tretinoin and Lupus-Erythematosus--Systemic

To investigate the disturbance in serum levels of interleukin-17 (IL-17) and transforming growth factor-beta1 (TGF-β1) and gene expression of retinoic acid-related orphan receptor-gamma t (ROR-γt) and forkhead box-P3 (FOX-P3) in patients with systemic lupus erythematosus (SLE) and to study their association with disease pathogenicity and activity. Newly diagnosed active patients with SLE (n=88) and healthy volunteers (n=70) were included. Serum IL-17 and TGF-β1 were measured using enzyme-linked immunosorbent assay. Gene-expression profiles of ROR-γt and FOX-P3 were screened using real-time polymerase chain reaction. The IL-17/TGF-β1 and ROR-γt/FOX-P3 levels were also calculated. The mean age of the patients was 30.96±8.25 years; they were 82 women and 6 men. Of the patients, 11.4% manifested mild disease while 88.6% had severe disease. The serum level of TGF-β1 was significantly lower (70.2±34.9 vs. 200.23±124.77 pg/ml), while both IL-17 (614.7±317.5 vs. 279.76±110.65 pg/ml) and IL-17/TGF-β1 (18.5±30.1 vs. 1.66±0.9) levels were significantly higher, in patients than in controls (p<0.0001). The gene-expression level of FOX-P3 (0.6±0.8 vs. 13.68±39.35) was reported to be lower, while ROR-γt (3.9±3.5 vs. 1.99±2.09) and ROR-γt/FOX-P3 (18.6±21.1 vs. 7.63±17.19) levels were significantly higher, in patients than in controls (p<0.0001). Disturbance in serum levels of IL-17 and TGF-β1 in T helper-17 and T-regulatory cells proliferation was highlighted through an imbalance in the gene expression of FOX-P3 and ROR-γt, as both are signature genes for the two cell types, respectively. These findings underscore the critical role of IL-17 and TGF-β1 in SLE development, rendering them potential targets for developing novel immunotherapeutic strategies.

Topics: Adult; Eosinophil Cationic Protein; Female; Forkhead Transcription Factors; Gene Expression; Humans; Interleukin-17; Lupus Erythematosus, Systemic; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Transforming Growth Factor beta1; Tretinoin; Virulence; Young Adult

Behçet's disease (BD) and systemic lupus erythematosus (SLE) are two autoimmune inflammatory diseases of indefinite etiology. However, up till now, no study has explored the exact regulatory mechanisms of lncRNA maternally expressed gene-3 (MEG3) over the balance between regulatory T-cells (Treg) and T helper-17 (Th17) cells in BD and SLE.. The current study aimed to investigate the role of lncRNA MEG3 in the interplay between the anti-inflammatory Treg/transcription factor forkhead box P3 (FOXP3) axis versus the pro-inflammatory Th17/retinoic acid orphan receptor-γt (RORγt) axis.. 100 subjects, 35 with BD and 35 with SLE in addition to 30 healthy participants were included in the study. Gene expression analysis was performed and ShinyGO database was utilized for in-depth analysis and graphical visualization of the gene ontology (GO) and pathway enrichment analysis for lncRNA and the other target genes.. The current results demonstrate the upregulation of lncRNA MEG3 in BD but not SLE patients. Moreover, significant differences in RORγt and FOXP3 were found between BD and SLE patients. The present findings linked lncRNA MEG3 to BD activity scores as well as CRP levels. Finally, lncRNA MEG3 showed excellent diagnostic power for BD, in addition to adequate discriminative power that can be used to differentiate between BD and SLE.. The current study objectively elucidated a framework for the involvement of Treg/Th17 through transcription factors RORγt and FOXP3, in addition to their links to the downstream cytokines network including TGF-ꞵ, IL-10, IL-17 and IL-23 in BD and SLE pathogenesis and activity.

Topics: Anti-Inflammatory Agents; Behcet Syndrome; Forkhead Transcription Factors; Humans; Interleukin-10; Interleukin-17; Interleukin-23; Lupus Erythematosus, Systemic; Nuclear Receptor Subfamily 1, Group F, Member 3; RNA, Long Noncoding; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

We previously showed that all-

Topics: Animals; Bacterial Translocation; Contraindications, Drug; Dendritic Cells; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Drug Synergism; Dysbiosis; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Glomerulonephritis; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; RNA; RNA-Seq; Specific Pathogen-Free Organisms; Spleen; Terpenes; Tretinoin; Vitamin A

Recently, we demonstrated that treatment with all- trans-retinoic acid (tRA) induced a paradoxical effect on immune activation during the development of autoimmune lupus. Here, we further describe its negative effects on mediating neuroinflammation and neurodegeneration. Female MRL/lpr mice were orally administered tRA or VARA (retinol mixed with 10% tRA) from 6 to 14 weeks of age. Both treatments had a significant effect on brain weight, which correlated with histopathological evidence of focal astrogliosis, meningitis, and ventriculitis. Infiltration of CD138- and Iba1-positve immune cells was observed in the third ventricle and meninges of treated mice that co-labeled with ICAM-1, indicating their inflammatory nature. Increased numbers of circulating plasma cells, autoantibodies, and total IgG were also apparent. IgG and C3 complement deposition in these brain regions were also prominent as was focal astrogliosis surrounding the ventricular lining and meninges. Using Fluoro-Jade staining, we further demonstrate that neuroinflammation was accompanied by neurodegeneration in the cortex of treated mice compared with vehicle controls. These findings indicate that vitamin A exposure exacerbates the immunogenic environment of the brain during the onset of systemic autoimmune disease. Vitamin A may therefore compromise the immuno-privileged nature of the central nervous system under a predisposed immunogenic environment.

Topics: Animals; Autoantibodies; Brain; Complement C3; Disease Models, Animal; Female; Immunoglobulin G; Lupus Erythematosus, Systemic; Meningitis; Mice, Inbred MRL lpr; Tretinoin; Vitamin A; Vitamins

The aim of this study was to determine the role of vitamin A in modulating T helper 17 (Th17) and regulatory T cell (Treg) balance in systemic lupus erythematosus (SLE) patients. Sixty-two female SLE patients and sixty-two female controls were measured for vitamin A levels from serum by enzyme-linked immunosorbent assay (ELISA) and percentages of Th17 and Treg from peripheral blood mononuclear cells (PBMC) by flow cytometry. We also performed an in vitro study to evaluate the effects of retinoic acid treatment (0, 0.1, 0.2, and 0.3 μg/ml) in modulating Th17/Treg balance in CD4(+) T cell culture from hypovitaminosis A SLE patients. Th17 and Treg percentages from cell cultures were measured by flow cytometry. Vitamin A levels in the SLE patients were lower compared to those in the healthy control (46.9 ± 43.4 vs. 75.6 ± 73.1 ng/ml, p = 0.015). Vitamin A levels also had a negative correlation to Th17 percentages in the SLE patients (p = 0.000, R = -0.642). Th17 percentages in the hypovitaminosis A SLE patients were higher compared to those SLE patients with normal vitamin A levels (10.9 ± 5.3 vs. 2.9 ± 2.2 %, p = 0.000). Treatment of 0.3 μg/ml of retinoic acid could increase Treg differentiation (33.9 ± 1.6 vs. 21.8 ± 1.1 %, p = 0.000) and decrease Th17 differentiation (27.2 ± 2.5 vs. 37.4 ± 1.3 %, p = 0.000). In conclusion, vitamin A has important roles in modulating Th17/Treg balance in the SLE patients shown by the significant decrease of vitamin A levels in the SLE patients which negatively correlate with Th17 population, and treatment of retinoic acid could decrease Th17 and increase Treg percentages in CD4(+) T cells cultures.

Topics: Adult; Female; Flow Cytometry; Humans; Lupus Erythematosus, Systemic; Lymphocyte Activation; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin; Vitamin A; Young Adult

Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease affecting multiple organs in the body, but therapeutic options are still very limited and often come with adverse effects. Increasing evidence has underlined an important role of the Toll-like receptor 7 (TLR-7)/TLR-9/interleukin-1 receptor-associated kinase 1 (IRAK-1)/interferon regulatory factor 7 (IRF-7) pathway in the development and progression of SLE. Notably, the prolyl isomerase Pin1 is an essential regulator of IRAK-1 in TLR-7/TLR-9 signaling, but its role in SLE is unknown. We undertook this study to determine whether Pin1 is activated and plays any role in the development and treatment of SLE.. Activation of Pin1 and TLR-7/TLR-9/IRAK-1/IRF-7 signaling was determined in various cell types among peripheral blood mononuclear cells from healthy controls and SLE patients. The effects of Pin1 and TLR signaling on SLE development were determined using validated Pin1 short hairpin RNA (shRNA), Pin1 genetic knockout, and the small-molecule Pin1 inhibitor all-trans-retinoic acid (ATRA) in immune cells and in several strains of lupus-prone mice.. We found abnormal activation of Pin1 and its downstream targets IRAK-1 and IRF-7 in SLE patients. Furthermore, inhibition of Pin1 using either validated Pin1 shRNA or ATRA blocked TLR-7-induced activation of IRAK-1 and IRF-7 in SLE patient-derived immune cells. Moreover, in multiple lupus-prone animals, both Pin1 knockout and ATRA strikingly attenuated the expression of autoimmunity, including skin lesions, lymphadenopathy, splenomegaly, glomerulonephritis, proteinuria, and production of anti-double-stranded DNA antibodies and CD4-CD8- T cells, and also prolonged overall survival in MRL/lpr and B6.lpr mice.. Pin1 plays a critical role in the development of SLE, and Pin1-targeted therapy offers a promising new strategy for treating SLE.

Topics: Animals; Cell Culture Techniques; Cell Line; Flow Cytometry; Gene Knockdown Techniques; Humans; Immunoblotting; In Vitro Techniques; Interferon Regulatory Factor-7; Interleukin-1 Receptor-Associated Kinases; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Mice, Knockout; Molecular Targeted Therapy; Monocytes; NIMA-Interacting Peptidylprolyl Isomerase; RNA, Small Interfering; Signal Transduction; T-Lymphocytes; Th17 Cells; Toll-Like Receptor 7; Toll-Like Receptor 9; Tretinoin

Roles of all-trans-retinoic acid (tRA), a metabolite of vitamin A (VA), in both tolerogenic and immunogenic responses are documented. However, how tRA affects the development of systemic autoimmunity is poorly understood. Here we demonstrate that tRA have paradoxical effects on the development of autoimmune lupus in the MRL/lpr mouse model. We administered, orally, tRA or VA mixed with 10% of tRA (referred to as VARA) to female mice starting from 6 weeks of age. At this age, the mice do not exhibit overt clinical signs of lupus. However, the immunogenic environment preceding disease onset has been established as evidenced by an increase of total IgM/IgG in the plasma and expansion of lymphocytes and dendritic cells in secondary lymphoid organs. After 8 weeks of tRA, but not VARA treatment, significantly higher pathological scores in the skin, brain and lung were observed. These were accompanied by a marked increase in B-cell responses that included autoantibody production and enhanced expression of plasma cell-promoting cytokines. Paradoxically, the number of lymphocytes in the mesenteric lymph node decreased with tRA that led to significantly reduced lymphadenopathy. In addition, tRA differentially affected renal pathology, increasing leukocyte infiltration of renal tubulointerstitium while restoring the size of glomeruli in the kidney cortex. In contrast, minimal induction of inflammation with tRA in the absence of an immunogenic environment in the control mice was observed. Altogether, our results suggest that under a predisposed immunogenic environment in autoimmune lupus, tRA may decrease inflammation in some organs while generating more severe disease in others.

Topics: Age Factors; Animals; Autoimmunity; Brain; Disease Models, Animal; Female; Inflammation Mediators; Kidney; Leukocytes; Lung; Lupus Erythematosus, Systemic; Lymphatic Diseases; Mice; Mice, Inbred MRL lpr; Skin; Tretinoin

CD25(+) FOXP3(+) CD4(+) regulatory T cells (Tregs) are induced by transforming growth factor β (TGFβ) and further expanded by retinoic acid (RA). We have previously shown that this process was defective in T cells from lupus-prone mice expressing the novel isoform of the Pbx1 gene, Pbx1-d. This study tested the hypothesis that CD4(+) T cells from systemic lupus erythematosus (SLE) patients exhibited similar defects in Treg induction in response to TGFβ and RA, and that PBX1-d expression is associated with this defect.. Peripheral blood mononuclear cells (PBMCs) were collected from 142 SLE patients and 83 healthy controls (HCs). The frequency of total, memory and naïve CD4(+) T cells was measured by flow cytometry on fresh cells. PBX1 isoform expression in purified CD4(+) T cells was determined by reverse transcription polymerase chain reaction (RT-PCR). PBMCs were stimulated for three days with anti-CD3 and anti-CD28 in the presence or absence of TGFβ and RA. The expression of CD25 and FOXP3 on CD4(+) T cells was then determined by flow cytometry. In vitro suppression assays were performed with sorted CD25(+) and CD25(-) FOXP3(+) T cells. CD4(+) T cell subsets or their expansion were compared between patients and HCs with two-tailed Mann-Whitney tests and correlations between the frequencies of two subsets were tested with Spearman tests.. The percentage of CD25(-) FOXP3(+) CD4(+) (CD25(-) Tregs) T cells was greater in SLE patients than in HCs, but these cells, contrary to their matched CD25(+) counterparts, did not show a suppressive activity. RA-expansion of TGFβ-induced CD25(+) Tregs was significantly lower in SLE patients than in HCs, although SLE Tregs expanded significantly more than HCs in response to either RA or TGFβ alone. Defective responses were also observed for the SLE CD25(-) Tregs and CD25(+) FOXP3(-) activated CD4(+) T cells as compared to controls. PBX1-d expression did not affect Treg induction, but it significantly reduced the expansion of CD25- Tregs and prevented the reduction of the activated CD25(+) FOXP3(-) CD4(+) T cell subset by the combination of TGFβ and RA.. We demonstrated that the induction of Tregs by TGFβ and RA was defective in SLE patients and that PBX1-d expression in CD4(+) T cells is associated with an impaired regulation of FOXP3 and CD25 by TGFβ and RA on these cells. These results suggest an impaired integration of the TGFβ and RA signals in SLE T cells and implicate the PBX1 gene in this process.

Topics: Adult; Aged; Antineoplastic Agents; CD4-Positive T-Lymphocytes; Cell Division; Cells, Cultured; Female; Flow Cytometry; Forkhead Transcription Factors; Humans; Immunologic Memory; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Leukocyte Common Antigens; Lupus Erythematosus, Systemic; Male; Middle Aged; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin; Young Adult

Tissue and organ differentiation is tightly controlled to ensure proper development and function of the growing embryo as well as cells such as lymphocytes that differentiate throughout the adult stage. Therefore it is vital that the genes and the protein they encode that are involved in these processes function accurately. Hence, any mutation or error that occurs along the way can result in extensive damage, which is expressed in various ways in the embryo and can result in immune pathogenesis, including immunodeficiency and autoimmune diseases, when lymphocyte development is altered. A number of studies have been carried out to look at the genes regulating transcription in tissue differentiation, including the transcription factors Pbx1. This gene is of particular interest to us as we have identified that it is associated with systemic lupus erythematosus susceptibility (Cuda et al., in press). This perspective summarizes the known roles of Pbx1 in tissue differentiation as well as our recent findings associating genetic variations in Pbx1 to lupus susceptibility, and we will speculate on how this gene controls the maintenance of immune tolerance in T cells.

Topics: Animals; Cell Differentiation; Chromatin Immunoprecipitation; DNA-Binding Proteins; Genetic Loci; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Immune Tolerance; Lupus Erythematosus, Systemic; Lymphocyte Activation; Mice; Mice, Transgenic; Pre-B-Cell Leukemia Transcription Factor 1; Protein Structure, Tertiary; Proto-Oncogene Proteins; Signal Transduction; T-Lymphocytes, Regulatory; Transcription Factors; Tretinoin

A patient with systemic lupus erythematosus had the additional finding of hypertrophic lupus erythematosus. The lesions cleared with an 11-week course of isotretinoin alone. She has remained without recurrence for 9 months. This is the first reported case of total resolution of hypertrophic lupus erythematosus with a short course of isotretinoin.

Topics: Adult; Diagnosis, Differential; Female; Humans; Isotretinoin; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Tretinoin

Isotretinoin, a synthetic retinoid that has been prescribed for over 500,000 patients with cystic acne, has been associated with both spinal hyperostosis and a disorder similar to diffuse idiopathic skeletal hyperostosis. We describe a syndrome of tendon and ligament calcification, primarily in extraspinal locations, that we have observed after long-term therapy for psoriasis and disorders of keratinization with etretinate, another synthetic retinoid. Of 38 patients who had received etretinate (average dose, 0.8 mg per kilogram of body weight per day; average duration, 60 months), 32 (84 percent) had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of involvement were the ankles (29 patients [76 percent]), pelvis (20 patients [53 percent]), and knees (16 patients [42 percent]); spine involvement was uncommon in this group of etretinate-treated patients. Involvement tended to be bilateral and multifocal. Fifteen (47 percent) of the 32 affected patients had no bone or joint symptoms at the sites of radiographic abnormality. Thus, tendon and ligament calcification can occur without vertebral involvement as well as in association with it (for example, as part of the spectrum of diffuse idiopathic skeletal hyperostosis). We have identified extraspinal tendon and ligament calcification as a toxic effect that is commonly associated with long-term etretinate therapy.

Topics: Adult; Aged; Calcinosis; Etretinate; Female; Humans; Isotretinoin; Knee Joint; Ligaments; Lupus Erythematosus, Systemic; Male; Middle Aged; Pelvis; Prospective Studies; Psoriasis; Radiography; Skin Diseases; Spinal Diseases; Tendons; Tretinoin

Previous studies have shown that resident peritoneal macrophages from mice with systemic lupus erythematosus (SLE) show defective Fc-mediated phagocytosis and binding of opsonized sheep erythrocytes (EA) in vitro. Possible causes of this defect in (NZB X NZW)F1 (B/W) mice were investigated. These included a maturational block in peritoneal macrophage differentiation, the production by peritoneal cells of a factor which inhibits Fc receptor expression and phagocytosis, and an abnormal response by macrophages of autoimmune mice to prostaglandins. Resident peritoneal macrophages of B/W mice did not show a maturational block since incubation with either (a) differentiating agents such as 4 beta-phorbol 12 beta-myristate 13 alpha acetate or retinoic acid, or (b) lymphokine (LK), prepared by Con A stimulation of mouse spleen cells, failed to enhance Fc-mediated phagocytosis and binding by B/W cells relative to controls. However, LK from B/W and B6AF1 cells stimulated Fc-mediated phagocytosis and binding by bone-marrow (BM)-derived macrophages of CBA/H mice; B/W LK also stimulated BM cells from B/W mice. Peritoneal cell supernatants did not inhibit phagocytosis of Fc receptor expression by BM-derived macrophages in vitro. Prostaglandin E treatment of peritoneal or BM-derived macrophages in vitro failed to restore decreased phagocytosis and binding of EA induced by culture in indomethacin and failed to stimulate phagocytosis by untreated cultures. The reason for the observed defect remains obscure.

Topics: Animals; Bone Marrow Cells; Indomethacin; Lupus Erythematosus, Systemic; Lymphokines; Macrophages; Mice; Mice, Inbred Strains; Phagocytosis; Prostaglandins; Receptors, Fc; Tetradecanoylphorbol Acetate; Tretinoin