Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients

Kichul Ko, Yelena Koldobskaya, Elizabeth Rosenzweig, Timothy B. Niewold

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberArticle 309
JournalFrontiers in Immunology
Volume4
Issue numberOCT
DOIs
StatePublished - 2013

Fingerprint

African Americans
Systemic Lupus Erythematosus
Autoantibodies
Interferons
RNA-Binding Proteins
Antibodies
Gene Expression
Pattern Recognition Receptors
Interferon Type I
Real-Time Polymerase Chain Reaction
RNA
Antigens
Serum
Population
Genes

Keywords

  • Ancestral background
  • Autoantibodies
  • Interferon alpha
  • Interferon gamma
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients. / Ko, Kichul; Koldobskaya, Yelena; Rosenzweig, Elizabeth; Niewold, Timothy B.

In: Frontiers in Immunology, Vol. 4, No. OCT, Article 309, 2013.

Research output: Contribution to journalArticle

Ko, Kichul ; Koldobskaya, Yelena ; Rosenzweig, Elizabeth ; Niewold, Timothy B. / Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients. In: Frontiers in Immunology. 2013 ; Vol. 4, No. OCT.
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abstract = "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.",
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T1 - Activation of the interferon pathway is dependent upon autoantibodies in African-American SLE patients, but not in European-American SLE patients

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AU - Niewold, Timothy B.

PY - 2013

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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.

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KW - Interferon gamma

KW - Systemic lupus erythematosus

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