Vitamin D and juvenile systemic lupus erythematosus: Lights,shadows and still unresolved issues

Systemic lupus erythematosus (SLE) and juvenile SLE (jSLE) are autoimmune disorders naturally associated with several genetic, environmental, hormonal, and immunological contributing factors. It has been assumed that vitamin D deficiency may have a role in the immune activation of patients with SLE and play an active part in many comorbidities and even complications. A host of clinical studies suggested that vitamin D exerts inhibitory effects on many immunological abnormalities associated with SLE, also in children and adolescents, while different reports have hypothesized that vitamin D may be associated with accelerated cardiovascular disease in SLE. This review updates and summarizes the information related to the immunoregulatory effects of vitamin D and its importance in jSLE, discusses the innumerable correlations between vitamin D and disease activity, including clinical expression and gene polymorphisms of vitamin D receptor as well as the recommendations for vitamin D supplementation in these patients. Despite the excitement raised by many data obtained about vitamin D and its influence on several aspects of the disease, further well-designed perspective trials are required to define the exact role that vitamin D may have in the management of both SLE and jSLE.     

Annexin A1 as a target for managing murine pristane-induced systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a polygenic pathological disorder which involves multiple organs. Self-specific B cells play a main role in the lupus pathogenesis by generating autoantibodies as well as by serving as important autoantigen-presenting cells. Autoreactive T lymphocytes, on the other hand, are responsible for B cell activation and proliferation, and cytokine production. Therefore, both factors promote the idea that a down-modulation of activated self-reactive T and B cells involved in the pathogenic immune response is a reasonable approach for SLE therapy. Annexin A1 (ANX A1) is expressed by many cell types and binds to phospholipids in a Ca²⁺ dependent manner. Abnormal expression of ANX A1 was found on activated B and T cells in both murine and human autoimmunity, suggesting its potential role as a therapeutic target. While its role on T lymphocytes is through formyl peptide receptor-like molecules (FPRL), and the formed ANX A1/FPRL pathway modulates T cell receptor signalling, there is still no fool-proof data available for the role of ANX A1 in B cells. We employed a lupus model of Balb/c mice with pristane-induced SLE which very closely resembles human lupus. In the present study, we investigated the possibility to modulate the autoimmune response in a pristane-induced mouse model of SLE using an anti- ANX A1 antibody. Administration of this monoclonal antibody resulted in the inhibition of T-cell activation and proliferation, suppression of IgG anti-dsDNA antibody-secreting plasma cells and of proteinuria, decreased disease activity and prolonged survival compared to control group.     

Interleukin-17 in systemic lupus erythematosus: A comprehensive review

Abstract

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease of multifactorial pathoaetiology. One of the most serious manifestations is lupus nephritis. The pathogenesis of SLE has not been well elucidated, but it has been reported that interleukin-17 (IL-17) and Th17 cells play important roles in the pathogenesis of SLE. IL-17A, a member of IL-17 family, amplifies the immune response by inducing the local production of chemokines and cytokines, recruiting neutrophils and monocytes, augmenting the production of autoantibodies, and aggravating the inflammation and damage of target organs such as the kidney in SLE. In recent years, several IL-17A pathway inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibody and the anti-17RA monoclonal antibody. Several agents have shown great success in Phase II trials in multiple autoimmune diseases such as psoriasis, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, and non-infectious uveitis, which has sparked the urgent need of anti-IL-17A as innovative therapeutic option in controlling disease activity of moderate-to-severe SLE. Here, we review and summarize current progress in IL-17A and SLE from in vitro studies, human expression studies, and animal models, providing novel insight into its therapeutic potential.     

The natural killer T cell ligand alpha-galactosylceramide prevents or promotes pristane-induced lupus in mice

Systemic lupus erythematosus is a systemic autoimmune disease characterized by inflammation in organs such as kidneys and presence of autoantibodies against nuclear antigens. We have previously shown that CD1d deficiency in BALB/c mice exacerbates lupus nephritis and autoantibody production induced by the hydrocarbon oil pristane. Here, we have tested the impact of activating CD1d-restricted natural killer T (NKT) cells on pristane-induced lupus-like autoimmunity in BALB/c and SJL mice. Repeated in vivo treatment of pristane-injected BALB/c mice with the NKT cell ligand alpha-galactosylceramide (alpha-GalCer) prior to the onset of florid disease suppressed proteinuria, in a manner that was dependent on CD1d and IL-4 expression. In sharp contrast, however, similar treatment of pristane-injected SJL mice with alpha-GalCer resulted in increased proteinuria. Consistent with these dichotomous effects of NKT cell activation on the development of lupus-like autoimmunity, NKT cells in BALB/c and SJL/J mice exhibited a mixed Th1/Th2 and a Th1-biased cytokine production profile, respectively. These findings demonstrate that NKT cell activation with alpha-GalCer suppresses or promotes pristane-induced lupus-like autoimmunity in mice, in a strain-dependent manner.     

雷公藤内酯醇对系统性红斑狼疮患者DC细胞功能及成熟的影响

目的 通过体外实验研究雷公藤内酯醇(triptolide)对系统性红斑狼疮(systemic lupus erythematosus,SLE)患者树突状细胞(dendritic cell,DC)功能及成熟的影响,为进一步阐明雷公藤内酯醇的免疫学活性提供依据.方法 从SLE患者外周血分离单个核细胞,流式细胞仪分选DC,加入0、5、10、30μg/L的雷公藤内酯醇共孵育,24h后收集上清液,ELISA检测IFN-α、IL-6、TNF-α量,5d后收集细胞,流式细胞仪检测DC表型CD11c、CD80、CD86阳性率,光镜观察DC的形态,扫描电镜观察DC的超微结构.结果 雷公藤内酯醇显著减低活动期与非活动期SLE患者IFN-α、IL-6、TNF-α量,并呈雷公藤内酯醇浓度依赖性(P＜0.05);雷公藤内酯醇可抑制SLE患者DC的分化和成熟,并呈雷公藤内酯醇浓度依赖性(P＜0.05).结论 雷公藤内酯醇能够减弱SLE患者DC的功能,并抑制其分化和成熟.     

I型干扰素信号通路与系统性红斑狼疮发病机制的研究进展

系统性红斑狼疮（SLE）是一种常见的自身免疫性疾病,多数患者血清中干扰素-α（IFN-α）水平升高,并且在淋巴细胞和组织中出现大量IFN诱导应答基因。含有核酸的免疫复合物作为IFN—α的诱导物,结合外源性因素的作用,可激活体内依赖Toll样受体（TLR）和不依赖TLR等多条信号通路,刺激产生更多的IFN-α,形成恶性循环,启动和维持SLE的自身免疫过程。     

Alpha‐melanocyte stimulating hormone ameliorates disease activity in an induced murine lupus‐like model

Alpha‐melanocyte stimulating hormone (α‐MSH) is a neuropeptide exhibiting anti‐inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α‐MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α‐MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α‐MSH analogue [Nle4, DPhe7]‐α‐MSH (NDP–MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti‐nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α‐smooth muscle actin (α‐SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin‐releasing factor (CRF) and α‐MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)‐6, IL‐10, proteinuria and mesangial cell proliferation together with glomerular expression of α‐SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP‐MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP–MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α‐SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α‐MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.     

The genetics and biology of Irf5-mediated signaling in lupus

Recently much attention was attracted to the importance of the type I interferon pathway in the initiation and development of the autoimmune disease systemic lupus erythematosus (SLE). Many SLE patients have increased serum levels of IFN-α and display an IFN gene expression “signature” characterized by strong overexpression of IFN-responsive genes in leukocytes and target tissues. Moreover, about 20% of cancer patients treated with IFN-α therapy manifest symptoms resembling SLE and some later develop the disease. One of the key genes of the IFN-α pathway, IRF5, was found to be strongly associated with SLE. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic inserion/deletion in exon 6, which contributes to the diversity in the isoform pattern of IRF5. Interestingly, recent studies have not found association of IRF5 with the other autoimmune diseases, such as rheumatoid arthritis or psoriasis, suggesting the unique role for IRF5 in the development of lupus. Here, we present the current knowledge on IRF5 genetics and its biological function and discuss the possible ways in which IRF5 contributes to susceptibility to SLE.     

Vitamin D and systemic lupus erythematosus: an update

Vitamin D is a steroid hormone that, in addition to its actions on calcium and bone metabolism, exhibits a plethora of regulatory effects on growth, proliferation, apoptosis and function of the cells of the immune system that are relevant to the pathophysiology of systemic lupus erythematosus (SLE). Hypovitaminosis D is highly prevalent in SLE as a result of avoidance of sunshine, photoprotection, renal insufficiency and the use of medications such as glucocorticoids, anticonvulsants, antimalarials and the calcineurin inhibitors, which alter the metabolism of vitamin D or downregulate the functions of the vitamin D receptor. Low levels of vitamin D correlate with disease activity, and is associated with osteoporosis, fatigue and certain cardiovascular risk factors in SLE patients. This review updates the recent evidence on the relationship between vitamin D status and the onset, activity and complications of SLE, and summarizes the recommendations for vitamin D supplementation.     

Th1, Th2, and Th17 cytokines in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the breakdown of immune tolerance leading to excessive inflammation and tissue damage. Imbalance in the levels of cytokines represents one of the multifactorial causes of SLE pathogenesis and it contributes to disease severity. Deregulated levels of T helper type 1 (Th1), type 2 (Th2), and type 17 (Th17) cytokines have been associated with autoimmune inflammation. Growing evidence has shown deregulated levels of Th1, Th2, and Th17 cytokines in SLE patients compared to healthy controls associated with disease activity and severity. In this review, we describe and discuss the levels of Th1, Th2, and Th17 cytokines in SLE patients, and clinical trials involving Th1, Th2, and Th17 cytokines in SLE patients. In particular, with the exception of IL-2, IL-4, and TGF-β1, the levels of Th1, Th2, and Th17 cytokines are increased in SLE patients associated with disease severity. Current phase II or III studies involve therapeutic antibodies targeting IFN-α and type I IFN receptor, while low-dose IL-2 therapy is assessed in phase II clinical trials.     

Injection of IL-12- and IL-18-encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms

IL-12 and IL-18 are mediators involved in the onset and progression of the autoimmune disease developing in MRL/Mp-Tnfrsf6(lpr) (lpr) mice, which display symptoms similar to the human systemic lupus erythematosus (SLE). The pathology is characterized by progressive lymphadenopathy and auto-antibody-mediated multiple organ failure, e.g. glomerulonephritis, or pneumonitis and a concomitant increase in serum levels for IFNgamma and tumor necrosis factor-alpha (TNFalpha). In this study, we intramuscularly injected lpr mice with plasmids encoding IL-12 and IL-18, either alone or in combination, in order to affect the development of the autoimmune disease. Five biweekly injections of the combined plasmids starting at 4-5 weeks of age diminished serum levels of TNFalpha and reduced the ability of lymphocytes from treated mice to produce IFNgamma in vitro. Injection of both plasmids synergistically attenuated the development of autoimmune syndromes, lymphoproliferation in secondary lymphoid organs, proteinuria and kidney damage, and pneumonitis. We conclude that IL-12 and IL-18 synergistically affect the pathogenesis of the T(h)1-dependent autoimmune syndrome of lpr mice and that approaches that target both IL-12 and IL-18 may be a therapeutic option in the treatment of autoimmune SLE.     

Combined steroid-cyclosporin treatment of chronic autoimmune diseases

Summary Twenty-one patients suffering from different autoimmune diseases (14 from systemic lupus erythematosus, 4 from rheumatoid arthritis, one from Sjögren's syndrome, one from systemic hypersensitivity vasculitis, and one from diffuse proliferative glomerulonephritis) were treated with a combined immuno-suppressive regimen. Cyclosporin was given at a dose of 5 mg/kg/day together with steroids. In addition, the rheumatoid arthritis patients also received methotrexate. In all patients a kidney biopsy was performed after a treatment period of 17 to 42 months (mean duration 21.7 months). The cumulative cyclosporin dose at the time of biopsy varied from 1.071 to 4.587 mg/kg. Patients suffering from systemic lupus erythematosus and rheumatoid arthritis were assessed according to a scoring system set up for this purpose. The combined therapy proved useful in these patients as reflected in the diminution of the respective activity scores, improvement of kidney function, and diminution of proteinuria. Histological examination of the kidney biopsy specimens showed only minimal activity in patients with systemic lupus erythematosus. No unequivocal signs of renal toxicity could be detected. In the last group, the condition of the patient with Sjögren's syndrome was stabilized and the patient with systemic vasculitis improved clinically. Neither patient had signs of kidney lesions. The patient with diffuse proliferative glomerulonephritis, in whom kidney biopsy was performed before and after treatment, showed improvement of kidney function, diminution of proteinuria, and diminution of inflammatory activity within the kidney, and no signs of cyclosporin toxicity.Abbreviations CyA Cyclosporin - MTX Methotrexate - NSAID Nonsteroidal antiinflammatory drugs - RA Rheumatoid arthritis - SLE Systemic lupus erythematosus - TFA index Index of extent of tubular atrophy, intersitital fibrosis, and arteriolopathy     

miR-150对降植烷诱导的狼疮鼠肺出血的影响

本研究旨在观察miR-150在降植烷诱导的狼疮鼠中对肺出血的发生和严重程度的影响并初步探讨其可能的机制。实验选用8周龄C57/B6小鼠和miR-150基因缺陷小鼠,腹腔注射降植烷(pristane),在注射后的第7天、第10天、第14天观察肺脏大体病理变化,苏木素-伊红(HE)染色观察肺组织病理变化并进行病理评分。发现注射降植烷第10天和(或)第14天后C57/B6组和miR-150缺陷小鼠组均发生不同程度的肺出血,后者的严重程度大于前者。肺组织病理评分显著升高;miR-150缺陷组与C57/B6组比较血浆TNF-α表达升高,右肺上叶组织湿干比值(W/D)也显著升高。提示在降植烷诱导的狼疮鼠模型中miR-150参与了肺出血的发病过程,miR-150有望成为预测狼疮肺出血的生物标记物。     

Transgenic overexpression of anti-double-stranded DNA autoantibody and activation of Toll-like receptor 4 in mice induce severe systemic lupus erythematosus syndromes

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characteristized by the presence of autoantibodies against double-stranded DNA (anti-dsDNA) in sera at high levels. Bacterial infections in SLE are associated with higher morbidity and mortality. Our goal was to observe the interaction between these 2 factors in the pathogenesis of lupus. We generated transgenic mice with monoclonal anti-dsDNA to investigate the development of lupus. By challenging the mice in vitro and in vivo with Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPS), we were able to examine the role of bacterial infection in SLE. In our study, the transgenic mice with a secreted form of anti-dsDNA were found to have higher levels of anti-nuclear antibodies, anti-dsDNA, blood urea nitrogen, and proteinuria. The splenocytes of the mice stimulated with LPS secreted more anti-dsDNA, IFN-γ, and IL-10. After injecting them with LPS in vivo, we further found higher immune complex depositions and IL-10 in the kidneys of the transgenic mice. Moreover, the LPS-injected transgenic mice had higher mortality rate. This is the first transgenic model to demonstrate that only 2 risk factors, pathogenic anti-dsDNA and TLR4 activation, induce severe SLE syndromes in normal mice through the overproduction of IL-10 and IFN-γ. These findings imply that anti-dsDNA and bacterial infections have pivotal roles in the pathogenesis of SLE; the inhibition of TLR4 may be regarded as a therapeutic target.     

Immunomodulatory vitamin D effects on regulatory T-cells and cytokines in an in vitro study on patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting various organs. Decreased numbers of regulatory T-cells (Treg cells; CD4⁺CD25^highFoxp3⁺) are associated with the pathogenesis of SLE. A vitamin D deficiency was observed in many lupus patients. In the present study, peripheral blood mononuclear cells were isolated and cultured in the presence or absence of vitamin D, and total Tregs percentage was analyzed by flow cytometry. In addition, the level of expressions of Foxp3, TGFβ, and IL6 genes were analyzed by real-time-PCR. The results indicated that vitamin D treatment increased the percentage of Treg cells, and the expression of Foxp3 and TGFβ, and decreased the expression of IL6 in SLE patients.     

Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells

Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling.     

A subgroup of lupus patients with nephritis,innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cells and lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.     

系统性红斑狼疮患者的Th细胞亚群平衡失调的初步研究

为分析Th亚群平衡失调在系统性红斑狼疮 (SLE )发生发展中的变化特点 ,以ELISA法检测血清IL 10、IL 12水平 ,以细胞内细胞因子的流式细胞术检测SLE患者PBMC的不同Th细胞亚群分泌细胞因子的变化特点 ,应用三色荧光标记技术分析Th1/Th2细胞表型。结果显示 :SLE患者血清IL 10水平显著高于正常人 ,而IL 12呈低水平表达。SLE患者CD4 + IFN γ IL 10 + 细胞亚群百分率显著高于正常人 ,IFN γ+ IL 10 与IFN γ IL 10 + 细胞亚群的比值明显降低 ,IFN γ+ IL 10 + 双阳性的CD4 + T细胞亦显著增多。SLE患者的CD4 + CCR5 CCR3+ 细胞亚群百分率与正常人比较显著升高 ,CD4 + CCR5 + CCR3 细胞亚群与正常人比较 ,示发现有显著差异 ,CD4 + CCR5 + CCR3 /CD4 + CCR3+ CCR5 比值显著低于正常对照组。这些结果提示 :SLE高水平IL 10与IL 12的低水平表达呈负相关 ;患者体内分泌IL 10的Th细胞数增多 ;Th细胞表面趋化因子受体的表达提示SLE存在CCR5 CCR3+ 细胞亚群的优势活化、数量增多 ,CCR5 + CCR3 /CCR3+ CCR5 细胞比例失调 ,从而导致免疫网络平衡被破坏。