Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus.

OBJECTIVE: We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE. METHODS: 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE. RESULTS: Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04). CONCLUSIONS: Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.

In Vivo Therapeutic Success of MicroRNA-155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage.

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (miR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR-155 in various autoimmune disorders. The purpose of this study was to examine the role of miR-155 in the development of DAH in pristane-induced lupus using miR-155-knockout (miR-155(-/-)) mice and miR-155 antagomir to silence miR-155. METHODS: DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA-155 antagomir was administered intravenously to silence miR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real-time quantitative polymerase chain reaction analysis was used for single-gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. RESULTS: MicroRNA-155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR-155(-/-) mice as well as by in vivo silencing of miR-155 using a miR-155 antagomir. MicroRNA-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF-κB signaling were inhibited by pristane and were reactivated in miR-155(-/-) mice. In particular, the antiinflammatory factor peroxisome proliferator-activated receptor α was identified as a direct target of miR-155. CONCLUSION: MicroRNA-155 promotes pristane-induced lung inflammation. It contributes to ectopic activation of NF-κB signaling pathways by targeting multiple negative regulators. MicroRNA-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.

Association of systemic lupus erythematosus with uranium exposure in a community living near a uranium-processing plant: a nested case-control study.

OBJECTIVE: To explore the hypothesis that cases of systemic lupus erythematosus (SLE) would be found more frequently in community members with high prior uranium exposure in the Fernald Community Cohort (FCC). METHODS: A nested case-control study was performed using data from the FCC, a volunteer population of individuals who had resided near a uranium ore-processing plant in Fernald, Ohio during the years of plant operation; uranium plant workers were excluded. Members of the FCC were monitored for 18 years. SLE cases were identified using the American College of Rheumatology 1997 revised classification criteria, laboratory testing, and medical record review. Each case was matched to 4 controls by age, race, and sex. Sera from potential cases and controls were screened for autoantibodies. Cumulative exposure to uranium particulates was calculated using a dosimetry model. Logistic regression with covariates was used to calculate the odds ratios (ORs) with 95% confidence intervals (95% CIs) for the probability of an association between uranium exposure and SLE. RESULTS: The FCC comprised 4,187 individuals with minimal levels of uranium exposure, 1,273 with moderate exposure, and 2,756 with high exposure. The diagnosis of SLE was confirmed in 23 of 31 individuals who had been assigned International Classification of Diseases, Ninth Revision codes for lupus, and was also confirmed in 2 of 43 individuals who had been prescribed hydroxychloroquine. The female to male ratio was 5.25:1. Of the 25 confirmed SLE cases, 12 were in the high exposure group. The presence of SLE was associated with higher levels of uranium exposure (OR 3.92, 95% CI 1.13-13.59; P = 0.031). CONCLUSION: High uranium exposure is associated with SLE, as compared to matched controls, in this sample of uranium-exposed individuals. Potential explanations for this relationship include possible autoimmune or estrogen effects of uranium, somatic mutation, epigenetic effects, or effects of some other unidentified accompanying exposure.