Genetic dissection of murine lupus susceptibility locus SLE1C identifies estrogen-related receptor gamma as a novel regulator of autoimmunity.

摘要

Systemic lupus erythematosus (SLE) is a chronic autoinflammatory disease that manifests in many forms ranging from mild to acute and affecting multiple organ systems. It is characterized by the presence of pathogenic antinuclear antibodies (ANA) that result in the deposition of immune complexes in basement membranes throughout the body. These immune complexes can then induce inflammatory responses that over time lead to tissue destruction. This capability of tissue destruction anywhere in the body is the reason for the multifaceted nature of the disease. Patients with the highest mortality are those in which the kidneys are involved. In such cases, immune complex deposits result in glomerulonephritis (GN), eventually leading to kidney failure and death. Because the genetic and environmental factors that cause SLE are poorly understood, treatment is generally limited to regimens of immunosuppressive therapies, which tend to have detrimental side effects. Thus there is an imminent need for the discovery of improved treatments.;The focus of the work in our lab is on identifying genetic factors responsible for SLE etiology using the NZM2410 recombinant inbred mouse strain. Derived from NZB and NZW, its parental strains are the basis of the classic NZB/W F1 lupus mouse model. Linkage analysis of a cohort of NZM x B6 F1 backcrossed to NZM identified three major lupus susceptibility loci. Among these, Sle1, located on Chromosome 1, has been shown to be required for initiation of the disease by mediating a loss of tolerance to nuclear antigens. Subsequently, Sle1 was determined to be composed of three subloci, Sle1a, Sle1b, and Sle1c. Further characterization of the Sle1c sublocus found it to be a complex locus as well, with decreased germinal center and T dependent immune responses mapping to the telomeric portion, and CD4+ T cell hyperactivation and increased chronic graft-versus-host disease (cGVHD) mapping to the centromeric portion of the locus. In this project phenotypic mapping was used to refine the centromeric Sle1c2 sublocus to a 675Kb interval. Recombinant congenic strains with the NZW-derived Sle1c2 interval introgressed exhibited CD4+ T cell activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice were found to have a robust expansion of INFγ expressing TH1 cells. Also, when the Sle1c2 locus in NZB x B6 F1 mice was NZB/NZW as compared to NZB/B6, B cell activation, autoantibody production, and GN were exacerbated, verifying the locus as a bona fide lupus susceptibility locus.;Of the two genes in the Sle1c2 interval, only one, Estrogen-related receptor gamma (Esrrg), had detectable expression in CD4 + T cells. Furthermore, congenic B6.Sle1c2 mice expressed less Esrrg than B6 controls in CD4+ T cells, and Esrrg expression had a very strong negative correlation to CD4+ T cell activation. Taken together, I propose Esrrg to be a novel target for the therapeutic intervention of SLE.