Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor ␥ chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T H17) and follicular CD4 T helper cells (T FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T H17 cells and was not limited to conventional CXCR5 ؉ TFH but instead was produced broadly by ICOS ؉ CD4 ؉ splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.autoimmune disease ͉ autoantibodies ͉ B cells ͉ T cells S ystemic lupus erythematosus (SLE) in humans is a chronic, multigenic autoimmune disease characterized by a wide spectrum of clinical abnormalities, the production of multiple autoantibodies, and the generation of immune complexes that often lead to severe renal disease. The production of autoantibodies is indicative of a profound breakdown in humoral tolerance mechanisms and B cell hyperactivity caused either by B cell-intrinsic abnormalities or immunoregulatory defects of other cell types. Mouse models genetically programmed to develop characteristics of SLE have proven useful for characterizing this disease process and for identifying potential therapeutic targets. Among the most interesting models of SLE are the BXSB mice bearing the Y chromosome-linked autoimmune acceleration (Yaa) mutation (1). Affected animals develop a remarkably severe disease characterized by lymphoid hyperplasia, monocytosis, hypergammaglobulinemia, and severe immune complex-mediated glomerulonephritis. In contrast to the female prevalence of SLE in humans, this disease is male-biased because of the epistatic effects of BXSB-background autosomal alleles in combination with Yaa. This mutant locus is the result of the duplication of at least 17 genes in the X chromosome, including Toll-like receptor 7 (Tlr7), and their placement in the Y chromosome (2, 3). Remarkably, severe autoimmune disease results from the presence of an extra copy of these X-chromosome genes in Yaa mice in combination with BXSB-background autosomal alleles.IL-21 is a pleiotropic member of the ␥-chain family of cytokines, which engages the IL-21 receptor (IL-21R) and the common cytokine re...

Historically our ability to identify genetic variants underlying complex behavioral traits in mice has been limited by low mapping resolution of conventional mouse crosses. The newly developed Diversity Outbred (DO) population promises to deliver improved resolution that will circumvent costly fine mapping studies. The DO is derived from the same founder strains as the Collaborative Cross (CC), including three wild derived strains. Thus the DO provides more allelic diversity and greater potential for new discovery compared to crosses involving standard mouse strains. We have characterized 283 male and female DO mice using open-field, light-dark box, tail-suspension, and visual-cliff avoidance tests to generate 38 behavioral measures. We identified several quantitative trait loci (QTL) for these traits with support intervals ranging from 1 to 3 Mb in size. These intervals contain relatively few genes (ranging from 5 to 96). For a majority of QTL, using the founder allelic effects together with whole genome sequence data, we could further narrow the positional candidates. Several QTL replicate previously published loci. Novel loci were also identified for anxiety- and activity-related traits. Half of the QTLs are associated with wild-derived alleles, confirming the value to behavioral genetics of added genetic diversity in the DO. In the presence of wild-alleles we sometimes observe behaviors that are qualitatively different from the expected response. Our results demonstrate that high-precision mapping of behavioral traits can be achieved with moderate numbers of DO animals, representing a significant advance in our ability to leverage the mouse as a tool for behavioral genetics.

High-throughput genome technologies have produced a wealth of data on the association of genes and gene products to biological functions. Investigators have discovered value in combining their experimental results with published genome-wide association studies, quantitative trait locus, microarray, RNA-sequencing and mutant phenotyping studies to identify gene-function associations across diverse experiments, species, conditions, behaviors or biological processes. These experimental results are typically derived from disparate data repositories, publication supplements or reconstructions from primary data stores. This leaves bench biologists with the complex and unscalable task of integrating data by identifying and gathering relevant studies, reanalyzing primary data, unifying gene identifiers and applying ad hoc computational analysis to the integrated set. The freely available GeneWeaver (http://www.GeneWeaver.org) powered by the Ontological Discovery Environment is a curated repository of genomic experimental results with an accompanying tool set for dynamic integration of these data sets, enabling users to interactively address questions about sets of biological functions and their relations to sets of genes. Thus, large numbers of independently published genomic results can be organized into new conceptual frameworks driven by the underlying, inferred biological relationships rather than a pre-existing semantic framework. An empirical ‘ontology’ is discovered from the aggregate of experimental knowledge around user-defined areas of biological inquiry.