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

Szegedi, Andrea; Simics, Enikő; Aleksza, Magdolna; Horkay, Irén; Gaál, Krisztina; Sipka, Sándor; Hunyadi, J.; Kiss, Emese

doi:10.1093/rheumatology/keh643

Cited by 42 publications

(41 citation statements)

References 22 publications

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“…15) may at least in part be due to the generation of oxidized lipids in the skin. Some of the benefits of UVA-1 phototherapy include a decrease of T cells by UV-induced apoptosis (57) and a decrease in the Th1/ Th2 cell ratio in the inflamed tissue (58). In this context it is interesting that we previously demonstrated that oxidized phospholipids limit the capacity of DC to stimulate T cells to initiate Th-1 responses (29).…”

Section: Discussionmentioning

confidence: 99%

Photooxidation Generates Biologically Active Phospholipids That Induce Heme Oxygenase-1 in Skin Cells

Грубер

Oskolkova

Leitner

et al. 2007

Journal of Biological Chemistry

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Heme oxygenase-1 (HO-1) is a key enzyme in the cellular response to tissue injury and oxidative stress. HO-1 enzymatic activity results in the formation of the cytoprotective metabolites CO and biliverdin. In the skin, HO-1 is strongly induced after long wave ultraviolet radiation (UVA-1). Here we show that UVA-1 irradiation generates oxidized phospholipids derived from 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) that mediate the expression of HO-1 in skin cells. Using EO6 antibodies that recognize oxidized phospholipids, we show that UVA-1 irradiation of dermal fibroblasts generates oxidation-specific epitopes. Irradiation of arachidonate-containing phospholipids with UVA-1 led to formation of defined lipid oxidation products including epoxyisoprostanephosphatidylcholine that induced HO-1 expression in dermal fibroblasts, in keratinocytes, and in a three-dimensional epidermal equivalent model. In addition, we demonstrate that the oxidation of PAPC by UVA-1 is a singlet oxygen-dependent mechanism. Together, we present a novel mechanism of UVA-1-induced HO-1 expression that is mediated by the generation of biologically active phospholipid oxidation products. Because UVA-1 irradiation is a mainstay treatment of several inflammatory skin diseases, structural identification of UVA-1-generated biomolecules with HO-1-inducing capacity should lead to the development of drugs that could substitute for irradiation.

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Section: Discussionmentioning

confidence: 99%

Photooxidation Generates Biologically Active Phospholipids That Induce Heme Oxygenase-1 in Skin Cells

Грубер

Oskolkova

Leitner

et al. 2007

Journal of Biological Chemistry

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“…However, in a subgroup of patients with severe lupus nephritis, the intracellular cytokine ratio shifts to a Th1 phenotype [44, 45]. In disease-alleviated SLE patients, decreased IFN- γ -producing cells and increased IL-4-producing CD4 + T cells were observed after corticoid treatment [43] and low-dose UV phototherapy [46], respectively. Although Th1/2-related cytokines might contribute to SLE progression and severity, the cytokine profiles of activated iNKT cells from SLE patients are yet to be determined.…”

Section: Function Of Inkt Cells Associated With Sle Diseasementioning

confidence: 99%

Modulatory Function of Invariant Natural Killer T Cells in Systemic Lupus Erythematosus

Chuang

Wang

et al. 2012

Clinical and Developmental Immunology

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Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Multiple organ failure in SLE can be caused by immune dysfunction and deposition of autoantibodies. Studies of SLE-susceptible loci and the cellular and humoral immune responses reveal variable aberrations associated with this systemic disease. Invariant natural killer T (iNKT) cells are a unique subset of lymphocytes that control peripheral tolerance. Mounting evidence showing reductions in the proportion and activity of iNKT cells in SLE patients suggests the suppressive role of iNKT cells. Studies using murine lupus models demonstrate that iNKT cells participate in SLE progression by sensing apoptotic cells, regulating immunoglobulin production, and altering the cytokine profile upon activation. However, the dichotomy of iNKT cell actions in murine models implies complicated interactions within the body's milieu. Therefore, application of potential therapy for SLE using glycolipids to regulate iNKT cells should be undertaken cautiously.

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“…As to mechanisms, the therapy reportedly lowers levels of anticardiolipin antibodies 5, as in this patient, these having being cited as contributory to pulmonary hypertension 6; it lowers SSA antibodies 7, characteristically elevated in the ILD of SLE 8; it decreases proportions of cells producing interferon-gamma 9, a major effector molecule in S LE 10; and it promotes macrophage function, impaired in SLE and needed to remove apoptotic bodies, the diminished clearance of which is thought to be central in SLE 5, 11. However, what seems most germane in the specific action of UV-A1 photons on ILD and PH is its unique capacity to generate singlet oxygen, a reactive oxygen species that activates the production of heme oxygenase-1 (HO-1) 12.…”

Section: Discussionmentioning

confidence: 71%

Interstitial Lung Disease and Pulmonary Hypertension Responsive to Low-Dose Ultraviolet A1 Irradiation in Lupus

Jabara

Dahlgren²,

McGrath³

2010

JCR: Journal of Clinical Rheumatology

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In three placebo-controlled, double-blind studies, low-dose, full body UVA1 irradiation administered 2-3 times a week had a remedial action in patients with systemic lupus erythematosus (SLE) [1][2][3] . SLE Activity Measure (SLAM) and SLE Disease Activity Index (SLEDAI) scores decreased significantly. The therapy mitigated fatigue, joint pain, rashes, cognitive dysfunction, and photosensitivity within days to weeks, and over the years appeared to maintain these gains 4 . In only one of these studies was an effect on dyspnea recorded, 4/4 patients experiencing decreases 3 . Although the lungs are clearly a target in SLE, there has been no patient with pulmonary disease, prior to this report, monitored for changes in pulmonary measures during prolonged UVA1 irradiation therapy. Case ReportA 39-year-old woman with SLE of five years duration presented with fatigue, a malar rash, polyarthritis, photosensitivity, dyspnea, interstitial lung disease (ILD) and pulmonary hypertension (PH). She had a history also of mouth ulcers, intermittent leukopenia, pericarditis, and recurrent pleurisy. She had an ANA of 1: 640, an IgM anticardiolipin antibody of 21 MPL U/mL (normal: 0-9), an increased anti-RNP, and prior to entering the study, elevated anti-SSA antibodies. Anti-dsDNA antibodies were absent and the sedimentation rate, CRP, and C3 were normal throughout the study. At the outset of the treatment, the C4 was low at 16 mg/dl (normals 18-45) and the WBC 2.7 (×10 3 ), but the C4 became normal and the WBC, ranged from 4-6 (×10 3 ) after the start of therapy. She had been taking 8 mg of methylprednisolone a day and 200 mg of hydroxychloroquine twice daily for over a year. The initiation of low-dose (8J/ cm 2 ) full body, twice weekly exposures to UVA1 irradiation, as previously described 1 , led to resolution of her fatigue and malar rash within days, polyarthritis and cognitive deficits within weeks, and photosensitivity within months, during which she discontinued her prednisone but continued the hydroxychloroquine. Although the study was not directed at interstitial lung disease (ILD) or pulmonary hypertension (PH), over the long term her pleurisy subsided, dyspnea diminished, restricted pulmonary volume increased, and the DLCO as measured by single-breath standard technique increased from 14 to 24 ml/min/mmHg ( Figure), representing a 65% to 105% increase of predicted. Pulmonary pressures, measured by trans-thoracic ultrasound, decreased from 45 to 25 mmHg. Her ANA remained at 1: 640, ENA and anticardiolipin antibodies became negative, and the anti dsDNA, sedimentation rate and CRP remained normal. She gradually discontinued her prednisone and progressed through a successful pregnancy while continuing the UVA1 therapy. Unfortunately, due to an unforeseen and permanent interruption of therapy, her condition deteriorated, the DLCO decreased to 17 mm/min/mmHg ( Figure) and the patient required resumption of corticosteroid therapy. Her lung volumes worsened with pulmonary function studies revealing a mild restrictive defect....

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

Cited by 42 publications

References 22 publications

Photooxidation Generates Biologically Active Phospholipids That Induce Heme Oxygenase-1 in Skin Cells

Photooxidation Generates Biologically Active Phospholipids That Induce Heme Oxygenase-1 in Skin Cells

Modulatory Function of Invariant Natural Killer T Cells in Systemic Lupus Erythematosus

Interstitial Lung Disease and Pulmonary Hypertension Responsive to Low-Dose Ultraviolet A1 Irradiation in Lupus

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