Genomic view of systemic autoimmunity in MRLlpr mice

Abstract

MRLlpr mice develop spontaneous systemic autoimmunity with many hallmarks of the human disease systemic lupus erythematosus. Although a variety of genes have been implicated in this model, disease pathogenesis is still poorly understood. In an effort to identify novel genes and pathways, we performed genome-wide mRNA expression analysis in the spleens and kidneys of MRLlpr mice throughout the disease course. Samples were collected from cohorts of C57BL/6, MRL þ / þ and MRLlpr mice, and profiled by flow cytometry and gene expression microarrays. Serum autoantibodies and renal pathology were studied in parallel. We identified 236 genes in MRLlpr spleen that showed significant threefold or greater changes in expression between 6 and 20 weeks. Of interest, a number of interferon-responsive genes were expressed early, and remained dysregulated throughout the disease course. Many chemokines, cell surface proteins, transcription factors and cytokines, including IFN-gamma, also showed altered expression as disease progressed. Analysis of kidneys indicated the presence of severe inflammation that coincided with evidence for changes in kidney function and elevated expression of IFNinducible genes, complement components and antigen presentation genes. These data provide a unique genomic view of the progression to fatal autoimmunity in MRLlpr mice, and provide new candidate genes and pathways to explore.

Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients

“…In the MRL/lpr lupus-prone mouse, 24 interferon-regulated genes are differentially expressed in the spleen relative to MRL+/+ controls. 41 The finding that interferon-γ expression progressively increased in the spleens of MRL/lpr mice with time, whereas the levels of interferon-α and interferon-β remained stable, suggest an 'interferon-γ signature' in the MRL/lpr lupus-prone mouse. 41 Interestingly, MRL/lpr mice also have T-cell DNA methylation defect as demonstrated by reduced T-cell Dnmt1 expression, and hypomethylation with overexpression of methylation-sensitive genes such as CD70, 42 similar to what we observed in the dnMEK/ CD2-rtTA mouse model.…”

IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

“…Several recent studies have examined the contributions of TLRs and IFN-I to SLE disease in the MRL/lpr model (33,74,75). DNA microarray analysis of MRL/lpr splenocyte subsets and kidneys clearly demonstrate an IFN-γ-regulated gene expression profile, whereas genes induced by IFN-I are not upregulated in MRL/lpr mice (76). This observation may explain why MRL/lpr mice deficient for the IFNAR1 chain of the IFNAR actually develop more severe disease: the lack of IFN-I signaling may further drive the IFN-γ response (75).…”

Microarray Analysis of Glomerular Gene Expression in Murine Lupus Nephritis

“…4). It was reported that renal IFN-γ mRNA expression of MRL / lpr mice is higher than that of control mice (4,27). Furthermore, a number of IFN-γ gene "signatures" were identified from our microarray data.…”

“…Microarray technology enables simultaneous monitoring of genome-wide mRNA expression analysis, providing an opportunity to study complex molecular interactions in disease processes (3). In fact, this technology was successfully applied to kidney tissue of MRL / lpr mice (4). In their study, however, whole kidney samples were used for the microarray analysis.…”