%0 Journal Article %J J Immunol %D 2008 %T Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. %A Lucas, Julie A %A Menke, Julia %A Rabacal, Whitney A %A Schoen, Frederick J %A Sharpe, Arlene H %A Kelley, Vicki R %K Animals %K Antigens, CD274 %K Antigens, CD80 %K Antigens, CD95 %K Antigens, Surface %K Apoptosis Regulatory Proteins %K Autoimmune Diseases %K Bone Marrow Transplantation %K Female %K Genetic Predisposition to Disease %K Immunophenotyping %K Lupus Erythematosus, Systemic %K Male %K Membrane Glycoproteins %K Mice %K Mice, Inbred C57BL %K Mice, Inbred MRL lpr %K Mice, Knockout %K Mice, Transgenic %K Myocarditis %K Peptides %K Pneumonia %K Programmed Cell Death 1 Receptor %K Radiation Chimera %K Signal Transduction %X MRL/MpJ-Fas(lpr) (MRL-Fas(lpr)) 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-Fas(lpr) 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-Fas(lpr) mice. Unexpectedly, PD-L1(-/-);MRL-Fas(lpr) 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-Fas(lpr) mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1(-/-);MRL(+/+) mice lacking the Fas(lpr) 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. %B J Immunol %V 181 %P 2513-21 %8 2008 Aug 15 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/18684942?dopt=Abstract