Assessing the Molecular Validity of Spontaneous Lupus Mouse Models and Its Implication for Human Studies

Abstract

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by a loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Animal models have advanced our understanding of SLEs molecular basis, but the FDAs recent elimination of animal testing requirements for drug approval has raised concerns about their validity, prompting a reevaluation of their role in basic research, especially for heterogeneous diseases like SLE. MethodsFour different spontaneous SLE mouse models were studied: MRLlpr/lpr, NZB/W, BXSB.Yaa, and Tlr7.Tg6. Transcriptome sequencing from blood, spleen, and kidney, flow cytometry from the spleen, and cytokines and autoantibody measurement in plasma were performed at four time points. Similar molecular data from human SLE patients was used for the integration. ResultsThe study identified specific molecular pathways driving the phenotype in each mouse model and established optimal time points for future experimental designs. By comparing these pathways to human SLE, the most similar ones and their relationship with disease activity were identified, providing crucial insight into translational relevance. Importantly, disease severity across models was linked to the extent and timing of molecular dysregulations. As expected, MRLlpr/lpr showed the most aggressive phenotype with early immune activation and apoptosis dysregulation, while Tlr7.Tg6 presented late-onset signatures associated with interferon and inflammation. Shared molecular features with human SLE included interferon responses, T and B cell depletion, and neutrophil activation. Integration analysis revealed distinct yet overlapping immune pathways between models and species, with some signatures such as age-associated B cells and double-negative memory T cells being model-specific but potentially relevant to early disease processes. ConclusionsThese findings build a valuable framework for future SLE research, reinforcing the utility of mouse models in studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse data with human transcriptomes highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.