Abstract
Mouse models have contributed to the bulk of knowledge on Systemic Lupus Erythematosus (SLE). Nevertheless, substantial differences exist between human and mouse immune system. We aimed to establish and characterise a SLE model mediated by human immune system. Injection of pristane into immunodeficient mice reconstituted with human immune system (humanised mice) recapitulated key SLE features, including: production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis. There was a reduction in the number of human lymphocytes in peripheral blood, resembling lymphopenia in SLE patients. Concurrently, B cells and T cells were systemically hyperactivated, with a relative expansion of CD27+ and CD27−IgD− memory B cells, increased number of plasmablasts/plasma cells, and accumulation of effector memory T cells. There was also an increased production of human pro-inflammatory cytokines, including: IFN-γ, IL-8, IL-18, MCP-1, and IL-6, suggesting their role in SLE pathogenesis. Increased expression of type I IFN signature genes was also found in human hepatocytes. Altogether, we showed an SLE model that was mediated by human immune system, and which recapitulated key clinical and immunological SLE features. The advancements of humanised mice SLE model would provide an in vivo platform to facilitate translational studies and pre-clinical evaluations of human-specific mechanisms and immunotherapies.
Highlights
Systemic Lupus Erythematosus (SLE) is a chronic, relapsing autoimmune disorder where the immune system targets multiple self-nuclear antigens, leading to chronic organ damage and mortality[1]
This showed that the human immune system is necessary and sufficient for the induction of SLE pathogenesis, leading to increased mortality in hu-mice; and, on the other hand, the residual mouse myeloid cells did not contribute significantly to the pathogenesis
Hu-mice containing stable engraftment of human immune system in immunodeficient mouse have proven to be instrumental in the study of human immunology, for human-specific infectious diseases and cancer models[15]
Summary
Systemic Lupus Erythematosus (SLE) is a chronic, relapsing autoimmune disorder where the immune system targets multiple self-nuclear antigens, leading to chronic organ damage and mortality[1]. Spontaneous models using inbred strains, such as the NZB/W F1 mice[7], MRL/lpr mice[8], and BXSB/Yaa mice models[9], possess genetic backgrounds that confers SLE susceptibility, and develop spontaneous nephritis and autoantibodies production These spontaneous models have been useful in studying the complex genetic contribution in SLE. A model of SLE induced in human immune system would allow numerous in vivo studies of human-specific SLE pathogenesis in manners that is not possible in human It would facilitate translational studies for the development and evaluation of targeted immunotherapy for human SLE
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