title: Autophagy is activated in systemic lupus erythematosus and required for plasmablast development.
abstract: BACKGROUND
  Autophagy has emerged as a critical homeostatic mechanism in T lymphocytes, influencing proliferation and differentiation. Autophagy in B cells has been less studied, but genetic deficiency causes impairment of early and late developmental stages
  
  
  OBJECTIVE
  To explore the role of autophagy in the pathogenesis of human and murine lupus, a disease in which B cells are critical effectors of pathology.
  
  
  METHODS
  Autophagy was assessed using multiple techniques in NZB/W and control mice, and in patients with systemic lupus erythematosus (SLE) compared to healthy controls. We evaluated the phenotype of the B cell compartment in Vav-Atg7(-/-) mice in vivo, and examined human and murine plasmablast formation following inhibition of autophagy.
  
  
  RESULTS
  We found activation of autophagy in early developmental and transitional stages of B cell development in a lupus mouse model even before disease onset, and which progressively increased with age. In human disease, again autophagy was activated compared with healthy controls, principally in naïve B cells. B cells isolated from Vav-Atg7(F/F) mice failed to effectively differentiate into plasma cells following stimulation in vitro. Similarly, human B cells stimulated in the presence of autophagy inhibition did not differentiate into plasmablasts.
  
  
  CONCLUSIONS
  Our data suggest activation of autophagy is a mechanism for survival of autoreactive B cells, and also demonstrate that it is required for plasmablast differentiation, processes that induce significant cellular stress. The implication of autophagy in two major pathogenic pathways in SLE suggests the potential to use inhibition of autophagy as a novel treatment target in this frequently severe autoimmune disease.
authors.affiliation: Medical and Molecular Genetics and Division of Immunology, Infection, and Inflammatory Disease, King's College London, London, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Clarke
authors.affiliation: Medical and Molecular Genetics and Division of Immunology, Infection, and Inflammatory Disease, King's College London, London, UK.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ellinghaus
authors.affiliation: Medical and Molecular Genetics and Division of Immunology, Infection, and Inflammatory Disease, King's College London, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cortini
authors.affiliation: Nuffield Department of Clinical Medicine and Translational Immunology Laboratory, NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Stranks
authors.affiliation: Nuffield Department of Clinical Medicine and Translational Immunology Laboratory, NIHR BRC, University of Oxford, Oxford, UK.
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.affiliation: Department of Medicine, Centre for Complement and Inflammation Research, Imperial College London, London, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.affiliation: Medical and Molecular Genetics and Division of Immunology, Infection, and Inflammatory Disease, King's College London, London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D010950:Plasma Cells / Q000276:immunology*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*
keywords: Autoimmunity; B cells; Systemic Lupus Erythematosus