title: Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus.
abstract: IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the class-switched IgG autoantibody response in MRL/Faslpr/lprand C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent Ab responses, but it did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Tonika
authors.identifier: 0000-0002-6270-7234
authors.initials: T
authors.lastname: Lam
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Dennis V
authors.identifier: 0000-0002-9048-7048
authors.initials: DV
authors.lastname: Kulp
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lou
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Julia
authors.identifier: 0000-0002-7549-0812
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Rivera
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
authors.forename: Zhonghua
authors.identifier: 0000-0001-6906-107X
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.affiliation: Department of Biochemistry, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
authors.forename: Dmitri N
authors.initials: DN
authors.lastname: Ivanov
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and.
authors.forename: Guangming
authors.identifier: 0000-0001-7053-5009
authors.initials: G
authors.lastname: Zhong
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and pcasali@uthscsa.edu xuz3@uthscsa.edu.
authors.forename: Paolo
authors.identifier: 0000-0002-8982-5177
authors.initials: P
authors.lastname: Casali
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and pcasali@uthscsa.edu xuz3@uthscsa.edu.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002690:Chlamydia Infections / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D017578:Immunoglobulin Class Switching / Q000187:drug effects*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000090802:rab7 GTP-Binding Proteins
chemical_list: D001323:Autoantibodies; C000607523:CID1067700; D006574:Heterocyclic Compounds, 2-Ring; D007074:Immunoglobulin G; D016328:NF-kappa B; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins; D013890:Thiourea