title: PKK deficiency in B cells prevents lupus development in Sle lupus mice.
abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B-lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: D
authors.initials: D
authors.lastname: Oleksyn
authors.affiliation: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: A
authors.initials: A
authors.lastname: Vosoughi
authors.affiliation: Department of Biology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: J C
authors.initials: JC
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: R
authors.initials: R
authors.lastname: Misra
authors.affiliation: Department of Dermatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: A P
authors.initials: AP
authors.lastname: Pentland
authors.affiliation: Department of Pathology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: D
authors.initials: D
authors.lastname: Ryan
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: J
authors.initials: J
authors.lastname: Anolik
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: C
authors.initials: C
authors.lastname: Ritchlin
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: J
authors.initials: J
authors.lastname: Looney
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: A P
authors.initials: AP
authors.lastname: Anandarajah
authors.affiliation: Department of Pediatrics, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: G
authors.initials: G
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: L M
authors.initials: LM
authors.lastname: Calvi
authors.affiliation: Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: M
authors.initials: M
authors.lastname: Georger
authors.affiliation: Department Biomedical Engineering, University of Houston, Houston, TX 77204, United States.
authors.forename: C
authors.initials: C
authors.lastname: Mohan
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States.
authors.forename: I
authors.initials: I
authors.lastname: Sanz
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States; Department of Dermatology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States. Electronic address: luojing_chen@urmc.rochester.edu.
authors.forename: L
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C430884:Ripk4 protein, mouse
keywords: BCR; Lupus; Mouse model; PKK