Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice
Authors
Lucas, Julie AnnMenke, Julia
Rabacal, Whitney A.
Schoen, Frederick J.
Sharpe, Arlene H.
Kelley, Vicki R.
UMass Chan Affiliations
Laboratory of Molecular Autoimmune DiseaseGraduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2008-08-08Keywords
Animals; Antigens, CD80; Antigens, CD95; Antigens, Surface; Apoptosis Regulatory Proteins; Autoimmune Diseases; Bone Marrow Transplantation; Female; Genetic Predisposition to Disease; Immunophenotyping; Lupus Erythematosus, Systemic; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Knockout; Mice, Transgenic; Myocarditis; Peptides; Pneumonia; Radiation Chimera; Signal TransductionLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2008 Aug 15;181(4):2513-21.
DOI
10.4049/jimmunol.181.4.2513Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33024PubMed ID
18684942Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.181.4.2513