title: CD74 Deficiency Mitigates Systemic Lupus Erythematosus-like Autoimmunity and Pathological Findings in Mice.
abstract: CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6Faslprmice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN-γ or IL-6 induced CD74 expression in kidney TECs in vitro. The presence of kidney TECs fromFaslprmice, rather than from wild-type mice, produced significantly stronger histones, dsDNA, and ribonucleoprotein-Smith Ag complex-induced CD4+T cell activation. Splenocytes from CD74-deficientFaslprCd74-/-mice had muted responses in a MLR and to the autoantigen histones. Compared withFaslprCd74+/+mice,FaslprCd74-/-mice had reduced kidney and spleen sizes, splenic activated T cells and B cells, serum IgG and autoantibodies, urine albumin/creatinine ratio, kidney Periodic acid-Schiff score, IgG and C3 deposition, and serum IL-6 and IL-17A levels, but serum IL-2 and TGF-β levels were increased. Study of chronic graft-versus-host C57BL/6 mice that received donor splenocytes from B6.C-H2bm12/KhEg mice and those that received syngeneic donor splenocytes yielded similar observations. CD74 deficiency reduced lupus-like autoimmunity and kidney pathology in chronic graft-versus-host mice. This investigation establishes the direct participation of CD74 in autoimmunity and highlights a potential role for CD74 in kidney TECs, together with professional APCs in systemic lupus erythematosus.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Yi
authors.identifier: 0000-0002-3425-2404
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.|Research Institute of Nephrology, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Huimei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Biology, School of Life Science, Huzhou Teachers College, Huzhou, Zhejiang 313000, China.
authors.forename: Li
authors.identifier: 0000-0002-7649-8904
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; gshi@rics.bwh.harvard.edu yuxq@mail.sysu.edu.cn.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: Department of Rheumatology, Nan Fang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and.
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and.
authors.forename: George C
authors.identifier: 0000-0001-9589-2360
authors.initials: GC
authors.lastname: Tsokos
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Isaac E
authors.identifier: 0000-0002-4224-5060
authors.initials: IE
authors.lastname: Stillman
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Takaharu
authors.identifier: 0000-0002-3106-5224
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Peter
authors.identifier: 0000-0002-1502-502X
authors.initials: P
authors.lastname: Libby
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; gshi@rics.bwh.harvard.edu yuxq@mail.sysu.edu.cn.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000276:immunology; D008181:Lupus Nephritis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C045084:invariant chain