Journal
ANNALS OF THE RHEUMATIC DISEASES
Volume 71, Issue 3, Pages 463-468Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2011-200463
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Funding
- National Institutes of Health [AR060861, AI083790, DK42086, AI071651, RR024999, AR62277, AR42460, AI24717, CA141700, AR058621, AR002138, RR025741, AR30692, Mo1-RR0048, AR49084, AR33062, AR42476, MO1-RR00052, RR-01070]
- Lupus Research Institute
- Alliance for Lupus Research
- Arthritis National Research Foundation
- HHMI
- Connective Tissue Diseases Research Fund
- Swedish Research Council
- Gustaf Vth-80th-year Jubilee
- US Department of Veterans Affairs
- Wellcome Trust
- National Institute for Health and Research
- Mary Kirkland Center for Lupus Research
- Lou Kerr Chair in Biomedical Research
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Objective High serum interferon alpha (IFN alpha) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFN alpha production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. Methods 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African-American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNa activity was measured using a functional assay. Results In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9x10(-14) for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNa in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African-American patients with SLE a similar relationship between serology and IFNa was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African-American subjects and absent in African patients with SLE. Conclusions The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNa in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.(1) These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness(2) and are likely pathogenic in SLE.(3 4)
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