A Genetic Model for IRF5, Autoantibodies, and Interferon Alpha in Human Lupus Pathogenesis

Clinical Immunology (2009) 131, S4–S17

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Oral Presentations: Friday, June 12 #1201: Triggers of Autoimmunity Friday, June 12 10:45 am–11:00 am A Genetic Model for IRF5, Autoantibodies, and Interferon Alpha in Human Lupus Pathogenesis Timothy Niewold 1, Jennifer Kelly 2, Silvia Kariuki 1, Kenaz Thomas 2, Daniel Walker 2, Stan Kamp 2, Jacqueline Frost 3, Andrew Wong 4, Joan Merrill 2, Marta Alarcón-Riquelme 5, Mohammed Tikly 3, Rosalind Ramsey-Goldman 6, John Reveille 7, Michelle Petri 8, Jeffery Edberg 9, Robert Kimberly 9, Graciela Alarcón 9, Timothy Vyse 10, Judith James 2, Patrick Gaffney 2, Kathy Moser 2, Mary Crow 11, John Harley2. 1University of Chicago, Chicago, IL; 2 Oklahoma Medical Research Foundation, Oklahoma City, OK; 3University of the Witwatersrand, Johannesburg, South Africa; 4Medical Research Council, London, UK; 5 University of Uppsala, Uppsala, Sweden; 6Northwestern University Feinberg School of Medicine, Chicago, IL; 7 University of Texas-Houston Health Science Center, Houston, TX; 8Johns Hopkins University, Baltimore, MD; 9 University of Alabama at Birmingham, Birmingham, AL; 10 Imperial College, London, UK; 11Hospital for Special Surgery, New York, NY High interferon alpha (IFN-α) is implicated as a heritable risk factor for systemic lupus erythematosus (SLE). Interferon regulatory factor 5 (IRF5) haplotypes are associated with SLE susceptibility, and SLE-specific autoantibodies may stimulate IFN-α production through the Toll-like receptor/ IRF5 pathway. In European ancestry SLE patients, antidsDNA and anti-Ro autoantibodies were each associated with distinct IRF5 SNPs which form an SLE-risk haplotype. Comparing 1034 cases to 989 controls, this haplotype was strongly associated with SLE only in patients with these autoantibodies (anti-Ro or anti-dsDNA positive OR = 2.31, p = 7.2x10-15 vs. anti-Ro and anti-dsDNA negative OR = 1.44, p = 0.00035). In 555 African-American subjects, the European-derived SLE-risk haplotype demonstrated a similar autoantibody-dependent association with SLE. In both ancestral backgrounds, the IRF5 SLE-risk haplotype resulted in increased IFN-α only in patients with anti-dsDNA or antiRo autoantibodies. Healthy first degree relatives who

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typically lack these autoantibodies demonstrated no relationship between IRF5 genotype and serum IFN-α. These data suggest a disease model in which autoantibodies are directly pathogenic, cooperating with IRF5 variants to dysregulate IFN-α production and consequently increase risk of SLE. doi:10.1016/j.clim.2009.03.004

Age-and Gender-Specific Modulation of Serum Osteopontin and Interferon Alpha by Osteopontin Genotype in Systemic Lupus Erythematosus Silvia Kariuki 1, Julian Moore 1, Kyriakos Kirou 2, Mary Crow 2, Tammy Utset 1, Timothy Niewold1. 1University of Chicago, Chicago, IL; 2Hospital for Special Surgery, New York, NY Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon alpha (IFN-α) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-α is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to males. In the present study, the 3' UTR SLE-risk variant of OPN (rs9138 C) was associated with higher serum OPN and IFN-α in male SLE patients. In female patients, the association between rs9138 C and higher serum OPN and IFN-α was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of OPN genotype upon both serum OPN and IFN-α (pb 0.0001). In African-American subjects, we found an association between anti-RNP antibodies and SNPs in the 5' region, which has been inconsistently associated with SLE. Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. This study provides a biologic relevance for OPN variants at the protein level, and suggests an influence of this gene upon the IFN-α pathway in SLE. doi:10.1016/j.clim.2009.03.005