Sa.54. Positional Identification of Integrin- αMβ2 (ITGAM) as a Susceptibility Gene for Systematic Lupus Erythematosus (SLE)

S98 associated with the control of leptin on the function of human Treg cells, i.e. a downregulation of the cyclindependent kinase inhibitor p27 and the phosphorylation of the extracellular-related kinases 1/2 during leptin blockage two findings that help to explain the entry of these cells into the cell cycle and the “unlock” of their anergic state. These studies provide new information on how leptin can influence Treg cell function and can have implications for the modulation of the activity of these cells in the control of autoimmune disease.

Abstracts and SLE implicate the αMβ2-integrin adhesion pathway in disease development. doi:10.1016/j.clim.2008.03.275

Sa.55. Lupus Susceptibility Locus Sle2 Promotes B Cell Receptor Revision Kirthi Kumar, Hasna Kanta, Chandra Mohan. Ut Southwestern Medical Center, Dallas, TX

doi:10.1016/j.clim.2008.03.274

Sa.54. Positional Identification of Integrin- αMβ2 (ITGAM) as a Susceptibility Gene for Systematic Lupus Erythematosus (SLE) Swapan Nath, 1 Shizhong Han, 1 Xana Kim-Howard, 1 Harshal Deshmukh, 1 Parvathi Viswanathan, 1 Gail Bruner, 1 Jennifer Kelly, 1 Gary Gilkeson, 2 Rodger McEver, 1 Robert Kimberly, 4 Timothy Vyse, 6 Wei Chen, 3 Cheng Zhu, 3 Marta AlarcónRiquelme, 5 Edward Wakeland, 7 Sang-Cheol Bae, 8 Patrick Gaffney, 1 Kathy Moser, 1 Joan Merrill, 1 Judith James, 1 Ken Kaufman, 1 Joel Guthridge, 1 John Harley.1 1 Oklahoma Medical Research Foundation, Oklahoma City, OK; 2Medical 3 University of South Carolina, Charleston, SC; Georgia 4 Institute of Technology, Atlana, GA; The University of Alabama at Birmingham, Birmingham, AL; 5 Uppsala University, Uppsala, Sweden; 6 Hammersmith Hospital, London, United Kingdom; 7 The University of Texas Southwestern Medical Center, Dallas, TX; 8 Hanyang University Medical Center, Seoul, South Korea Systemic lupus erythematosus (SLE) is a systemic, autoimmune, inflammatory disease with a relatively strong genetic component. Previously, we reported 16p12-q12 as the second strongest SLE linkage signal after HLA region using a genome scan meta analysis. To identify SLE susceptibility genes, we conducted an association study using a directed candidate gene approach. Initially, 49 common SNPs from 11 candidate genes were evaluated using 1109 European American (EA) individuals, and two SNPs on ITGAM (CD11b) were significantly associated with SLE. We performed a follow up study using 26 common SNPs from ITGAM. Association between ITGAM and SLE risk was identified and replicated in 5583 EA individuals. The strongest association is identified with an exon-3 nonsynonymous SNP (rs1143679, P = 1.8 × 10(-24), OR = 1.8). Further, this association was replicated in two independent samples of African descent (AA: 1289 individuals, P = 0.0002, OR = 1.6, Gullah: 271 individuals, P = 0.003, OR = 2.1) and an independent Hispanic sample (922 individuals, P = 0.00009, OR = 2.0). Additionally, we evaluated 1449 Koreans, although this SNP is monomorphic. These results are also confirmed by family-based (EA samples) and admixture adjusted cases-control analysis (AA, Gullah and Hispanics). Our data provide strong evidence that ITGAM is a SLE susceptibility gene (overall P = 1.2 × 10(-30), OR (C.I.) = 1.7 (1.56-1.87)), and rs1143679 is a causal SNP, which contributes 10% to 15% to the population attributable risk. Therefore, genetic association between ITGAM

Purpose: B6 mice congenic for the NZM2410/NZW allele of the Sle2 lupus susceptibility locus display intrinsic B-cell hyperactivity. The Sle2 locus acts in epistasis with the lupus susceptibility loci Sle1 and Sle3 to engender full blown nephritis. These studies were designed to understand how Sle2 might breach B cell tolerance. Methods B6.Sle2 mice were bred to HEL-Ig only or HEL-Ig.sHEL transgenic mice and examined for breach in B cell tolerance. Results: Sle2 did not impair B-cell tolerance as B6.Sle2.HEL-Ig.sHEL and control B6. HEL-Ig.sHEL mice did not display serum anti-HEL Abs. Interestingly however, Sle2 bearing B-cell receptor (BCR) Tg mice exhibited enhanced BCR revision as supported by increased splenic endogenous IgMb expressing B-cells (B6. HEL-Ig, 10.3 ± 4.1% of B-cells vs B6.Sle2.HEL-Ig, 20.8 ± 2.6%, p b 0.05; B6.HEL-Ig.sHEL, 25.6 ± 4.6% vs B6.Sle2.HEL-Ig.sHEL, 44.2± 4.8%, p b 0.001, aged 8-12 months) and increased usage of endogenous Jκ1 LC. Moreover, B6.Sle2.HEL-Ig but not control B6.HEL-Ig mice displayed increased serum titers of polyclonal IgMb, Igλ and IgG. On autoantigen proteome arrays, sera from B6.Sle2.HEL-Ig mice displayed a wide spectrum of autoantibody specificities. Conclusion: Although the Sle2 locus did not impair B-cell tolerance, the HC and LC usage and serum autoantibody profiles suggest that this locus strongly potentiates BCR revision. Preliminary experiments indicate that Sle2 affects RAG reexpression in mature B-cells upon BCR ligation. Ongoing studies are aimed at unraveling molecular mechanisms by which Sle2 impairs BCR revision and autoimmunity. doi:10.1016/j.clim.2008.03.276

Sa.56. Efficacy Of XOMA 052 Anti-IL-1β Antibody In The DBA/1 Mouse Collagen-induced Arthritis Model Alex Owyang, Lin Esposito, Sandra Vanegas, Linda Masat, Elizabeth Pongo, Paul Larsen, John Corbin, Kiran Ahluwalia, Marina Roell, Arnold Horwitz, Mary Haak-Frendscho, Nathalie Dubois-Stringfellow, Seema Kantak, David Alleva. XOMA US LLC, Berkeley, CA Interleukin-1β (IL-1β) is a key cytokine involved in the pathology of arthritis and other inflammatory diseases, and its neutralization shows efficacy in both animal and human disease. The Human Engineered™ anti-IL-1β antibody, XOMA 052, was developed for treatment of inflammatory diseases and has a very high affinity (KD = 0.3 pM) to human IL-1β (rHuIL-1β). This antibody neutralizes the bioactivity of rHuIL-1β in the D10.G4.1 (D10) cellular proliferation assay with an IC50 of 2.5 pM, and is currently in clinical trials for