title: Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis.
abstract: OBJECTIVE
  Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA.
  
  
  METHODS
  The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions.
  
  
  RESULTS
  MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1β, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells.
  
  
  CONCLUSIONS
  Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Institute of Immunology, First Bethune Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Lianjie
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Yingni
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018920:Coculture Techniques; D018450:Disease Progression; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D010003:Osteoarthritis / Q000276:immunology; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology