cholecalciferol and Autoimmune-Diseases

Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.

Topics: Autoimmune Diseases; Cholecalciferol; Chronic Disease; Humans; Vitamin D Deficiency

Vitamin D deficiency is an established risk factor for many autoimmune diseases and the anti-inflammatory properties of vitamin D underscore its potential therapeutic value for these diseases. However, results of vitamin D3 supplementation clinical trials have been varied. To understand the clinical heterogeneity, we reviewed the pre-clinical data on vitamin D activity in four common autoimmune diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), in which patients are commonly maintained on oral vitamin D3 supplementation. In contrast, many pre-clinical studies utilize other methods of manipulation (i.e. genetic, injection). Given the many actions of vitamin D3 and data supporting a vitamin D-independent role of the Vitamin D receptor (VDR), a more detailed mechanistic understanding of vitamin D3 activity is needed to properly translate pre-clinical findings into the clinic. Therefore, we assessed studies based on route of vitamin D3 administration, and identified where discrepancies in results exist and where more research is needed to establish the benefit of vitamin D supplementation.

Topics: Autoimmune Diseases; Cholecalciferol; Humans; Receptors, Calcitriol; Vitamin D Deficiency

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Autophagy; Benzylisoquinolines; Cholecalciferol; Humans; Immune System Diseases; Immunity, Innate; Indoles; Infections; Isoquinolines; Lysosomes; Maprotiline; Metformin; Neoplasms; Phenols; Pyrroles; Resveratrol; Sirolimus; Spermidine; Stilbenes; Tetrahydroisoquinolines; Trehalose

Relapsing polychondritis (RP) is a rare autoimmune-mediated disease characterized by inflammation involving cartilaginous tissues. We report here a case of RP in a 38-year-old Japanese man with 13-year duration of psoriasis vulgaris treated with topical steroids and vitamin D

Topics: Adalimumab; Administration, Cutaneous; Adult; Antirheumatic Agents; Autoantibodies; Autoimmune Diseases; Biopsy; C-Reactive Protein; Cholecalciferol; Collagen Type II; Ear Cartilage; Glucocorticoids; Humans; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 3; Polychondritis, Relapsing; Psoriasis; Severity of Illness Index

Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; B-Lymphocytes; Cholecalciferol; Dendritic Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immune Tolerance; Nitriles; Sulfones; T-Lymphocytes

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Topics: Antigen Presentation; Autoimmune Diseases; Bacterial Infections; Blood Bactericidal Activity; Cathelicidins; Cholecalciferol; Gene Expression Regulation; Humans; Immunomodulation; Inflammation; Signal Transduction; Skin

Vitamin D3 deficiency and insufficiency are common in women of child-bearing age. This may be cause for concern because vitamin D3 is a well known regulator of immune function and epidemiological evidence has suggested that immune disorders, including autoimmune diseases, could have developmental origins. However, it is not known whether a developmental deficiency in vitamin D3 could lead to persistent changes in the immune system in adult offspring. Given the prominence of receptors for vitamin D3 within immune cells we hypothesised that the developmental absence of vitamin D3 may alter thymic development and thus produce associated functional changes in T cells. We have developed a model of developmental vitamin D3 (DVD) deficiency in Sprague-Dawley rats, in which the vitamin D3 deficiency is transient and restricted to gestation. First we demonstrate that DVD deficiency induced an increase in central but not peripheral immune organ size. Second when stimulated, lymphocytes from DVD-deficient rats exhibit a pro-inflammatory phenotype. This is the first study to show that a transient vitamin D3 deficiency restricted to gestation can persistently alter aspects of immune phenotype and function in the adult offspring. Given an increased incidence of vitamin D3 deficiency in women of child-bearing age these findings may be highly relevant for autoimmune disorders with a developmental basis.

Topics: Animals; Autoimmune Diseases; Cholecalciferol; Cytokines; Disease Models, Animal; Female; Immune System; Immunophenotyping; Leukocytes, Mononuclear; Lymphocytes; Models, Biological; Organ Size; Rats; Rats, Sprague-Dawley; Th1 Cells; Vitamin D Deficiency

Vitiligo is a multifactorial disorder characterized by the appearance of white maculae that may spread over the entire body skin. Depigmentation arises from the loss of functioning melanocytes. Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity. Segmental vitiligo (SV) frequently stabilizes few years after its onset. Vitiligo etiology involves multiple pathogenetic factors, most of them working in concert. Impaired antioxidative defences lead to accumulation of reactive oxygen species (ROS), which affect melanocytes. Mitochondrial membrane lipid peroxidation may participate to ROS overproduction. A temporal sequence may connect oxidative stress and autoimmunity. Overall, a genetic predisposition renders vitiligo melanocytes more susceptible to precipitating factors than normal healthy melanocytes. The definition of isolated or superimposed manifestations of polygenic skin disorders has been proposed for SV and SV-NSV association. Keratinocytes and melanocytes are both affected and apoptosis, ageing or melanocythorragy are the ultimate effects of the complex deregulation in vitiligo skin. Pathogenetic therapies mainly act by inducing immunosuppression and stimulation of melanocyte proliferation and migration. Here the most popular hypotheses for the pathogenesis of vitiligo are summarized. Fundamental cellular, biochemical and molecular alterations accounting for melanocyte destruction in vitiligo are also described. Last, pathogenetic approaches in the treatment of such a complex disease are discussed, with particular consideration on the cellular and molecular targets of the current therapies.

Topics: Animals; Antioxidants; Apoptosis; Autoimmune Diseases; Calcineurin Inhibitors; Cholecalciferol; Dermatologic Agents; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Melanocytes; Oxidative Stress; Photochemotherapy; Skin Transplantation; Vitiligo

There is a recent renewed interest in vitamin D metabolism and pathophysiology, due to its recent description as a hormone with a positive impact on global health rather than a strictly bone hormone: vitamin D could be a protective factor against infection, autoimmunity, cardiovascular morbidity, and cancer. By contrast, vitamin D deficiency appears to be increasingly frequent worldwide. We propose a review of these new aspects of vitamin D metabolism, with a focus on vitamin D status in a local pediatric cohort. There is an urgent need for revisiting current guidelines on vitamin D supplementation and for closely monitoring serum vitamin D in children with chronic diseases, i.e., at greater risk of cardiovascular impairment, bone morbidity, infectious disease, and acute inflammation.

Topics: Autoimmune Diseases; Bacterial Infections; Bone and Bones; Bone Density Conservation Agents; Bone Diseases; Cardiovascular Diseases; Child; Cholecalciferol; Evidence-Based Medicine; France; Global Health; Humans; Inflammation; Meta-Analysis as Topic; Neoplasms; Prevalence; Risk Factors; Virus Diseases; Vitamin D; Vitamin D Deficiency

Vitamin D has many important roles in calcium and phosphorus metabolisms, the prevention of the cancer, therapeutic effects of autoimmune disease, and the protective effects on the atherosclerotic cardiovascular disease and diabetes. These functions are quite essential factors for the treatment of anti-aging medicine. We had given 1,000 IU/day vitamin D(3) to the patients who had low vitamin D levels in their blood and confirmed the increased vitamin D levels into the optimal range after the treatment. To keep the normal functions of the bone mineral metabolisms and the immune function, it is clinically relevant to detect the vitamin D levels in the blood and support these levels using supplements in the vitamin D deficient patients. Vitamin D is now one of the most essential vitamins in the anti-aging medicine.

Topics: Aging; Atherosclerosis; Autoimmune Diseases; Bone and Bones; Calcium; Cholecalciferol; Diabetes Mellitus; Female; Humans; Male; Neoplasms; Phosphorus; Vitamin D

Topics: Administration, Topical; Adrenal Cortex Hormones; Antioxidants; Autoimmune Diseases; Calcineurin Inhibitors; Cholecalciferol; Humans; Laser Therapy; PUVA Therapy; Tumor Necrosis Factor-alpha; Ultraviolet Therapy; Vitiligo

The high prevalence of vitamin D deficiency and insufficiency in the human population results from its inadequate cutaneous production and low dietary intake. Vitamin D status in the organism is determined by circulating levels of 25-hydroxycholecalciferol [25(OH)D3]. 25(OH)D3 is metabolized by a renal 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) into the vitamin D hormone 1,25 dihydroxycholecalciferol (calcitriol), which generates a wide range of biological responses via both the regulation of gene transcription and nongenomic pathways. Most of the circulating metabolite originates from cholecalciferol, which is synthesized in the skin upon exposure to the UVB spectrum of sunlight. The dietary source of vitamin D is extraordinarily low (10%) compared with endogenous production (90%). Recent epidemiological data demonstrated a strong association between poor vitamin D status (i.e. serum 25(OH)D3 levels below 50 nmol/l) and increased risk for chronic illnesses of various etiology. It is now recognized that maintaining a serum 25(OH)D3 level of 80 nmol/l (32 ng/ml) or greater is beneficial in the prevention of osteoporosis, cardiovascular diseases, certain autoimmune diseases, and some forms of cancer. It seems that sensible sun exposure and the use of supplements are the most effective ways of preventing vitamin D deficiency. The aim of the present article is to review new developments related to vitamin D deficiency and insufficiency and their consequences.

Topics: Autoimmune Diseases; Calcium; Calcium, Dietary; Causality; Cholecalciferol; Comorbidity; Dietary Supplements; Humans; Kidney; Neoplasms; Osteoporosis; Sunlight; Vitamin D; Vitamin D Deficiency

Isolated and acquired hypoparathyroidism occurs as an autoimmune disorder either alone or in association with other autoimmune diseases. Reduced PTH (parathyroid hormone) secretion due to disorder of Ca-sensing regulation in parathyroid gland is most commonly caused by activating mutations of the CaSR (Ca-sensing receptor) gene. There has been accumulating evidence that it also occurs as a result of activating autoantibodies directed to CaSR. Hypoparathyroidism is one of the most common endocrine manifestation in APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) , which is also known as APS (Autoimmune Polyendocrinopathy Syndrome) type I . In APECED, the spectrum of epitope responsible for the hypoparathyroidism is presumably CaSR. It remains unclear how autoimmunity against CaSR occurs and how much patients caused by this disorder exist.

Topics: Autoantibodies; Autoimmune Diseases; Cholecalciferol; Humans; Hypoparathyroidism; Polyendocrinopathies, Autoimmune; Receptors, Calcium-Sensing

Immunosuppressive and anti-inflammatory agents are able to generate tolerogenic DCs, leading, in some cases, to induction or enhancement of regulatory T cells with suppressive activity. This novel mechanism of action, shared by several immunosuppressive and anti-inflammatory agents, is becoming firmly established and contributes to explain their functional properties. The possibility to manipulate DCs in vivo using more or less conventional low molecular weight drugs, enabling them to exert tolerogenic activities, could be exploited to better control a variety of chronic inflammatory conditions, from autoimmune diseases to allograft rejection.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Differentiation; Cholecalciferol; Dendritic Cells; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Membrane Glycoproteins; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, Immunologic; Receptors, Interleukin-2; T-Lymphocytes

The physiologic range for circulating 25-hydroxyvitamin D3 [25(OH)D; the measure of Vitamin D nutrient status] concentration in humans and other primates extends to beyond 200 nmol/L (>80 ng/mL). This biologic "normal" value is greater than current population norms for 25(OH)D. Concentrations of 25(OH)D that correlate with desirable effects extend to at least 70 nmol/L, with no obvious threshold. Randomized clinical trials using 20 mcg (800 IU) per day of Vitamin D show that this suppresses parathyroid hormone, preserves bone mineral density, prevents fractures, lowers blood pressure and improves balance. Calcium absorption from diet correlates with 25(OH)D in the normal range. Health effects of Vitamin D beyond osteoporosis are mostly supported by the circumstantial evidence of epidemiologic studies and laboratory research. These include prevention of cancer and the autoimmune diseases, insulin-dependent diabetes and multiple sclerosis. One mcg per day of Vitamin D(3) (cholecalciferol) increases circulating 25(OH)D by about 1 nmol/L (0.4 ng/mL). A recommended dietary allowance (RDA) is the long-term daily intake level that meets the total requirements for the nutrient by nearly all healthy individuals (it would presume no sunshine). If 70 nmol/L is regarded as a minimum desirable target 25(OH)D concentration, then current recommendations of 15 mcg per day do not meet the criterion of an RDA.

Topics: Adult; Autoimmune Diseases; Blood Pressure; Cholecalciferol; Fractures, Bone; Humans; Neoplasms; Nutrition Policy

To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk.. Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design.. Nationwide in the United States.. 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment.. Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence.. The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others.. 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease.. Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).. ClinicalTrials.gov NCT01351805 and NCT01169259.

Topics: Aged; Autoimmune Diseases; Cholecalciferol; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Treatment Outcome

The imbalance of the immune system can lead to the occurrence of autoimmune diseases. Controlling and regulating the proliferation and function of effector T (Teff) cells and regulatory T (Treg) cells becomes the key to treating these diseases. Dendritic cells (DCs), as dedicated antigen-presenting cells, play a key role in inducing the differentiation of naive CD4+ T cells. In this study, we designed a cationic lipid-assisted PEG-PLGA nanoparticle (NPs/VD3/siLkb1) to deliver 1,25-dihydroxyvitamin D3 (VD3) and small interfering RNA (siRNA) to DC cells in the draining lymph nodes. By modulating the phenotypic changes of DC cells, this approach expands Treg cells and reduces the occurrence of autoimmune diseases. Thus, this study provides a novel approach to alleviating the occurrence and development of autoimmune diseases while also minimizing the risk of unwanted complications.

Topics: Autoimmune Diseases; Cholecalciferol; Dendritic Cells; Humans; Nanoparticles; RNA, Small Interfering

In 2013, the group of Cicero Coimbra, Brazil, reported the clinical efficacy of high doses of vitamin D3 in patients suffering from autoimmune skin disorders ("Coimbra protocol", CP). However, hypercalcemia and the subsequent impaired renal function may be major concerns raised against this protocol.. We report for the first time for a broad spectrum of autoimmune diseases in 319 patients (mean age (±SD) 43.3 ± 14.6 years, 65.5% female, 34.5% male) safety data for high doses of orally applied vitamin D3 (treatment period: up to 3.5 years) accompanied by a strict low-calcium diet and regular daily fluid intake of at least 2.5 L.. Mean vitamin D3 dose was 35,291 ± 21,791 IU per day. The measurement of more than 6100 single relevant laboratory parameters showed all mean values (±SD) within the normal range for total serum calcium (2.4 ± 0.1 mmol/L), serum creatinine (0.8 ± 0.2 mg/dL), serum creatinine associated estimated GFR (92.5 ± 17.3 mL/min), serum cystatin C (0.88 ± 0.19 mg/L), serum TSH (1.8 ± 1 mIU/L), and for 24 h urinary calcium secretion (6.9 ± 3.3 mmol/24 h). We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively.. Our data show the reliable safety of the CP in autoimmune patients under appropriate supervision by experienced physicians.

Topics: Adult; Autoimmune Diseases; Brazil; Calcium; Cholecalciferol; Creatinine; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Vitamin D

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes-31% of both ASD and AID genes, and vitamin D-sensitive genes-20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms.

Topics: Autism Spectrum Disorder; Autoimmune Diseases; Cholecalciferol; Databases, Genetic; Fragile X Mental Retardation Protein; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Signal Transduction; TOR Serine-Threonine Kinases

1,25-dihydroxyvitamin D

Topics: Animals; Autoimmune Diseases; Calcitriol; Cholecalciferol; Cholesterol; Emulsions; Male; Mice; Mice, Inbred BALB C; Myocarditis; Pyroptosis; Signal Transduction; Treatment Outcome

Topics: Agammaglobulinemia; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Infections; Calcium; Cholecalciferol; Electrolytes; Female; Humans; Hypocalcemia; Hypokalemia; Hypoparathyroidism; Hypophosphatemia; Immunoglobulins, Intravenous; Immunologic Deficiency Syndromes; Magnesium; Middle Aged; Thymoma; Weight Loss

To compare 3 different cholecalciferol supplementation regimens in patients with rheumatic diseases.. One hundred fifty-four patients who completed a 6-month course of cholecalciferol supplementation, of whom 111 had an autoimmune/inflammatory rheumatic disease (ARD) and 43 osteoarthritis (NARD), were retrospectively identified from a database of 872 consecutive adult patients who attended a tertiary level immuno-rheumatology clinic from 2007 to 2010. Patients with renal failure or primary hyperparathyroidism were excluded. Plasma 25-hydroxy vitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations were evaluated at baseline and after completion of treatment with (i) a single oral dose of cholecalciferol 300,000 IU, followed by oral cholecalciferol 800-1000 IU daily for 6 months [high-dose loading treatment (HLT) group; n = 40]; (ii) a single oral dose of cholecalciferol 100,000 IU, followed by daily oral cholecalciferol as above [low-dose loading treatment (LLT) group; n = 30]; or (iii) daily oral cholecalciferol as above but without the loading dose [standard therapy (ST); n = 84].. The rates of serum 25(OH)D and PTH normalization (defined as values > 75 nmol/l and < 72.9 pg/ml, respectively) were as follows: HLT, 52.5% (95% CI 37.5-68.5) and 69.2% (95% CI 54.7-83.3); LLT, 36.7% (95% CI 19.7-54.3) and 53.8% (95% CI 36.2-71.8); ST, 31.0% (95% CI 21.1-40.9) and 35.0% (95% CI 14.1-55.9). All regimes increased 25(OH)D (p < 0.001) but only HLT reduced PTH (p < 0.01) in comparison to baseline. The ARD group had a similar 25(OH)D increase but a smaller PTH reduction than the NARD (p < 0.05).. An HLT cholecalciferol regimen is needed to correct hypovitaminosis D of patients with rheumatic diseases, with superior 25(OH)D normalization and PTH suppression rates at 6 months.

Topics: Aged; Autoimmune Diseases; Bone Density Conservation Agents; Cholecalciferol; Dose-Response Relationship, Drug; Female; Humans; Male; Medical Records; Middle Aged; Osteoarthritis; Parathyroid Hormone; Retrospective Studies; Rheumatic Diseases; Vitamin D; Vitamin D Deficiency

Recent reports suggest a role of hypovitaminosis D in the pathogenesis of inflammatory autoimmune diseases (ARD); we investigated 25(OH)vitamin D plasma level before and after supplementation in ARD and NARD (non-ARD: osteoporosis and/or OA) patients. We retrospectively evaluated 572 consecutive clinical records of adult patients at immuno-rheumatology and rehabilitative units of our institution from January 2006 to October 2009. We excluded patients with vitamin D supplementation or renal failure, primary hyperparathyroidism, liver failure. We recorded 25(OH)vitamin D plasma concentration of 245 patients together with other clinical data. We then evaluated 25(OH)vitamin D plasma concentration of 100 (43 ARD and 57 NARD) patients previously included who underwent 750-1,000 UI/die 25(OH)vitamin D supplementation for at least 6 months. Appropriate statistical analysis was performed. The median 25(OH)vitamin D concentration was not significantly different between 119 ARD [33.4 (IQR 22.5-54.9) nmol/l] and 126 NARD patients 32.9 (IQR 18.7-50.2). In stepwise logistic regression, female sex (F:13.7), winter-spring season (F:5.6) and older age (F:5.3), but not ARD, predicted plasma 25(OH)vitamin D <75 nmol/l. Cholecalciferol supplementation increased 25(OH)vitamin D plasma concentration equally in both ARD and NARD; however, only 29/100 patients reached a plasma level ≥75 nmol/l without differences between ARD and NARD (χ(2) = n.s.). Hypovitaminosis D is common in rheumatic patients. Sex and age but not ARD are risk factors for this condition. 750-1,000 UI/die of cholecalciferol is not sufficient to normalize plasma level in these patients. Increase of plasma 25(OH)vitamin D after treatment is not influenced by the presence of an inflammatory autoimmune disease.

Topics: Aged; Autoimmune Diseases; Cholecalciferol; Female; Humans; Male; Middle Aged; Retrospective Studies; Rheumatic Diseases; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

It is well-recognized that vitamin D₃ has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D₃ status. Here, we investigated if and to what extent seasonality of vitamin D₃ levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D₃ and 1,25(OH)(2)D₃ levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in naïve CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D₃ status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings.

Topics: Adult; Autoimmune Diseases; Cholecalciferol; Cytokines; Environmental Exposure; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Seasons; Sunlight; T-Lymphocyte Subsets

To determine whether vitamin D(3) modulates monocytic expression of intracellular Toll-like receptors (TLRs) 3, 7 and 9.. Human monocytes were isolated from peripheral blood and cultured with 100 nM vitamin D(3) for 24, 48 and 72 h. Expression of CD14 and TLR2, TLR3, TLR4, TLR7 and TLR9 were examined by flow cytometry. Monocytes exposed to vitamin D(3) for 48 h were then stimulated with a TLR9 agonist for a further 24 h. The level of IL-6 secretion was measured by ELISA.. CD14 was up-regulated, whereas TLR2, TLR4 and TLR9 expression was down-regulated by vitamin D(3) exposure in a time-dependent manner. TLR3 expression was unaffected by vitamin D(3) and there was no measurable expression of TLR7 on the monocytes. TLR9-induced IL-6 production was impaired in monocytes treated with vitamin D(3) compared with untreated cells.. The intracellular TLRs are differentially regulated by vitamin D(3), with TLR9 being down-regulated by vitamin D(3) exposure whereas TLR3 was unaffected. This decreased TLR9 expression in monocytes had a downstream functional effect as these cells subsequently secreted less IL-6 in response to TLR9 challenge. This may have significant biological relevance and may be a factor in the association of vitamin D deficiency with susceptibility to autoimmune disease.

Topics: Autoimmune Diseases; Cells, Cultured; Cholecalciferol; Down-Regulation; Humans; Interleukin-6; Monocytes; Statistics as Topic; Time Factors; Toll-Like Receptor 9

The association between vitamin D deficiency and asthma epidemic has been recognized. Tumor necrosis factor (TNF)-alpha and chemokines play important roles in pathogenesis of asthma. However, whether vitamin D has immunoregulatory function on TNF-alpha and chemokines expression in human monocytes is still unknown. The human monocytic cell line, THP-1 cells and human primary monocytes were pretreated with various concentration of 1alpha,25-(OH)(2)D(3) for 2 h before stimulation with lipopolysaccharide (LPS). Supernatants were collected 24 or 48 h after LPS stimulation. The levels of TNF-alpha, interferon-inducible protein 10 (IP-10)/CXCL10 (the Th1-related chemokine), macrophage-derived chemokine (MDC)/ CCL22 (the Th2-related chemokine), and interleukin 8 (IL-8)/CXCL8 (the neutrophil chemoattractant) were measured by ELISA. 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and IP-10 expression in LPS-stimulated THP-1 and human primary monocytes. However, 1alpha,25-(OH)(2)D(3), especially in higher concentration, could significantly enhance MDC expression. 1alpha,25-(OH)(2)D(3) had no significant effects on IL-8 expression. We found 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha and Th1-related chemokine IP-10, which both play important roles in pathogenesis of severe refractory asthma and autoimmune diseases. However, 1alpha,25-(OH)(2)D(3) enhanced Th2-related chemokine MDC, which may result in Th2 inflammatory cell recruitment and thus adversely affect asthmatic patients. Although vitamin D has potential utility in the treatment of asthma and autoimmune diseases, excessive use of vitamin D may not be suitable in patients with Th2 allergic diseases.

Topics: Asthma; Autoimmune Diseases; Calcitriol; Cell Line; Cells, Cultured; Chemokine CCL22; Chemokine CXCL10; Chemokines; Cholecalciferol; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8; Lipopolysaccharides; Monocytes; Osmolar Concentration; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation; Vitamin D Deficiency

Chronic non bacterial prostatitis is a chronic inflammatory syndrome. Its etiology and physiopathology are unclear and treatments are empirical and ineffective in most cases. Autoimmunity has been proposed as an etiology. In the present report, we investigated the impact of vitamin D receptor silencing, by use of VDR-KO NOD mice and the immune-modulating effect of the vitamin D3 analog TX527 on the development of Experimental Autoimmune Prostatitis in NOD mice. VDR-KO NOD mice developed a more aggressive form of autoimmune prostatitis characterized by a greater lymphoproliferative response against prostate antigen in vitro (6.92+/-4.77 vs. 2.47+/-0.41 21 days after disease induction, p<0.05) and higher levels of specific INFgamma secretion (471+/-6 vs. 386+/-5pg/ml, p<0.01). This was accompanied in vivo by more severe lesions and augmented mononuclear cell infiltration in the prostate gland. On the other hand, although analog-treated mice showed a significant reduction in the spleen T-cell specific proliferative response against prostate antigen in vitro, no effect on disease development was observed. We conclude that vitamin D receptor modulation holds the promise of interfering with autoimmune prostatitis. Introduction of more powerful analogs, or combinations with anti-T-cell reagents may represent therapeutic solutions for these group of patients.

Topics: Alkynes; Animals; Autoimmune Diseases; Cells, Cultured; Cholecalciferol; Disease Models, Animal; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Prostatitis; Receptors, Calcitriol

A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients.. Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores.. A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D.. Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Topics: Adult; Aged; Autoimmune Diseases; Calcium; Cholecalciferol; Fibromyalgia; Humans; Middle Aged; Osteoporosis; Retrospective Studies; Rheumatic Diseases; Vitamin D; Vitamin D Deficiency

D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D-hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D-hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cholecalciferol; Colon; Disease Models, Animal; DNA-Binding Proteins; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; Humans; Immune System; Inflammatory Bowel Diseases; Interleukin-10; Mice; Mice, Knockout; Nuclear Proteins; Receptors, Calcitriol; Receptors, Tumor Necrosis Factor; RNA; Transcription Factors; Tumor Necrosis Factor-alpha; Vitamins

Vitamin D deficiency is now recognized as an epidemic in the United States. The major source of vitamin D for both children and adults is from sensible sun exposure. In the absence of sun exposure 1000 IU of cholecalciferol is required daily for both children and adults. Vitamin D deficiency causes poor mineralization of the collagen matrix in young children's bones leading to growth retardation and bone deformities known as rickets. In adults, vitamin D deficiency induces secondary hyperparathyroidism, which causes a loss of matrix and minerals, thus increasing the risk of osteoporosis and fractures. In addition, the poor mineralization of newly laid down bone matrix in adult bone results in the painful bone disease of osteomalacia. Vitamin D deficiency causes muscle weakness, increasing the risk of falling and fractures. Vitamin D deficiency also has other serious consequences on overall health and well-being. There is mounting scientific evidence that implicates vitamin D deficiency with an increased risk of type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common deadly cancers. Vigilance of one's vitamin D status by the yearly measurement of 25-hydroxyvitamin D should be part of an annual physical examination.

Topics: Animals; Autoimmune Diseases; Bone and Bones; Cardiovascular Diseases; Cholecalciferol; Diet; Health Status; Humans; Hypertension; Neoplasms; Nutritional Requirements; Sunlight; Vitamin D; Vitamin D Deficiency

Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway (BN) rats. This syndrome is the consequence of T cell-dependent polyclonal B cell activation and autoantibody production. We have previously shown that HgCl2-induced autoimmune perturbations can be prevented in BN rats by the administration of cyclosporin A (CsA). The most potent vitamin D3 metabolite 1,25(OH)2 D3 (Vit D3) shares certain immunomodulatory properties with CsA. We therefore chose to compare the effects of Vit D3 to those of CsA in BN rats treated with HgCl2 in order to establish whether Vit D3 either alone or in combination with CsA can attenuate an autoimmune syndrome in vivo.. BN rats were treated with HgCl2 according to a standard protocol. Subgroups of rats were also given CsA alone, Vit D3 or synthetic analogues of Vit D3 alone, or combinations of both agents. Different doses and routes of administration were compared. The following markers of disease activity were evaluated: mortality, peak proteinuria, serum IgE concentrations, and renal immunoglobulin deposition.. Disease activity was markedly attenuated in all rats treated with CsA alone. Vit D3 and certain of its synthetic analogues administered alone also tempered the autoimmune process, but to a lesser extent than did CsA. The effect of CsA alone was so potent, that no additive or synergistic effects could be demonstrated when CsA was administered in combination with Vit D3.. Despite similar described immunomodulatory effects in vitro, CsA is clearly more effective than Vit D3 in preventing HgCl2 autoimmune disease in BN rats. This suggests that there is a difference in the cellular targets of these two agents in vivo, and/or a difference in the potency with which HgCl2-triggered immune activation is suppressed.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Calcium; Cholecalciferol; Cyclosporine; Drug Therapy, Combination; Female; Glomerulonephritis; Immunoglobulin E; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mercuric Chloride; Proteinuria; Rats; Rats, Inbred BN; Serum Albumin

We examined the immunoregulating effect of 22-oxa-1 alpha,25-dihydroxyvitamin D3 (22-oxa-1 alpha,25(OH)2D3), a synthetic analogue of vitamin D3 with an oxygen atom at C22 in the side chain skeleton, on spontaneously developing autoimmune disorders in MRL/Mp-lpr/lpr (MRL/l) mice. The oral administration of the compound significantly prolonged the average life span of the mice and showed a significant reduction in proteinuria. Histopathological investigations also revealed that pathological conditions such as renal arteritis, granuloma or arthritis of the knee joints were much lighter in the treated group than in the untreated group. Furthermore, the lymphocyte phenotypes in thymus, lymphnode, and spleen were partially normalized and became similar to those found in young control animals by the treatment with 22-oxa-1 alpha,25(OH)2D3. These results suggest that this compound inhibits the development of lupus nephritis in MRL/l mice and may be therapeutically effective on the mice.

Topics: Animals; Antigens, Surface; Antineoplastic Agents; Autoimmune Diseases; Calcitriol; Cholecalciferol; Kidney; Knee Joint; Male; Mice; Mice, Inbred Strains; Organ Specificity; Proteinuria; Specific Pathogen-Free Organisms