81%), respectively. The 5- and 10-year incidence of chronic toxicity of Grade 3 or greater was 28% (95% CI, 18-60%) and 40% (95% CI, 16-72%), respectively. Univariate analysis showed that chronic toxicity of Grade 1 or greater correlated with SLE renal involvement (p < 0.006) and possibly with the presence of five or more American Rheumatism Association criteria (p < 0.053). Chronic toxicity of Grade 3 or greater correlated with an absence of photosensitivity (p < 0.02), absence of arthritis (p < 0.03), and presence of a malar rash (p < 0.04). CONCLUSIONS: The risk of acute and chronic toxicity in patients with SLE who received radiotherapy was moderate but was not prohibitive of the use of radiotherapy. Patients with more advanced SLE may be at increased risk for chronic toxicity.

Role of distinct immune components in the radiation-induced abrogation of systemic lupus erythematosus development in mice.

The New Zealand Black x New Zealand White F1 [(NZB/NZW) F1] mouse develops an autoimmune condition resembling aspects of human systemic lupus erythematosus (SLE). We investigated the effects of a novel prophylactic thoraco-abdominal gamma irradiation protocol on the onset and evolution of lupus in these animals. Survival of irradiated mice was higher when compared with nonirradiated mice. Kidney lesions were milder and autoantibody levels were lower in irradiated mice. To identify possible mechanisms involved in the radiation-induced improvement of disease, distinct components of humoral and cellular immune responses were evaluated. Because B-1 cells are known to be involved in various autoimmune diseases, we investigated the participation of these cells in SLE progression. Unexpectedly, B-1 cells were not depleted in (NZB/NZW) F1, even after several rounds of irradiation. No alterations were found in viability and physiology of B-1 cells in SLE animals with the exception of constitutive overexpression of the anti-apoptotic molecule Bcl-2, which may account for the observed radioresistance. Thus, a role for B-1 cells in murine SLE cannot be excluded, since the irradiation protocol did not effectively eliminate these cells. Additionally, we demonstrate a marked delay in the ability of splenocytes to repopulate the spleen after irradiation in (NZB/NZW) F1, in contrast to leucocytes in other cellular compartments. The implications of these findings for the fate of SLE in this model are discussed.

Ultraviolet-A (UVA-1) radiation suppresses immunoglobulin production of activated B lymphocytes in vitro.

Previous studies have shown that low-dose ultraviolet-A (UVA-1) total body irradiations were capable of improving disease activity in patients with systemic lupus erythematosus (SLE). We hypothesized that UVA-1-induced suppression of immunoglobulin production by activated B cells in the dermal capillaries could be (partly) responsible for this effect. Our experiments with donor skin demonstrated that approximately 40% of UVA-1 could penetrate through the epidermis. Irradiation of peripheral blood mononuclear cells (PBMCs) with 2 J/cm(2) of UVA-1 resulted in 20% cell death. This toxic effect could be prevented totally by preincubation of the cell cultures with catalase. This indicates that the generation of hydrogen peroxide plays a role in UVA-1 cytotoxicity. T cells and B cells appeared to be less susceptible to UVA-1 cytotoxicity than monocytes. With the use of a CD40-CD40L B cell activation method we measured immunoglobulin production after various doses of UVA-1 irradiation (0-2 J/cm(2)). The doses of 2 J/cm(2) caused a significant decrease of IgM, IgG, IgA and IgE production under the conditions of interleukin (IL)-10 or IL-4 (IgE) stimulation. Although UVA-1 can cause apoptosis of B lymphocytes, we show that relatively low doses of UVA-1 radiation also affect the function of these cells. Both effects may be responsible for the observed improvement of disease activity in SLE patients.

Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus.

OBJECTIVE: Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of dermatological diseases. We examined the effectiveness and reliability of low-dose UVA1 phototherapy (60 kJ/m2/treatment) in patients suffering from systemic lupus erythematosus (SLE). We studied the changes in immunological parameters. METHODS: The patients received a 9-week course of phototherapy according to the following regimen: five times a week during the first 3 weeks, three times a week during the second 3 weeks and twice during the last 3 weeks. Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and interleukin 4 (IL-4). RESULTS: Our study showed the improvement of clinical symptoms determined by the subjective clinical disease activity scoring and the SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant (P = 0.005). Immunological investigations detected a decrease in the frequency of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and Tc1/Tc2 ratios after UVA1 therapy. CONCLUSION: According to the literature, IFN-gamma has a pathogenic role in the development of SLE. We observed a decreased proportion of IFN-gamma-secreting cells, which we think is presumably one of the beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy does seem to be an effective adjuvant in the treatment of SLE patients.

Efficacy of UVA-1 cold light as an adjuvant therapy for systemic lupus erythematosus.

OBJECTIVE: The assessment of the efficacy of therapy of patients with moderately active systemic lupus erythematosus (SLE) with low doses of UVA-1 cold light. METHODS: A double blind, placebo-controlled, cross-over study design was used for the examination of the efficacy of low doses of UVA-1 radiation (12 J/cm2/day for 15 days) in 12 patients. RESULTS: UVA-1 treatment resulted in a significant decrease of well-validated disease activity indexes [the SLE Activity Measure (SLAM) (P < 0.001) and the SLE Disease Activity Index (SLEDAI) (P = 0.007)], whereas neither score improved significantly during placebo treatment. Furthermore, UVA-1 therapy proved to be more effective [mean decrease 4.8 points) than placebo (mean decrease -1.7 points (i.e. an increase)] when measured by the SLAM (P = 0.001, 95% CI -7.56 to -2.28), but not by the SLEDAI. Two patients had transient skin reactions at the beginning of treatment. CONCLUSION: UVA-1 therapy appears to be a useful adjuvant treatment modality for patients suffering from moderately active SLE. Its effect could possibly be explained by reduction of B-cell function or apoptosis of plasma cells.

Reversal of brain dysfunction with UV-A1 irradiation in a patient with systemic lupus.

Low-dose ultraviolet A-1 (UV-A1; 340-400 nm) bodily irradiation significantly reduces clinical manifestations of systemic lupus erythematosus (SLE). As neuropsychiatric-like symptoms respond prominently, a single patient was selected to undergo positron emission tomography (PET) before and after therapy to determine the effects of the therapy on the brain. The functional changes in 18F-deoxyglucose uptake as determined by PET imaging in this SLE patient indicated that improvement in brain function paralleled the reversal of cognitive deficits noted after the administration 160 kJ of bodily UV-A1 irradiation administered three times a week. Also of interest is that the UV-A1 irradiation, for the first time, ameliorated discoid lupus rashes, presumably due to a systemic action, as the lesions were for the first time covered during therapy.

Treatment of lupus erythematosus with pulsed dye laser.

BACKGROUND AND OBJECTIVES: The treatment of cutaneous lupus erythematosus (CLE) with dye and argon laser has been evaluated in a number of articles in recent years. The improvement of telangiectasias and chronic erythema of the cutaneous lesions was based on the selective photothermolysis ablation of the dilated capillaries and venules. STUDY DESIGN/MATERIALS AND METHODS: We describe the results of the treatment of cutaneous lesions of 14 patients; eight with discoid lupus erythematosus (DLE) and six with systemic lupus erythematosus (SLE). Three patients received a treatment with flashlamp pulsed dye laser (FPDL) (585 nm, 450 microseconds) with fluences in the range from 5 to 7.75 J/cm(2); the other 11 patients were treated with long pulsed dye laser (LPDL) (595 nm, 1.5-10 milliseconds) with fluences in the range from 6 to 13 J/cm(2) depending on the pulse duration. RESULTS: During a median follow-up of 10 months, we observed an average improvement in over 60% of the lesions. A few side effects were observed in all patients: four had transient hyperpigmentation and one patient had light scarring. Three patients had a relapse after more than 1 year; they were then offered conventional treatment. CONCLUSIONS: We confirm that pulsed dye laser is a good alternative treatment for the erythema in active cutaneous lesions of lupus erythematosus (LE).

Matched-control retrospective study of the acute and late complications in patients with collagen vascular diseases treated with radiation therapy.

BACKGROUND: Controversy surrounds the potential complication rate of patients with collagen vascular diseases (CVD) after radiation. We assess the acute and late complications (based on Radiation Therapy Oncology Group criteria) by a matched-control retrospective study. PATIRNTS/METHODS: The charts of 12,000 patients treated with radiation therapy at the University of Louisville from 1982 to 2001 were reviewed for CVD. A total of 38 patients with documented CVD were compared with a matched-control group of 38 patients without CVD. Median follow-up for patients with CVD was 35 months. The patients were matched on the basis of site treated, age, dose, date of treatment, sex, treatment goal, follow-up, tumor site and histology, therapeutic technique, and general treatment method. The patients with CVD included 21 patients with systemic lupus erythematosus (55%), two with scleroderma (5%), four with Raynaud's phenomena (11%), three with fibromyalgia (8%), three with polymyalgia rheumatica (8%), three with Sjögren's syndrome (8%), and two with polymyositis-dermatomyositis (5%). Twenty-nine patients received curative doses, and nine patients received palliative doses. RESULTS: No difference was observed in the incidence of acute or late complications between the two groups. For CVD and matched-control patients receiving curative doses, the incidence of acute reaction for grade II was 49% versus 58% and for grade III was 7% versus 7%, respectively. The incidence of late reactions for patients with CVD and the matched control patients for grade I was 3% versus 7%, for grade II was 7% versus 3%, and for grade III was 7% versus 7%, respectively. The patients treated with palliation had a similar incidence of acute reaction in the CVD and the matched-control groups. No patients in the CVD or matched-control group had fatal complications. Only patients with scleroderma had a slight increase in acute and late complications. CONCLUSION: This is the largest matched-control study thus far in the literature. In the comparison between the patients with CVD and the matched-control patients, there was no significant difference in the incidence of acute or late complication. However, there was a higher incidence of radiation complications in patients with scleroderma. Importantly, no fatal complication was noted in any of the patients with CVD.

Ultraviolet therapy in lupus.

This review examines the use of ultraviolet (UV) therapy in lupus erythematosus (LE), a disorder usually associated with abnormally increased photosensitivity. In addition to the abnormal cutaneous response to ultraviolet radiation (UVR) exposure, photo-aggravation of systemic disease activity in systemic LE (SLE) may also occur. However, courses of UVR exposure may also be used in the treatment or prophylaxis of various photodermatoses, and LE now appears to be included in that group. Thus, several studies have reported apparent benefits of phototherapy in both cutaneous and systemic LE, although the underlying mechanisms remain obscure and final confirmation of such efficacy is still awaited in continuing studies.

UVA-1 cold light treatment of SLE: a double blind, placebo controlled crossover trial.

OBJECTIVE: Treatment of patients with systemic lupus erythematosus (SLE) often implies strong drugs with possibly serious side effects. Thus there is a need for new immunosuppressive treatments. Long wave ultraviolet A (UVA-1) cold light therapy is an anti-inflammatory, immunomodulatory treatment with a possible systemic effect and few side effects. In the current study low dose UVA-1 cold light treatment was tested to determine whether it reduces disease activity in SLE. METHODS: Eleven patients with SLE were treated with UVA-1 cold light treatment and a placebo light treatment in a double blind, placebo controlled, crossover study. In two consecutive 12 week periods the patients were treated in the first three weeks with UVA-1 and placebo treatment or vice versa. The primary variables were the SLE Disease Activity Index (SLEDAI) and SLE Activity Measure (SLAM). RESULTS: The mean SLAM and SLEDAI showed a significant decrease of 30.4% (p=0.0005) and 37.9% (p=0.016) respectively after three weeks of UVA-1 and a non-significant decline of 9.3% (p=0.43) and 12.2% (p=0.54) respectively after three weeks of placebo treatment. In this small trial the difference in reduction of the disease activity indices during UVA-1 compared with during placebo treatment failed to reach the conventional border of significance (p=0.07). The total score of quality of life measure RAND-36 did not improve significantly, but the subscore for vitality did improve. CONCLUSION: Low dose UVA-1 cold light treatment was strongly suggestive of lowering disease activity in this double blind placebo controlled study, and no side effects occurred.

[Ultraviolet A-I phototherapy for skin diseases]. / Toepassingen van ultraviolet-A-I-licht binnen de fotodermatologie.

Favourable effects of sunlight on various skin diseases include inhibition of rapid proliferation of cells (psoriasis), modulation of cells in an inflammatory infiltrate (atopic eczema) and stimulation of proteolytic enzymes (scleroderma). The ultraviolet (UV) fraction of the solar spectrum is the most biologically active because it is almost completely absorbed by the skin. UVB and the combination of psoralens with UVA (PUVA) have become important therapeutic modalities, especially for psoriasis and eczema. Lamps producing long wave UV radiation are available: UVA-I light. Owing to its longer wavelength it penetrates more deeply into the skin and gives less risk of development of skin cancer than other forms of UV radiation. Good results are reported of application of UVA-I in patients suffering from atopic dermatitis, scleroderma, urticaria pigmentosa, and systemic lupus erythematosus.

Longterm ultraviolet-A1 irradiation therapy in systemic lupus erythematosus.

OBJECTIVE: In a recent series of short term studies ultraviolet-A1 (UV-A1; 340-400 nm) dermal irradiation proved effective in reducing signs and symptoms of disease activity in patients with systemic lupus erythematosus (SLE). To determine if the effectiveness persisted with longterm therapy, we followed the progress of 6 of these patients for an average of 3.4 (range 2.4-4.5) yrs. The 6 had had significant decreases in signs and symptoms of disease activity during the first 12 weeks of the earlier studies while receiving 3 to 5 low dose UV-A1 irradiations weekly and were asked to continue into longterm therapy. METHODS: Longterm therapy consisted of 1 or 2 irradiations of 6-15 J/m2 (15-30 min, or about 1/8-1/4 minimal erythema dose) per week. We assessed their progress every 3 mo with the systemic lupus activity measures. RESULTS: Despite the smaller number of weekly treatments, the gains achieved during the initial 12 weeks of the early studies not only persisted but increased slightly. Tanning was moderate to absent, the therapy was well tolerated, and there was no apparent toxicity. CONCLUSION: UV-A1 radiation induced remissions in SLE persist with longterm therapy; 1 or 2 weekly exposures suffice; there appears to be no significant toxicity.