ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 689

Activation of the Interferon Pathway Is Dependent Upon Autoantibodies in African-American SLE Patients, but Not in European-American SLE Patients

Kichul Ko1, Yelena Koldobskaya1, Elizabeth Rosenzweig2 and Timothy B. Niewold1, 1Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, 2Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Gene expression studies have been instrumental in defining important aspects of the complex immunological pathogenesis in systemic lupus erythematosus (SLE) which is a heterogeneous disease that manifests differently by ancestry, and by the presence of autoantibodies directed at RNA binding proteins (anti-RBP).  Moreover, anti-RBP antibodies are associated with high serum interferon (IFN)-α, which plays an important role in pathogenesis of SLE.   Our overall hypothesis was that the molecular pathogenesis of SLE differs between African-American (AA) and European-American (EA) SLE patients, and between those with anti-RBP antibodies and those who lack these antibodies.  We aimed to explore this hypothesis using peripheral blood gene expression profiling.

Methods: Whole blood RNA from 33 female SLE patients and 16 matched female controls from AA and EA ancestral backgrounds was analyzed on Affymetrix Gene 1.0 ST gene expression arrays.  Two-tailed t-tests were performed to compare the expression values between cases and controls in each ancestry.  Differentially expressed genes with a cutoff P of 0.05 were further explored using Ingenuity Pathway Analysis (IPA) to compare the top canonical pathways amongst the sample groups.  An independent replication cohort of more than 100 SLE patient samples and 30 controls was used to test the hypotheses generated by the microarray data, using qPCR to quantify gene expression. 

Results: Both AA and EA female (AAF and EAF respectively) patients with positive anti-RBP antibodies (RBP+) showed similar IFN-related canonical pathways such as IFN Signaling (P = 1.3 x 10-7 and 6.3 x 10-11 in AAF vs. EAF patients respectively), Antigen Presenting Pathway (P = 1.8 x 10-5 and 2.5 x 10-6) and a number of pattern recognition receptor pathways.  The key pathway difference was shown between AAF and EAF patients with negative anti-RBP antibodies (RBP-) as EAF patients also showed IFN Signaling (P = 1.0 x 10-5) and Antigen Presenting Pathway (P = 1.3 x 10-11) whereas AAF patients with RBP- did not reveal any IFN-related pathways.  A replication study was performed through qPCR on 3 IFN-inducible genes, IFIT1, MX1 and PKR, and showed similar results.  All three genes were strongly up-regulated in RBP+ patients in both ancestries, and PKR was up-regulated in EAF patients with RBP- but these findings were completely absent in AAF patients with RBP-.

Conclusion: Our data show that IFN-induced gene expression is completely dependent on the presence of autoantibodies in AA SLE patients but not in EA patients.  Further studies are needed to explore other novel pathways that may define the heterogeneity in SLE, especially in the RBP- AA group.

Disclosure:

K. Ko,
None;

Y. Koldobskaya,
None;

E. Rosenzweig,
None;

T. B. Niewold,
None.

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