title: B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease.
abstract: Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2K(b) was administered intrabronchially into Batf (-/-) and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf (-/-) mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction. There was lack of Abs to SAgs, reduction of Sag-specific interleukin (IL)-17 T cells, IL-6, IL-23, IL-17, IL-1β, fibroblast growth factor-6, and CXCL12 and decreased Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and retinoid-related orphan receptor γT. Further, micro-RNA (miR)-301a, a regulator of Th17, was reduced in Batf (-/-) mice in contrast to upregulation of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) in anti-MHC-induced OAD animals. We also demonstrate an increase in miR-301a in the bronchoalveolar lavage cells from lung transplant recipients with Abs to human leukocyte antigen. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti-MHC-induced rejection. Targeting BATF should be considered for preventing chronic rejection after human lung transplantation.
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors: Z
authors: Z
authors: Xu
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors: S
authors: S
authors: Ramachandran
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors: M
authors: M
authors: Gunasekaran
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors: D
authors: D
authors: Nayak
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors: N
authors: N
authors: Benshoff
authors: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors: R
authors: R
authors: Hachem
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors: A
authors: A
authors: Gelman
authors: Department of Surgery, Washington University School of Medicine, St. Louis, MO.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors: T
authors: T
authors: Mohanakumar
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016040:Lung Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D015395:Histocompatibility Antigens Class I; D020381:Interleukin-17; C573832:MIRN301 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: autoimmunity, lung failure/injury, alloantibody; basic (laboratory) research/science, translational research/science; lung transplantation/pulmonology, immunobiology, molecular biology