Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
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PMID:[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases]. 857 69

The purpose of this study was to evaluate whether vitamin D receptor (VDR) genes BsmI polymorphisms were markers for susceptibility to or severity of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 47 Chinese patients with SLE. In addition, 90 unrelated, healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of polymerase chain reaction (PCR)-based restriction analysis. A PCR product length was determined to be 580bp (BB) whereas two fragments of 405 and 175bp were determined to be excisable lengths (bb) by BsmI endonuclease. The relationship between Bsm polymorphisms and clinical manifestations of SLE was evaluated. We found that BB was significantly more common and bb less common in SLE than in control group (chi2 = 54.2, P < 0.0001). In addition, the frequency of B allele was also significantly more common in patients with SLE than in the healthy control subjects (chi2 = 38.7, P < 0.0001), giving an odds ratio of 7.14 (95% confidence interval 3.53-14.4). In the SLE patients, we did not detect any associations of VDR genotype with the clinical, laboratory profiles, or lupus nephritis (chi2 = 2.34, P = 0.3). This study indicated an increased distribution of VDR BB genotype and B allelic frequencies in the Chinese SLE patients in Taiwan. However, there were no associations between the frequency of VDR allelic variations and clinical manifestations, laboratory profiles, or lupus nephritis.
Lupus 2002
PMID:Association of vitamin D receptor gene BsmI polymorphisms in Chinese patients with systemic lupus erythematosus. 1189 16

The analysis of the molecular basis of autoimmune diseases is currently under intense investigation. The identification of novel mechanisms underlying the pathogenesis of these diseases generates the possibility for the development of new therapeutic agents. In this review we summarize the results leading to novel insights concerning the molecular processes involved in the pathogenesis of rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis and diabetes type 1. We focus on the role of transcription factors such as nuclear factor kappa B, activator protein 1, peroxisome proliferator-activated receptor, vitamin D receptor and the glucocorticoid receptor that mediate pro- and anti-inflammatory effects and therefore represent direct or indirect targets for therapeutic intervention.
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PMID:Transcription factors in autoimmune diseases. 1537 67

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

The immunomodulatory role of 1,25-dihydroxyvitamin D3 is well known. An association between vitamin D receptor (VDR) gene BsmI polymorphisms and systemic lupus erythematosus (SLE) has been reported. To examine the characteristics of VDR gene BsmI polymorphisms in patients with SLE and the relationship of polymorphisms to the susceptibility and clinical manifestations of SLE, VDR genotypings of 101 Thai patients with SLE and 194 healthy controls were performed based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between VDR gene BsmI polymorphisms and clinical manifestations of SLE was evaluated. The distribution of VDR genotyping in patients with SLE was 1.9% for BB (non-excisable allele homozygote), 21.78% for Bb (heterozygote), and 76.23% for bb (excisable allele homozygote). The distribution of VDR genotyping in the control group was 1.03% for BB, 15.98% for Bb, and 82.99% for bb. There was no statistically significant difference between the two groups (p = 0.357). The allelic distribution of B and b was similar within the groups (p = 0.173). The relationship between VDR genotype and clinical manifestation or laboratory profiles of SLE also cannot be statistically demonstrated. In conclusion, we cannot verify any association between VDR gene BsmI polymorphism and SLE. A larger study examining other VDR gene polymorphisms is proposed.
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PMID:Vitamin D receptor gene BsmI polymorphisms in Thai patients with systemic lupus erythematosus. 1650 61

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)(2)D(3) levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1,25(OH)(2)D(3) on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)(2)D(3), although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1 alpha-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)(2)D(3) and/or activation. Importantly, 1,25(OH)(2)D(3) up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1,25(OH)(2)D(3) may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.
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PMID:Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. 1764 Oct 30

The identification of vitamin D receptor in cells involved in the immune response and the discovery that activated dendritic cells produce vitamin D hormone suggested that vitamin D could exert immunoregulatory effects. Patients with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE) show low 25-OH vitamin D serum levels. In particular, SLE patients have multiple risk factors for vitamin D deficiency and disease severity seems correlated with lower 25-OH vitamin D serum levels. Treatment of vitamin D deficiency could be particularly important in SLE patients due to concomitant insults on their tissues such as bone, and in view of the possible immunomodulatory effects exerted by vitamin D.
Lupus 2008 Jan
PMID:Review: vitamin D, immunity and lupus. 1808 76

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D(3), is a secosteroid hormone essential for bone and mineral homeostasis. It regulates the growth and differentiation of multiple cell types, and displays immunoregulatory and anti-inflammatory properties. Cells involved in innate and adaptive immune responses--including macrophages, dendritic cells, T cells and B cells--express the vitamin D receptor (VDR), and can both produce and respond to 1,25(OH)(2)D(3). The net effect of the vitamin D system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity. Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will guide the development of pharmacological VDR agonists for use in the clinic. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus erythematosus, and possibly also multiple sclerosis, type 1 diabetes, inflammatory bowel diseases, and autoimmune prostatitis.
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PMID:Control of autoimmune diseases by the vitamin D endocrine system. 1859 91

It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.
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PMID:Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. 1954 51

Recent research has implicated vitamin D deficiency (serum levels of 25-hydroxyvitamin D <50 nmol/L) with a number of chronic conditions, including autoimmune conditions such as multiple sclerosis, lupus, and psoriasis, and chronic conditions such as osteoporosis, osteoarthritis, metabolic syndrome, fibromyalgia and chronic fatigue syndrome. It has been assumed that low levels of 25-hydroxyvitamin D (25-D) accurately indicate vitamin D storage and vitamin D receptor (VDR)-mediated control of calcium metabolism and innate immunity. To evaluate this assumption, 25-D and 1,25-dihydroxyvitamin D3 (1,25-D) levels were measured in 100 Canadian patients with these conditions. Additionally, other inflammatory markers (CK, CRP) were measured. Results showed a strong positive association between these autoimmune conditions and levels of 1,25-D >110 pmol/L. However, there was little association with vitamin D deficiency or the other inflammatory markers, meaning that the results challenge the assumption that serum levels of 25-D are a sensitive measure of the autoimmune disease state. Rather, these findings support the use of 1,25-D as a clinical marker in autoimmune conditions. High levels of 1,25-D may result when dysregulation of the VDR by bacterial ligands prevents the receptor from expressing enzymes necessary to keep 1,25-D in a normal range.
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PMID:Vitamin D metabolites as clinical markers in autoimmune and chronic disease. 1975 77


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