title: Autoantibodies from long-lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis.
abstract: OBJECTIVE
  We have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus.
  
  
  METHODS
  Splenic CD138+ antibody-secreting cells (ASCs) from >6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1(-/-) mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed.
  
  
  RESULTS
  The adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1(-/-) mice. Rag1(-/-) mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer.
  
  
  CONCLUSIONS
  These findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, , Berlin, Germany.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Cheng
authors.forename: Imtiaz M
authors.initials: IM
authors.lastname: Mumtaz
authors.forename: Laleh
authors.initials: L
authors.lastname: Khodadadi
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Bimba F
authors.initials: BF
authors.lastname: Hoyer
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D049109:Cell Proliferation; D004247:DNA / Q000276:immunology; D005260:Female; D018398:Homeodomain Proteins / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007156:Immunologic Memory / Q000276:immunology; D007668:Kidney / Q000276:immunology; D008181:Lupus Nephritis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D018398:Homeodomain Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C064658:RAG-1 protein; D004247:DNA
keywords: Autoantibodies; Autoimmune Diseases; Autoimmunity; B cells; Systemic Lupus Erythematosus