Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Cutting edge: Transitional T3 B cells do not give rise to mature B cells, have undergone selection, and are reduced in murine lupus.

As the immediate precursors to mature follicular B cells in splenic development, immature transitional cells are an essential component for understanding late B cell differentiation. It has been shown that T2 cells can give rise to mature B cells; however, whether T3 B cells represent a normal stage of B cell development, which has been widely assumed, has not been fully resolved. In this study, we demonstrate both in vitro and in vivo that T3 B cells do not give rise to mature B cells and are instead selected away from the T1-->T2-->mature B cell developmental pathway and are hyporesponsive to stimulation through the BCR. Significantly reduced numbers of T3 B cells in young lupus-prone mice further suggest that the specificity of this subset holds clues to understanding autoimmunity.

Update in rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by polyarticular symmetrical arthritis. Inflammatory mediators targeting joint structures produce joint inflammation with pain, functional loss, joint destruction and permanent deformity. Currently, no cure for RA exists but the increasing use of combination therapy and immunomodulatory agents has led to improved quality of life and long-term outlook for many of these patients. While traditionally employed therapies have provided limited disease suppression, advances in our understanding of the molecular pathogenesis of RA have resulted in new therapies targeting very specific components of the inflammatory process. These new treatments have shown very promising results with improved efficacy and an overall decreased toxicity profile. This review provides an overview for practicing clinicians of the current immunosuppressive therapies in RA with an emphasis on newer biological agents regarding their mechanisms of action, efficacy, side effects and monitoring recommendations. Developing therapeutics will be briefly discussed.