Successful Short Desensitization Treatment Protocol with Narrowband UVB Phototherapy (TL-01) in Polymorphic Light Eruption.

INTRODUCTION: Polymorphic light eruption (PLE) is a common idiopathic photodermatosis that typically presents with pruritic papular or papulovesicular lesions on sun-exposed skin between spring and autumn. In many subjects PLE is mild, and can usually be prevented by the use of broad-spectrum topical sunscreens and a gradual increase in sunlight exposure. However, in some individuals, sunlight exposure results in florid PLE and they often benefit from prophylactic desensitization treatment using phototherapy in early spring, an artificial method that induces a "hardening" phenomenon. OBJECTIVE: To describe and evaluate the efficacy of a short desensitization protocol, based on a one-month-treatment, administered twice a week with narrow band UVB in subjects with severe polymorphic light eruption (PLE). METHODS: A retrospective, open planned and non-randomized study to assess the efficacy of UVB phototherapy in prevention of polymorphic light eruption. RESULTS: Fifteen subjects diagnosed with severe PLE were treated with the standard protocol in our Photobiology Unit between 2014 and 2015. The effect of hardening was sustained during follow up in 87.5% of desensitization treatments. A statistically significant association (p<0.05) between the years of duration of the PLE and the response to treatment was found. CONCLUSIONS: The effect of hardening was maintained in the vast majority of subjects, obtaining a good benefit with no PLE episodes during all the summer. We demonstrate that our standard protocol is effective, and produces a successful outcome for the majority of PLE subjects. Our protocol is shorter than those currently applied, being favourable both for the patient and the physician.

No significant effects of Poly(I:C) on human umbilical cord-derived mesenchymal stem cells in the treatment of B6.MRL-Fas(lpr) mice.

OBJECTIVE: Our study aimed to compare the curative effect and immunoregulation between MSCs activated by Poly(I:C) for 24hours and unactivated MSCs on lupus mice. MATERIALS AND METHODS: MSCs were pretreated by Poly(I:C) at 50µg/mL for 24h. B6.MRL-Fas(lpr) mice were divided into UC-MSC treated group, FLS treated group, Poly(I:C) preconditioned MSC treated group (P-MSC) and untreated group randomly. All treated mice were infused with 1×10(6) MSCs or FLSs at the 24th week and were sacrificed 4 weeks later. The spleen weight, serum immunoglobulin G (IgG) levels, serum anti-double stranded DNA (anti-dsDNA) antibody levels, immune cell subsets, renal lesions and IgG deposition in the kidney were evaluated. The effects of two kinds of MSCs on the proliferation and apoptosis of CD4+ T cells were detected by flow cytometry. The TLR3 expression at protein level in MSCs was assessed with and without Poly(I:C) treatment. The expression of immunoregulatory factors were detected by qRT-PCR in different dose and duration of Poly(I:C). RESULT: Poly(I:C) preconditioned MSCs had similar therapeutic effects in lupus mice compared with untreated MSCs in vivo. Furthermore, Poly(I:C) treated MSCs and untreated MSCs had comparable inhibitory effects on proliferation of T cells, and Poly(I:C) could enhance the expression of TLR3 at protein and mRNA level. Poly(I:C) could partly alter the mRNA levels of immunoregulatory factors, such as hepatocyte growth factor, transforming growth factor ß1, vascular endothelial growth factor, but did not have significant changes in cyclooxygenase 2, interleukin 6, tumor necrosis factor α, indoleamine 2,3-dioxygenase, interferon γ and chemokine (C-C motif) ligand 2. CONCLUSION: Our study did not find that Poly(I:C) treatment could enhance the therapeutic effect of MSCs in lupus mice in vivo.

Effects of water-soluble tacrolimus-PEG conjugate on insulin-dependent diabetes mellitus and systemic lupus erythematosus.

The effects of a water-soluble tacrolimus-PEG conjugate (KI-102) on insulin-dependent diabetes mellitus and systemic lupus erythematosus were investigated. KI-102 was stable at pH 4.0-4.5 and 4°C. The area under the concentration-time curve, the time of maximum concentration, and the maximum concentration were 43.4 ng·h/mL, 0.85 h, and 8.1 ng/mL, respectively, similar to those of FK506. Mice that administered KI-102 at 4.32 mg/kg had the plasma glucose concentrations that decreased to 7.5 mmol/L after 170 days, similar to that of mice administered FK506 at 0.6 mg/kg. There were no incidences of diabetes when KI-102 was administered at 86.4 mg/kg after 24 weeks. The group that administered 43.2 mg/kg had decreases in the concentrations of ß-hydroxybutyrate (60%), triglyceride (24%), and cholesterol (30%). KI-102 administered at 180 mg/kg reduced serum anti-dsDNA antibody activity by 64% compared with a control. Urinary albumin concentration in the same group decreased 81% compared with the control. These results indicate that KI-102 may be practically applicable as prodrug of FK506.

[Therapeutic effect of mineral water of the Belokurikha spa resort on the level of antinuclear antibodies and chromosomal aberrations in synovial cells of patients with osteoarthrosis].

The objective of this study was chromosomal analysis and measurement of anti-nuclear antibody level in synovial cells of 28 patients aged between 35 and 50 years with knee joint osteoarthrosis before and after radon therapy at an equivalent doe of 280 mSv per treatment course. It was shown that the presence of osteoarthrosis was associated with a rise in the number of synoviocytes characterized by cytogenetic defects in the form of various chromosomal aberrations the frequency of which positively correlated with the number of anti-nuclear antibodies. Radon therapy brought about a decreases in the titers of antinuclear antibodies in synovial cells and the number of chromosomal aberrations in their nuclear apparatus. These changes were accompanied by the enhancement of mitotic activity of synoviocytes, stimulation of protein synthesis in these cells, and activation of proliferative processes in the synovial medium of the joints.

Bullous systemic lupus erythematosus responding to dapsone.

A 29-year-old woman with a 4-week history of systemic lupus erythematosus presented acutely with a severe generalized tense vesicular and bullous eruption with involvement of mucosal surfaces. At the time of her initial diagnosis of systemic lupus erythematosus, she had declined treatment, preferring to explore complementary medical therapies. Skin biopsy showed subepidermal blister formation with inflammation at the dermoepidermal junction. Direct immunofluorescence revealed strongly positive linear deposition of IgG and IgM, and positive linear granular deposition of IgA along the basement membrane zone. Electron microscopy showed that the level of the basement membrane split was below the lamina densa. A diagnosis of bullous systemic lupus erythematosus was made and dapsone was commenced, with a dramatic improvement in her skin eruption. The patient again declined further treatment of her systemic disease and sought complementary therapies, and subsequently presented with cerebral involvement.

A new oligonucleotide-based ELISA for the detection of anti-double-stranded DNA antibodies.

The detection and measurement of antibodies to double-stranded (ds) DNA is important in the diagnosis and monitoring of patients with systemic lupus erythematosus (SLE). Several methods are available for their determination but none of them is completely satisfactory. Usually, purified dsDNA from different sources is used as antigen in the solid (enzyme-linked immunosorbent assay, ELISA) or liquid phase (Farr assay). Alternatively, anti-dsDNA antibodies can be demonstrated by immunofluorescence, using the haemoflagellate Crithidia luciliae (CLIFT). We have developed a new oligonucleotide-based anti-dsDNA ELISA in which dsDNA, constituted of a 5'photobiotinylated nucleic acid probe and its highly specific complementary oligonucleotide, is formed onto the solid-phase. To do that, a 40 bp probe is coated on the microplate wells via streptavidin-biotin bond and the in vitro (in solid-phase) developed hybrid between probe and its complementary helix used as capturing antigen. The assay has proved to be specific and the several experiments performed to ascertain the absence of single-stranded DNA (ssDNA) contamination and/or non specific binding to plastic, streptavidin, probe (without complementary chain) have all excluded any significant interference. To evaluate the clinical performance of this new assay, 114 serum samples from 68 SLE patients and 85 samples from 85 disease controls, in addition to 30 blood donors, were studied. The results were compared with commercial ELISAs, Farr assay and indirect immunofluorescence. The sensitivity and specificity were 66.2 and 96.4%, respectively, comparable and even better than those of the commercially available anti-dsDNA kits. Anti-dsDNA antibody levels, measured with the oligonucleotide-ELISA, correlated with SLE clinical activity determined using the European Consensus Lupus Activity Measurement (ECLAM) (r = 0.59, p < 0.0001). In conclusion, this assay has proved to be reproducible, and the results correlate well with other standard anti-dsDNA assays. The features of this new assay make it promising for clinical use.

Dietary fish oil increases CD8+ T-cells and decreases autoreactive T-cell activity in autoimmune NZB/W F1 mice.

To further elucidate the effect of different dietary fats on the pathogenesis of autoimmune diseases, five groups of New Zealand black/white (NZB/W) F1 mice were fed diets containing 200 g of different dietary fats including palm oil, lard-soybean oil (1:1, w/w), soybean oil, canola oil or fish oil. Serum levels of anti-DNA antibodies, proteinuria were followed every month and life span of the mice was determined. After 5 months of the respective diets, mice were killed at the age of 7 months and phenotypic analysis of splenic cells and peritoneal resident cells was performed. The pattern of production of cytokines in splenic T-cells was also investigated. The peritoneal resident cells were isolated for measurement of prostaglandin E2 (PGE2) levels. Significantly lower immunoglobulin G (IgG) anti-single-stranded DNA (ssDNA) and anti-double-stranded DNA (dsDNA) antibody levels were associated with less severe proteinuria and prolonged life span in mice fed dietary fish oil compared to mice fed other dietary oils. Phenotypic analysis of spleen cells showed increased CD8+ T-cells in the mice fed dietary fish oil compared to mice of the other dietary groups, and the percentage of natural killer (NK) cells in the mice fed dietary fish oil was also higher compared to the other dietary groups. The peritoneal resident cells produced lower PGE2 in mice fed fish oil compared to mice in the other dietary groups. To further investigate the effect of fish oil on autoreactive T-cells, splenic T-cells purified using a nylon wool column were stimulated with non-T-cells of young NZB/W F1 mice. Our data suggest that the anti-DNA antibody augmentation ability of T-cells in mice fed dietary fish oil was significantly decreased compared to mice in the other dietary groups. These data indicate that dietary fish oil might maintain the existence of CD8+ T-cells, decrease autoreactive T-cell activity and alleviate subsequent autoimmune processes in autoimmune prone NZB/W F1 mice.

Patología molecular de los gliomas / Molecular biology of gliomas

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Inhibition of autoimmune deterioration in MRL/lpr mice by vitamin E.

The potential of the antioxidant vitamin E to modulate the progress of the SLE-like (systemic lupus erythematosus) autoimmune disease in MRL/MP-lpr/lpr (MRL/lpr) mice is described. Mice were orally supplemented with 0.4 mg vitamin E per day 5 times per week from week 8 of age onwards and compared with mice on a commercial or a vitamin E-deficient diet. Supplementation with vitamin E extended the mean survival time from 157 to 196 days; the massive spleen and lymph node enlargements were reduced; mitogenic responses of B and T cells were normalized; the abnormal differentiation patterns of thymic and splenic cell sub-populations were changed; titers of anti-double stranded DNA antibodies, concentrations of serum amyloid P component (SAP, an acute phase protein), and proteinuria were reduced. The results indicate that vitamin E beneficially affects the development of the SLE-like disease in MRL/lpr mice suggesting a possible measure to reduce human SLE and probably various other autoimmune diseases in humans as well.

Clinical, laboratory, phototest and phototherapy findings in polymorphic light eruptions: a retrospective study of 133 patients.

In the present study, we retrospectively evaluated the clinical, laboratory, phototest and phototherapy findings in 133 patients (109 females and 24 males) with polymorphic light eruption (PLE). The median age of the patients at onset of PLE was 26 years (range, 3-62 years). The median duration of PLE at presentation was 6.5 years (range, 1 week to 25 years). Interestingly, we found two peaks in the distribution curve of the individual latent interval, the time between light exposure and the appearance of skin lesions. The first peak occurred at 1-1.5 hr and the second peak at 24 hrs after light exposure. Six of 33 patients tested had antinuclear antibodies (ANA). However, none of these ANA-positive patients had or developed systemic lupus erythematosus during follow-up. Phototesting revealed that minimal erythema doses for UVA and UVB fell within normal limits in 30 patients tested. Provocative phototesting was positive in 17 of 30 (57%) patients tested. The action spectrum fell within the UVA range in 10 (59%), the UVB range in 4 (23%), and both ranges in 3 (18%) of the 17 cases. Ninety-two patients received preventive phototherapy including broad-band UVB, broad-band UVA, or psoralen and ultraviolet A (PUVA). Follow-up information was available for 79 of these patients: the complete protection rate in the first summer season after therapy was 27% for UVB, 0% for UVA, and 53% for PUVA whereas the overall protection rate (including partial and complete responders) was 83% for UVA, 82% for UVB and 65% for PUVA. In contrast, the patients' histories revealed that the use of a sunscreen with a mean sun protection factor (SPF) of 14 did not prevent skin lesions in 88% of PLE patients.

[Functional analysis of an autoantigen reactive B cell clone derived from MRL/MP-lpr/lpr mice].

MRL/MP-lpr/lpr (MRL/lpr) mice are known to provide a good model for the study on the pathogenesis of systemic lupus erythematosus with massive involvement of abnormal T lymphocytes in the spleen and lymphonodes. However, a direct role of B cells of MRL/lpr mice in autoimmune responses is not clear until this time. In the present study, to investigate the characteristic of B cells of the mice, we tried to establish a B cell clone after hybridization between splenic B cells of these mice and 2.52 M, a HAT selective medium sensitive mutant B cell line in the presence of polyethylene glycol and dimethyl sulfoxide and examined its response to autoantigens. MRL27.4, a subclone of a resulting hybridoma, expressed IgM, B220, IKk, ICAM-1, and LEA-1 on the cell membrane as well as CD5 molecules by analysis with flow microfluorometory (FMF). Also, MRL27.4 was shown to exhibit rosette formation against blood cells treated with bromelain (Br-RBC) at a frequency of more than 95%, and to express DNA-receptor (DNA-R) on its surface by FMF analysis with biotin-labeled ssDNA. In contrast, the parental 2.52 M did not form rosettes with Br-RBC and the expression of DNA-R on the cell membrane of 2.52 M was significantly less compared with that of MRL27.4. Interestingly, MRL27.4 produced a high titer of IgM-anti-ssDNA antibodies and IL-6 after treatment with the purified RBC membrane or immobilized DNA. On the other hand, the parental 2.52 M neither produce IgM-anti-ssDNA antibodies nor IL-6 under the same conditions. The results suggest that MRL27.4 is an autoantigen reactive B cell clone derived from MRL/lpr mice and its surface DNA-R, by itself, function to autoantigens. In this process, there might be an autocrine network mediated by IL-6. In conclusion, MRL27.4 provides a good model for the study on the direct function of B cells of MRL/lpr mice during abnormal immune responses to autoantigens.

Combined treatment of autoimmune MRL/MP-lpr/lpr mice with a herbal medicine, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to) plus suboptimal dosage of prednisolone.

Therapeutic effects of combined treatment with a Chinese medicine prescription, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT) and suboptimal doses of prednisolone (PSL) on pathological findings of autoimmune-prone MRL/lpr mice were examined. Six-week-old MRL/lpr mice were treated orally with 1000 mg/kg of NYT, 0.5 or 2 mg/kg of PSL, 1000 mg/kg of NYT plus 0.5 or 2 mg/kg of PSL (combined treatment) or solvent only (control) six times per week. The rates of signs and symptoms of autoimmune disease (lymphadenopathy, proteinuria, dermatitis, loss of hair) were suppressed significantly in groups given PSL (2 mg/kg) alone, NYT alone and combined treatment with PSL (2 mg/kg) plus NYT (1000 mg/kg) compared with control, respectively, whereas treatment with PSL (0.5 mg/kg) alone did not inhibit their occurrence. ConA response and IL-2 production were also improved significantly in lymphocytes of mice given the combined treatment. Interestingly, treatment with NYT alone enhanced further the augmented IFN-gamma production in MRL/lpr mice but the combined treatment suppressed such an augmented production. The combined treatment dramatically reduced the level of anti-DNA antibodies in serum of MRL/lpr mice. By contrast, NYT alone treatment had no effect on autoantibodies production. These results suggest that combined treatment with NYT plus a suboptimal dose of PSL could be effective for systemic lupus erythematosus without severe side-effects.

Antinuclear antibodies are not induced by PUVA treatment in patients with uncomplicated psoriasis.

BACKGROUND: Previous investigations of antinuclear antibody (ANA) prevalence in patients undergoing PUVA therapy reported contrasting results. However, ANA tests were performed on low-sensitivity substrates that do not allow investigation of anti-Ro (SS-A) antibodies. OBJECTIVE: We assessed ANAs on a highly sensitive substrate. METHODS: ANAs were assayed on HEp-2 cells at regular intervals in 238 patients with psoriasis who were treated with PUVA therapy for 1 to 5 years and in 118 untreated control subjects with psoriasis. In addition, radioimmunoassay and counterimmunoelectrophoresis studies of anti-DNA and anti-extractable nuclear antigen antibodies were performed. RESULTS: Low titers of ANA developed in three patients in at least two consecutive determinations and in 10 patients in a single determination despite continuing treatments. The positive conversion rate was not statistically significant. Radioimmunoassay counterimmunoelectrophoresis studies of anti-DNA and anti-extractable nuclear antigen antibodies were never positive. CONCLUSION: In our experience PUVA therapy does not represent a risk factor for the induction of anti-Ro antibodies and other ANAs.

Novel autoimmune phenomena induced in vivo by a new DNA binding protein Nuc: a study on MRL/n mice.

We previously purified a 55 kDa protein that preferentially expands anti-DNA antibody production both in vitro and in vivo across the H-2 barrier from culture supernatants of KML1-7 cells, cloned from a lupus-prone MRL/lpr mouse. By using the purified protein, termed nucleobindin (Nuc), we cloned cDNA and produced recombinant(r) Nuc in Escherichia coli. To elucidate the function of rNuc in vivo, we initially injected intraperitoneally 5 micrograms of rNuc without adjuvant into female MRL/n mice at 8 weeks of age and continued injection twice a week. As early as 5 weeks after administration, all mice treated showed an increase in IgG anti-double stranded (ds) DNA antibodies accompanied by IgG hypergammaglobulinemia (HG). Of particular interest was that these mice also produced anti-U1RNP antibodies and rheumatoid factor (RF) of IgG class, but not anti-Sm antibodies. Histopathologically, hypercellularity with occasional crescents in the glomeruli was observed, but evidence for lupus nephritis was lacking, indicating that some factors other than Nuc are necessary for the development of a lupus syndrome observed in MRL/lpr mice. Similar administration of lipopolysaccharide into MRL/n mice failed to induce autoantibodies except for a slight increase in serum IgG, suggesting that these autoimmune responses are not due simply to polyclonal B-cell activation. The presence of rNuc will give us a clue for further understanding of autoimmunity.

Toxoplasma pericarditis mimicking systemic lupus erythematosus. Diagnostic and treatment difficulties in one patient.

A life-threatening T. gondii pericarditis developed in a patient with symptoms corresponding to systemic lupus erythematosus (SLE) with high concentrations of antinuclear antibodies and lymphadenopathy. The diagnosis would have been SLE-associated serositis, had not pericardial fluid been inoculated into mice, because pericarditis is frequently seen in SLE and false positive toxoplasma seroreactions may occur in ANA positive patients. High IgG T. gondii antibodies without increased IgM antibodies indicated reactivation rather than primary infection. Prolonged high-dose treatment with pyrimethamine-sulphadiazine was needed. Interestingly, the patient's SLE symptoms, including high ANA antibodies, declined to an unexpected remission after treatment for toxoplasmosis. This may not be mere coincidence, but may point to a causative role of toxoplasmosis in some cases of SLE.

[Toxic oil syndrome--an example of an exogenously-induced autoimmune disease]. / Das Toxische-Ol-Syndrom ("toxic oil syndrome")--Beispiel einer exogen induzierten Autoimmunerkrankung.

In 1981 epidemic poisoning with adulterated cooking oil occurred in Spain, affecting more than 20,000 people. The condition caused has since become known as the toxic oil syndrome (TOS). About 10-15% of the patients with acute symptoms developed a chronic disease with scleroderma-like skin manifestations, polyneuropathy and myositis. While the acute phase of the TOS was characterized by eosinophilia and elevated IgE, the chronic stage involved humoral autoimmune phenomena, such as antinuclear and antinucleolar antibodies, in many cases. In women with the chronic phase of TOS there was a possible prevalence of HLA-DR3 and HLA-DR4. The recently characterized eosinophilia-myalgia syndrome (EMS), which is thought to have been induced by contaminated L-tryptophan preparations, is similar to the TOS in some particulars. Understanding of the toxicological, immunological and genetic pathways leading to these diseases might give us some insight into the pathogenesis of spontaneously occurring autoimmune diseases, such as systemic scleroderma.

[The Ro/SSA antigen-antibody system. Studies of the effect of UVA-/PUVA irradiation and fibroblast activity on immune reaction with autoantibodies]. / Das Ro/SSA-Antigen-Antikörper-System. Untersuchungen zum Einfluss von UVA-/PUVA-Bestrahlung und Fibroblastenaktivitat auf die Immunreaktion mit Autoantikörpern.

The Ro/SSA antigen-antibody system is of great importance with regard to the cutaneous manifestations and the photosensitivity of patients suffering from lupus erythematosus (LE). On account of in vitro investigations on cultured fibroblasts taken from psoriatic skin, we evaluated both the effect of UVA/PUVA irradiation and that of the metabolic activity of cells on this antigen-antibody system. We found that UVA irradiation is able to demask Ro/SSA. Thus it becomes accessible so subsequent antibody binding, which can be seen as nuclear fluorescence positive for IgM. Incubation of vital cells with these autoantibodies and subsequent irradiation resulted in a high degree of cytoplasmic fluorescence (IgG, IgM) in part of the fibroblasts exposed to UVA. Regarding the clinical application of light protective agents in LE patients with antibodies to Ro/SSA, UVA light--aside from UVB--should be taken into consideration.