PMID- 25963626 OWN - NLM STAT- MEDLINE DCOM- 20160506 LR - 20181113 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 6 DP - 2015 May 12 TI - CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. PG - 7086 LID - 10.1038/ncomms8086 [doi] LID - 7086 AB - Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag(-/-) mice. The CD8alpha(+) DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4(+) T cells and autoantibodies specific for joint tissue are present, and arthritis severity correlates with the number of autoreactive CD4(+) T cells and plasmablasts in the joint-draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8alpha(+) DCs and other cells of the immune system. FAU - Huang, Qi-Quan AU - Huang QQ AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Perlman, Harris AU - Perlman H AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Birkett, Robert AU - Birkett R AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Doyle, Renee AU - Doyle R AUID- ORCID: 0000000310196783 AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Fang, Deyu AU - Fang D AD - Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Haines, G Kenneth AU - Haines GK AD - Department of Pathology, Mount Sinai Hospital School of Medicine, New York city, New York 10029, USA. FAU - Robinson, William AU - Robinson W AD - Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, VA Health Care System, Palo Alto, California 94304, USA. FAU - Datta, Syamal AU - Datta S AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Huang, Zan AU - Huang Z AD - Department of Biochemistry, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China. FAU - Li, Quan-Zhen AU - Li QZ AD - Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. FAU - Phee, Hyewon AU - Phee H AD - Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. FAU - Pope, Richard M AU - Pope RM AD - Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. LA - eng GR - R01 AR048269/AR/NIAMS NIH HHS/United States GR - K01 AR059754/AR/NIAMS NIH HHS/United States GR - AI108634/AI/NIAID NIH HHS/United States GR - R01 AI041985/AI/NIAID NIH HHS/United States GR - R01 AI079056/AI/NIAID NIH HHS/United States GR - P50 AR055503/AR/NIAMS NIH HHS/United States GR - AR054796/AR/NIAMS NIH HHS/United States GR - P01 HL108795/HL/NHLBI NIH HHS/United States GR - HL108795/HL/NHLBI NIH HHS/United States GR - R21 AI067590/AI/NIAID NIH HHS/United States GR - R21 AR065076/AR/NIAMS NIH HHS/United States GR - AR065076/AR/NIAMS NIH HHS/United States GR - AI041985/AI/NIAID NIH HHS/United States GR - R01 AR064546/AR/NIAMS NIH HHS/United States GR - P60 AR064464/AR/NIAMS NIH HHS/United States GR - AR050250/AR/NIAMS NIH HHS/United States GR - K26 OD010945/OD/NIH HHS/United States GR - AI079056/AI/NIAID NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - AR006634/AR/NIAMS NIH HHS/United States GR - R01 AI108634/AI/NIAID NIH HHS/United States GR - AR048269/AR/NIAMS NIH HHS/United States GR - AR059754/AR/NIAMS NIH HHS/United States GR - R01 AR050250/AR/NIAMS NIH HHS/United States GR - R01 AR054796/AR/NIAMS NIH HHS/United States GR - R56 AI079056/AI/NIAID NIH HHS/United States GR - AI067590/AI/NIAID NIH HHS/United States GR - AR055503/AR/NIAMS NIH HHS/United States GR - R01 AR066634/AR/NIAMS NIH HHS/United States GR - CA060553/CA/NCI NIH HHS/United States GR - AR064464/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150512 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Autoantibodies) RN - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein) RN - 0 (CD11c Antigen) SB - IM MH - Animals MH - Arthritis/genetics/*metabolism/pathology MH - Autoantibodies MH - Autoimmune Diseases MH - CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/*metabolism MH - CD11c Antigen/genetics/*metabolism MH - CD4-Positive T-Lymphocytes MH - Dendritic Cells MH - Female MH - Inflammation/genetics/*metabolism MH - Male MH - Mice MH - Mice, Knockout MH - T-Lymphocytes, Regulatory PMC - PMC4429912 MID - NIHMS677630 EDAT- 2015/05/13 06:00 MHDA- 2016/05/08 06:00 PMCR- 2015/05/15 CRDT- 2015/05/13 06:00 PHST- 2015/02/04 00:00 [received] PHST- 2015/04/01 00:00 [accepted] PHST- 2015/05/13 06:00 [entrez] PHST- 2015/05/13 06:00 [pubmed] PHST- 2016/05/08 06:00 [medline] PHST- 2015/05/15 00:00 [pmc-release] AID - ncomms8086 [pii] AID - 10.1038/ncomms8086 [doi] PST - epublish SO - Nat Commun. 2015 May 12;6:7086. doi: 10.1038/ncomms8086.