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* Laboratory of Molecular Autoimmune Disease, Renal Division, and
Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115
MRL/MpJ-Faslpr (MRL-Faslpr) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Faslpr mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (–/–) and PD-L1 intact (wild type, WT) MRL-Faslpr mice. Unexpectedly, PD-L1–/–;MRL-Faslpr mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8+ > CD4+), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1–/–;MRL-Faslpr mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1–/–;MRL+/+ mice lacking the Faslpr mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1–/–;MRL+/+ bone marrow cells induced myocarditis and pneumonitis in WT;MRL+/+ mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL+/+ mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.
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1 This work was supported in part by grants from the National Institutes of Health, R01 DK 52369 (to V.R.K.) and P01 AI 56299 (to A.H.S.), and Genzyme Renal Innovations Program (to V.R.K.). J.L. is supported by a Ruth L. Kirschstein National Research Service Award (F32 DK078416-01). J.M. received support from the Deutsche Forschungsgemeinschaft (ME-3194/1-1).
2 Address correspondence and reprint requests to Dr. Vicki Rubin Kelley, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: vkelley{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: Mø, macrophage; autoAbs, autoantibodies; PD-1, programmed-death 1; PD-L1, PD-1 ligand; WT, wild type; BM, bone marrow; DN, double negative.
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