Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
MicroRNA miR-146a, Type I Interferon, and Race in Systemic Lupus Erythematosus.
Dominguez1, Paul R., Satoh2, Minoru, Ceribelli1, Angela R., Sobel2, Eric S., Li2, Yi, Reeves2, Westley H., Chan2, Edward K. L.
A few microRNAs (miRNA) have known gene expression regulatory roles in innate immunity. miR-146, a NFkB regulated transcript, is activated during lipopolysaccharide stimulation of monocytes and is critical in endotoxin tolerance to prevent cellular overstimulation when in excess of the TLR4 ligand. Interestingly, miR-146a has been reported to be upregulated in PBMCs and synovial tissue in rheumatoid arthritis patients but reported downregulated in PBMCs of SLE patients. The aim of the study is to determine whether the repressed expression of miR-146a reported in Chinese SLE can be observed in our US SLE cohort with more diversity in ethnic background.
Blood samples were collected from 124 SLE patients (European Americans (EA) 48 F, 10 M; African Americans (AA) 41 F, 2 M; Latin Americans (LA) 11 F, 6 M; others 6 F)) fulfilling ACR criteria and this included 35 patients with 2 or more collections from multiple visits to our autoimmune center. Total RNA, isolated from leukocytes, was analyzed by Taqman qPCR. miRNA copy number was determined using a standard curve. Expression of Type I interferon (IFN) signature genes (ISGs) and other cytokine/chemokine including TNFa, CCL2, CCL19, and CxCL10 was determined by DDCT method. IFN score was calculated from ISGs (Mx1, OAS1, and Ly6e). Results were correlated with clinical data and analyzed by Wilcoxon/Kruskal-Wallis Test.
Comparing CCL2, ISGs, and IFN score levels by race, AA had significantly higher levels compared to EA (p=0.016) and LA (p0.004), but LA had significantly lower levels than EA (p=0.038). miR-146a appeared to be higher in EA than AA or LA but did not reach significance. Reduced miR-146a expression was also observed in SLE patients with nephritis but did not reach significance. Correlation of miR-146a level with other clinical parameters including arthritis, pleritius, pericarditis, lymphopenia etc. did not show statistical significance. When 35 returning patients divided based on changes in miR-146a level comparing the first and the last visit, 11 had increased in miR-146a vs. 17 reduced. In the miR-146a reduced group (p=0.001), Mx1 (p=0.03), Ly6e (p=0.04), OAS1 (p=0.02), IFN score (p=0.02) reduced significantly whereas no significance were found for TNFa, CCL2, and CXCL10. The miR-146a increased group (p=0.0003) was more heterogeneous and none of the markers had statistically significant difference.
Comparison in race demonstrates with statistical significance that LA has the lowest level of IFN while AA has the highest. The data show potentially two groups: a miR-146a responsive group where miR-146a maybe regulating IFN production and a miR-146a resistant group where IFN production appears independent of miR-146a. For SLE patients with decreasing levels of miR-146a in subsequent visit correlating with decreasing IFN score, this may represent the transition from active to remission state. In more active SLE, miR-146a levels most likely represent a balance in continuous IFN stimulation and innate controls as represented by patients with both high IFN score and miR-146a levels.
To cite this abstract, please use the following information:
Dominguez, Paul R., Satoh, Minoru, Ceribelli, Angela R., Sobel, Eric S., Li, Yi, Reeves, Westley H., et al; MicroRNA miR-146a, Type I Interferon, and Race in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :501