TY - JOUR
T1 - Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients
AU - Ko, Kichul
AU - Koldobskaya, Yelena
AU - Rosenzweig, Elizabeth
AU - Niewold, Timothy B.
PY - 2013
Y1 - 2013
N2 - Background: In systemic lupus erythematosus (SLE), antibodies directed at RNA-binding proteins (anti-RBP) are associated with high serum type I interferon (IFN), which plays an important role in SLE pathogenesis. African-Americans (AA) are more likely to develop SLE, and SLE is also more severe in this population. We hypothesized that peripheral blood gene expression patterns would differ between AA and European-American (EA) SLE patients, and between those with anti-RBP antibodies and those who lack these antibodies. 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. Ingenuity Pathway Analysis was used to compare the top differentially expressed canonical pathways amongst the sample groups. An independent cohort of 116 SLE patients was used to replicate findings using quantitative real-time PCR (qPCR). Results: Both AA and EA patients with positive anti-RBP antibodies showed over-expression of similar IFN-related canonical pathways, such as IFN Signaling (P = 1.3 × 10-7 and 6.3 × 10-11 in AA vs. EA respectively), Antigen Presenting Pathway (P = 1.8 × 10-5 and 2.5 × 10-6), and a number of pattern recognition receptor pathways. In anti-RBP negative (RBP-) patients, EA subjects demonstrated similar IFN-related pathway activation, whereas no IFN-related pathways were detected in RBP-AA patients. qPCR validation confirmed similar results. 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. This molecular heterogeneity suggests differences in IFN-pathway activation between ancestral backgrounds in SLE. This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.
AB - Background: In systemic lupus erythematosus (SLE), antibodies directed at RNA-binding proteins (anti-RBP) are associated with high serum type I interferon (IFN), which plays an important role in SLE pathogenesis. African-Americans (AA) are more likely to develop SLE, and SLE is also more severe in this population. We hypothesized that peripheral blood gene expression patterns would differ between AA and European-American (EA) SLE patients, and between those with anti-RBP antibodies and those who lack these antibodies. 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. Ingenuity Pathway Analysis was used to compare the top differentially expressed canonical pathways amongst the sample groups. An independent cohort of 116 SLE patients was used to replicate findings using quantitative real-time PCR (qPCR). Results: Both AA and EA patients with positive anti-RBP antibodies showed over-expression of similar IFN-related canonical pathways, such as IFN Signaling (P = 1.3 × 10-7 and 6.3 × 10-11 in AA vs. EA respectively), Antigen Presenting Pathway (P = 1.8 × 10-5 and 2.5 × 10-6), and a number of pattern recognition receptor pathways. In anti-RBP negative (RBP-) patients, EA subjects demonstrated similar IFN-related pathway activation, whereas no IFN-related pathways were detected in RBP-AA patients. qPCR validation confirmed similar results. 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. This molecular heterogeneity suggests differences in IFN-pathway activation between ancestral backgrounds in SLE. This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.
KW - Ancestral background
KW - Autoantibodies
KW - Interferon alpha
KW - Interferon gamma
KW - Systemic lupus erythematosus
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U2 - 10.3389/fimmu.2013.00309
DO - 10.3389/fimmu.2013.00309
M3 - Article
C2 - 24101921
AN - SCOPUS:84885411616
SN - 1664-3224
VL - 4
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - OCT
M1 - Article 309
ER -