Editors' ChoiceAutoimmunity

Apoptotic debris goes in the Bim

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Science Translational Medicine  22 Nov 2017:
Vol. 9, Issue 417, eaar2440
DOI: 10.1126/scitranslmed.aar2440


Lack of Bim expression in myeloid cells induces lupus nephritis in mice

Systemic lupus erythematosus (lupus) is an autoimmune disease that may result from failure of autoreactive lymphocytes to undergo apoptosis, or from failure of myeloid cells to eliminate apoptotic debris. Patients with lupus typically have autoantibodies and various clinical disease manifestations including glomerulonephritis, a severe inflammatory kidney disease that can cause renal failure. Although loss of B cell tolerance contributes to lupus, aberrant innate immune signaling including upregulation of type I interferon (IFN)–stimulated genes also seems to play a major part in disease pathogenesis.

Bim is a proapoptotic gene expressed in a variety of cell types. Genetic disruption of Bim in mice triggers severe lupus, but the precise mechanism of autoimmunity in Bim–/– mice was not defined. In a recent study published in The Journal of Experimental Medicine, Tsai et al. described LysM-Cre Bimfl/fl mice lacking Bim only in the myeloid compartment. Similar to the global Bim knockout mice, mice lacking Bim in myeloid cells developed severe lupus with glomerulonephritis, splenomegaly, lymphadenopathy, and a type I IFN signature—all hallmarks of systemic lupus. In contrast, mice lacking Bim specifically in CD4 T cells or B cells were healthy, even when crossed onto an autoimmune disease–prone background.

Most remarkably, genetic deletion of Bim in myeloid cells led to macrophage infiltration into the kidney and end-organ damage. Furthermore, kidney macrophages from LysM-Cre Bimfl/fl mice exhibited upregulation of IFN-stimulated genes and expressed lower levels of CD36, a scavenger receptor involved in clearing apoptotic bodies. In support of human disease relevance of their findings, a comparison of the gene expression signature in human lupus nephritis kidney and Bim-deficient mouse macrophages revealed an overlapping transcriptional signature. Patients with lupus nephritis also exhibit macrophage infiltration into the kidney, which contributes to renal destruction. Thus, in addition to describing the lymphocyte-independent role of Bim in lupus, the findings of Tsai et al. may ultimately lead to novel Bim-targeted therapies in patients with lupus nephritis.

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