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0000005559 00000 n %PDF-1.7 % 2011 Sep; 70(9): 15691574. HEp-2 cell slides (INOVA Diagnostics) with 1:80 dilution of sera were classified by intensities of immunofluorescence staining on a 0 to 4 scale based on comparison with a standard reference gallery (14). CCL-25, American Type Culture Collection, Manassas, Virginia, USA) were cultured with 50% patient serum for 6 h and then lysed. Prospective studies on ANA incidence in healthy aging individuals, including longitudinal data on vitamin D, are warranted and may reveal pathways by which vitamin D deficiency may contribute to the development of autoimmunity, a potential immunologic biomarker of cancer. Nonetheless, we performed a sensitivity analysis, excluding hypertensives. A recent study sought to examine the effects of oral vitamin D supplementation on disease activity in SLE; however, more than 70% of the patients in the study still had insufficient levels of vitamin D after 2 years of treatment.36 While this study did not report any improvements in SLE disease activity after oral administration of vitamin D, interpretation of the results is limited by the small percentage of patients with SLE who achieved adequate 25(OH)D levels. cDNA was then quantified using real-time PCR. When ANA prevalence was compared between non-Hispanic blacks and non-Hispanic whites, a statistically significant difference was observed (P = 0.05). Meier, Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H.C.S. 2016 AACR. Vitamin D-deficient patients had a higher mean number of ACR classification criteria (6.4 vs 5.3; p=0.026, unpaired t test). Decreased T-cell regulation and increased B-cell activity may result in higher production of autoantibodies, including ANA (6). An official website of the United States government. Funding This work was supported by the National Institutes of Health (NIAID: HHSN266200500026C, AR058554, RR015577, AI082714, AI24717, AR24260, AI083194, AR052364 and AR053483), Kirkland Foundation Scholar Support, OMRF J Donald Capra Fellowship Support, US Department of Veteran Affairs and the OMRF Lou C Kerr Chair in Biomedical Research. 0000013002 00000 n Elevated ANA is sometimes found in healthy individuals and has been consistently associated with female sex and older age (1214).

The 6, 7). Pearson correlation was done to assess the relationship between pERK1/2 and 25(OH)D values. Patients with vitamin D deficiency also had higher mean (SD) serum IFN activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02). Vitamin D deficiency could also contribute to an increased IFN signature in myeloid dendritic cells. about navigating our updated article layout. Finally, NHANES does not include the institutionalized elderly, who are particularly prone to vitamin D deficiency; therefore, our findings may underestimate the relationship between vitamin D deficiency and ANA prevalence at older ages (27). 0000019267 00000 n Vitamin D deficiency was associated with an increased presence of autoantibodies in healthy controls. We hypothesized that middle-aged and older individuals with vitamin D deficiency would have a higher prevalence of ANA than those with vitamin D levels in the normal range. Comorbid conditions or medications could contribute to the association between ANA and vitamin D. Ability to perform moderate/vigorous physical activity is only a crude indication of possibly comorbidity. 0000005586 00000 n Forward and reverse primers for the genes MX1, PKR and IFIT, which are known to be highly and specifically induced by IFN, were used in the reaction.32 Background gene expression was controlled by amplifying glyceraldehyde 3-phosphate dehydrogenase. Kirou KA, Lee C, George S, et al. Impact: Our findings support the growing evidence that vitamin D is an important immune modulator. Welchs correction was used in instances of unequal variance. Orbach H, Zandman-Goddard G, Amital H, et al. 0000017609 00000 n 0000260494 00000 n The estimated weighted prevalence of ANA positivity (score 3 or 4) was 17.5% in the U.S. population aged 50 and older. In single-predictor logistic regression models, both 25(OH)D (p=0.033) and number of autoantibody specificities (p=0.023) are significantly associated with IFN activity. Federal government websites often end in .gov or .mil. Higher dilutions may be useful to identify individuals with higher levels of ANA in clinical settings; however, research on ANA in this NHANES sample was designed to obtain an estimate of ANA prevalence in the general population, most of whom do not have a diagnosis of autoimmune disease. jones constantine martin europe arnold hugh conversion bo1 books Vitamin D deficiency in undifferentiated connective tissue disease. Interestingly, this same correlation was not seen in the controls, suggesting a potential geneenvironment interaction between SLE susceptibility genes and vitamin D. In this manner, vitamin D deficiency would contribute to B cell hyperactivation and autoantibody production in genetically susceptible individuals. Pelajo CF, Lopez-Benitez JM, Miller LC. Errors bars indicate SEM. Median fluorescent intensity values for the levels of pERK1/2 were used on CD79a-gated B cells to rank and normalise the data. Crow MK, Kirou KA. Vitamin D(3) and its synthetic analogs inhibit the spontaneous in vitro immunoglobulin production by SLE-derived PBMC. These prior analyses that showed ANA increasing with age included a broader age range covering the life course from 12 to 70+ years (14). 1X$2x^@\6BA*`(faRf0!!h-5X3_f~8q*BeL ;|020gWZ\0(`6V=]OkOipj`A1qFw2hz4!q-+i~1`bbdg`dpOe"C/PIF.I^fj4A3`!0 500oh`B3JP6 #T Toloza SM, Cole DE, Gladman DD, et al. Meier, D.P. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. 1). Patients with SLE with deficient levels of 25(OH)D (n=22) had no statistically significant differences among specific ACR classification criteria, disease activity scores (SLEDAI, SLAM, PGA), BMI or medication use than patients with SLE with non-deficient levels of 25(OH)D (n=10). By continuing to use our website, you are agreeing to, Cancer Epidemiology, Biomarkers & Prevention, Collection: Early-Onset Colorectal Cancer, Collection: US Cancer Disparities Statistics, Collection: Cancer Epidemiology in Hispanic/Latino Populations, Collection: Colorectal Cancer: Screening and Early-Onset CRC, Collection: Informing Public Health Policy, Disclosure of Potential Conflicts of Interest, https://doi.org/10.1158/1055-9965.EPI-16-0339, http://www.cdc.gov/nchs/data/nhanes/nhanes_01_02/VID_B_met_Vitamin_D.pdf, http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/VID_C_met_Vitamin_D.pdf, http://wwwn.cdc.gov/Nchs/Nhanes/2001-2002/L06VID_B.htm, Cancer Epidemiology, Biomarkers, & Prevention. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. As the first analysis conducted in a large, U.S. representative sample, this adds to a suggestive literature on vitamin D deficiency and ANA based on clinical studies of lupus patients and one small sample of clinical controls (7, 15). *p=0.02 (unpaired t test with Welchs correction of log-transformed data). While in vitro studies have demonstrated a suppressive action of vitamin D on Ig production and the IFN signature,18,24,25 an association between vitamin D status in patients with SLE and these disease features has not been previously reported. Log-transformation was done to normalise serum IFN activity measures. Covariates included age, sex, education (less than high school, high school, greater than high school), race/ethnicity (non-Hispanic white, non-Hispanic black, or other), season of blood collection (summer or winter), body mass index (BMI; kg/m2), self-report of at least 10 minutes of moderate or vigorous physical activity in the past 30 days (yes, no, unable), and NHANES cycle. europe david dr pdf prof chemistry books werner Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. The authors would also like to thank J Anderson, W Klein, G Vidal and J Levin for their technical assistance, as well as S Stewart for his assistance with the statistical analysis.

): H.C.S. 0000000016 00000 n 12). 0000003697 00000 n Helen C.S. The mean age of the 14 ANA-positive controls was significantly higher than the ANA-negative controls (54.1 vs 42.8 years; p=0.029, unpaired t test). IFN activity values reported represent the number of SD above the mean of healthy donors (n=141). After adjustment, those with severe vitamin D deficiency (<10 ng/mL) had 2.99 (95% CI, 1.257.15) times the odds of ANA compared with having normal vitamin D levels (30 ng/mL), while deficient and insufficient individuals had twice the odds of ANA. official website and that any information you provide is encrypted Anti-Ro-positive patients in this small cohort were not more likely to have documented photosensitivity than anti-Ro-negative patients (60% vs 77%; p=0.450, Fisher exact test). Linker-Israeli M, Elstner E, Klinenberg JR, et al. Beyond considering the molecular mechanisms by which vitamin D deficiency would predispose to autoimmunity, the extraordinarily high prevalence of vitamin D deficiency in ANA-positive healthy individuals and patients with SLE strongly suggests that repletion with vitamin D should be considered. Meier, D.P. 0000011074 00000 n Furthermore, when categorised into vitamin D-deficient (25(OH)D <20 ng/ml) or non-deficient (25(OH)D >20 ng/ml), patients with SLE and ANA-positive controls were more likely to be vitamin D deficient (69% and 71%, respectively) than ANA-negative controls (22% deficient) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively, Fisher exact test, figure 1B). H\00Q(T/ X/;_\BO#8lm=7|kb{K"uS[]D8z5ynaMxjPshNF{}ov5e{-lqP|3Y:L|C/l. 0000005447 00000 n 0000006980 00000 n 0000138417 00000 n 0000138070 00000 n Accessibility Conception and design: H.C.S. Before Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). 0000002777 00000 n (B) Patients with SLE with 25(OH)D levels <20 ng/ml had higher B cell activation (as measured by pERK1/2) than patients with 25(OH)D levels >20 ng/ml; *p=0.045 (unpaired t test with Welchs correction of log-transformed data). Hochberg MC. Kamen DL, Cooper GS, Bouali H, et al. Careers. hb``d```f @adt`GwYIoj`X\uPGaCW>?~=?7=9*}Yg+R*TJb*Q%gm[~vwXNV!s8*| =nGkM__lsumNU7hS-G2|NPRRZvf..p/w`Py& Specifically, vitamin D influences the efficiency of regulatory T lymphocytes and activity of T helper lymphocytes (Th17), both thought to be important for mediating and regulating autoimmune responses (6, 24). sharing sensitive information, make sure youre on a federal **p=0.003, *p=0.011 (Fisher exact test). Correspondence to: Judith A James, Arthritis and Clinical Immunology, Oklahoma, Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA; The publisher's final edited version of this article is available at. 0000012193 00000 n ANA-positive and ANA-negative controls had no significant difference in CSQ scores (median 1.0 (IQR 0.82.5) vs 1.0 (IQR 0.02.0); p=0.41, MannWhitney test). 0000010054 00000 n ANAs were detected using an Hep-2 indirect immunofluorescent assay (INOVA Diagnostics, San Diego, California, USA) according to the manufacturers instructions. **p=0.002 (unpaired t test). 0000147351 00000 n The hypothesis that vitamin D deficiency contributes to increased B cell activation in patients with SLE and increased production of autoantibodies, in particular those directed against nucleic acids, provides a mechanism for the association of vitamin D deficiency with increased IFN activity (working hypothesis shown in figure 4). Cancer Epidemiol Biomarkers Prev 1 December 2016; 25 (12): 15591563. The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA-negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis. Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). While vitamin D deficiency has been reported in many autoimmune diseases, this is the first observation in ANA-positive healthy individuals. National Library of Medicine Data were extracted from the medical records of the patients with SLE for ACR classification criteria, age of diagnosis and medication use. Search for other works by this author on: National Institute of Environmental Health Sciences. Participants in the 2001 to 2002 cycle were more likely to be vitamin D deficient than the 2003 to 2004 cycle (P = 0.02). Learn more Amital H, Szekanecz Z, Szcs G, et al. For this study, vitamin D deficiency was defined as 20 ng/ml.29 Vitamin D levels were determined from plasma samples obtained on the same date as the blood specimens procured to measure autoantibodies, serum IFN activity and B cell activation. However, in a logistic regression model with vitamin D status as the outcome and ANA positivity and age as the predictors, age did not predict vitamin D status (p=0.331) while ANA positivity remained a significant predictor (p=0.025). The authors would like to thank all the study participants for their time and commitment to the study as well as the referring physicians: Drs C Carson, A A Kumar, L Zacharias and physician assistants T Aberle and J K Shoemaker. In this sample restricted to middle-aged and older U.S. adults, ANA was not observed to increase with age in contrast to previous reports using NHANES data (14, 25). Error bars indicate SEM. 0000015359 00000 n ANA was not associated with age, education, race/ethnicity, BMI, or NHANES cycle. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status. Vitamin D involvement in rheumatoid arthritis and systemic lupus erythematosus. 0000003555 00000 n This study has several strengths. HHS Vulnerability Disclosure, Help Vitamin D deficiency is probably not sufficient to cause B cell hyperactivation and autoantibody production, but rather is a contributing factor along with other genetic and environmental risks. In these models the outcome variable was IFN activity, with high levels defined as IFN activity >1 SD above the mean of healthy controls and low levels defined as IFN activity <1 SD below the mean. Although no definitive study has been published demonstrating a beneficial effect of vitamin D supplementation on SLE disease severity, current knowledge supports vitamin D replacement for calcium homeostasis, bone health and potential immune system benefits. The https:// ensures that you are connecting to the 0000021917 00000 n 502 0 obj <>stream The best fitting single-predictor model was compared with a model with both 25(OH)D and number of autoantibody specificities as predictors using the likelihood ratio test, and the fit was significantly improved with the two-predictor model (2 =3.931, p=0.047). 0000004104 00000 n 0000135947 00000 n FOIA This provides epidemiological evidence to suggest that vitamin D deficiency in autoimmunity is not solely a consequence of lifestyle changes associated with the disease. jones constantine martin europe arnold hugh conversion bo1 books xref 0000007249 00000 n

60 kD Ro and nRNP A frequently initiate human lupus autoimmunity. Ptrend = 0.04. This relationship did not appear to be driven by differences in vitamin D distributions by race/ethnicity, based on the consistent pattern of higher ANA prevalence for relatively lower vitamin D levels (categorized by a race/ethnic specific median split) across all race/ethnic categories (Fig. We thank Drs. trailer Parks. Fourteen of the controls were determined to be ANA-positive. 0000021987 00000 n NOTE: Bold text indicates statistical significance at P = 0.05. aRaoScott 2 for categorical variables, Wald F statistic for continuous variables. Recent insights into the genetic basis of systemic lupus erythematosus. A hallmark of autoimmune disease is the presence of self-reactive autoantibodies, which are also of interest as immunologic biomarkers of cancer (911). We performed sensitivity analyses after excluding those with self-reported rheumatoid arthritis or thyroid problems, those unable to perform moderate physical activity, and premenopausal females (final analytic N = 747). 0000249202 00000 n 0 0000069054 00000 n A connective tissue disease screening questionnaire for population studies.

All statistical analyses were carried out with GraphPad Prism Version 5.01 (GraphPad Software, San Diego, California, USA; http://www.graphpad.com). 0000068484 00000 n Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. 0000006525 00000 n Heinlen LD, McClain MT, Ritterhouse LL, et al. Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Sandler, E.M. Simonsick, C.G. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon (IFN) activity in patients with systemic lupus erythematosus (SLE). Together with genetic susceptibility and other environmental factors, vitamin D deficiency could contribute to increased B cell activation and autoantibody production. mRNA was purified from cell lysates and cDNA was made from total cellular mRNA. No correlation was seen between B cell activity and 25(OH)D levels in controls (pERK1/2: r=0.05, p=0.79). Niewold TB, Kelly JA, Flesch MH, et al. 0000111775 00000 n To determine whether the relationship between 25(OH)D and IFN activity was dependent on the number of autoantibody specificities, various statistical models were compared using logistic regression. Serum samples were tested for IgG autoantibodies to human cellular antigens using standard immunofluorescence methods described previously (14). 2016 American Association for Cancer Research. 0000202387 00000 n One recent study examined this relationship in a small sample of clinical controls (7), but no population-based studies have been conducted. The SLE patient group had a median 25(OH)D level of 17.3 (IQR 11.921.2) ng/ml (figure 1A). Hua J, Kirou K, Lee C, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Antinuclear antibody (ANA)-positive healthy individuals and patients with systemic lupus erythematosus (SLE) are more likely to be deficient in vitamin D. (A) Median (IQR) 25-hydroxyvitamin D levels were 17.3 (11.921.2) ng/ml in patients with SLE (n=32), 17.4 (14.525.8) ng/ml in ANA-positive controls (n=14) and 29.4 (19.036.3) ng/ml in ANA-negative controls (n=18). endstream endobj 427 0 obj <>>>/Metadata 424 0 R/Names 428 0 R/Outlines 412 0 R/Pages 423 0 R/Type/Catalog/ViewerPreferences<>>> endobj 428 0 obj <> endobj 429 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Rotate 0/Tabs/W/Thumb 417 0 R/TrimBox[0.0 0.0 595.276 841.89]/Type/Page>> endobj 430 0 obj [431 0 R] endobj 431 0 obj <>/Border[0 0 0]/H/N/Rect[444.871 793.605 543.251 783.094]/Subtype/Link/Type/Annot>> endobj 432 0 obj <> endobj 433 0 obj <> endobj 434 0 obj <> endobj 435 0 obj <> endobj 436 0 obj <> endobj 437 0 obj [/ICCBased 461 0 R] endobj 438 0 obj <> endobj 439 0 obj <> endobj 440 0 obj [466 0 R] endobj 441 0 obj <>stream **p<0.01, KruskalWallis test with Dunns multiple comparison. 0000015491 00000 n 0000005110 00000 n Detection of ANA at a dilution of 1:120 or greater and anti-dsDNA at a dilution of 1:30 or greater was considered a positive result. Experimental studies have also shown that 1,25(OH)2D is able to skew the T cell compartment into a more anti-inflammatory and regulated state, with inhibitory actions on Th1 and Th17 cells and promoting the development of CD4 CD25 Foxp3+ regulatory T cells (Treg).17 Vitamin D has been shown to induce tolerogenic dendritic cells, which promote Treg cell development and enhance recruitment of Treg cells to inflammatory sites.17 Thus, there are several different possible pathways by which vitamin D can influence the pathogenesis of SLE, B cell activity and autoantibody production. This trend was not seen with any other measured lupus-associated antibody (dsDNA, La, Sm, nRNP, ribo P, aPL). Hajas A, Sandor J, Csathy L, et al. Many immune cells contain vitamin D receptorsincluding monocytes, macrophages, dendritic cells and activated T and B cellsand these immune cells possess the enzymatic machinery (1-hydroxylase, CYP27B1) necessary to convert vitamin D into its active form.17 Isolated peripheral blood mononuclear cells (PBMCs) from patients with SLE incubated with 1,25(OH)2D or its synthetic analogues significantly reduced cellular proliferation, as well as induce polyclonal and anti-dsDNA Ig production.18 1,25(OH)2D has also been shown to induce apoptosis in activated B cells and to inhibit the generation of plasma cells and postswitch memory B cells, as well as regulatory T cells.19,20 The importance of vitamin D in innate immunity has been highlighted by studies demonstrating that monocyte/macrophage responses to bacterial infections via Toll-like receptors (TLRs) are potentially stimulated by 25-hydroxyvitamin D (25(OH)D) following localised induction of both vitamin D receptor (VDR) and 1-hydroxylase.17, Interferon (IFN) has been shown to be a key cytokine in the pathogenesis of SLE.

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