title: Long-term B cell depletion in murine lupus eliminates autoantibody-secreting cells and is associated with alterations in the kidney plasma cell niche.
abstract: Autoantibodies to dsDNA, produced by autoreactive plasma cells (PCs), are a hallmark of systemic lupus erythematosus and play a key role in disease pathogenesis. Recent data suggest that autoreactive PCs accumulate not only in lymphoid tissues, but also in the inflamed kidney in lupus nephritis. We hypothesized that the variable efficacy of anti-CD20 (rituximab)-mediated B cell depletion in systemic lupus erythematosus may be related to the absence of an effect on autoreactive PCs in the kidney. In this article, we report that an enrichment of autoreactive dsDNA Ab-secreting cells (ASCs) in the kidney of lupus-prone mice (up to 40% of the ASCs) coincided with a progressive increase in splenic germinal centers and PCs, and an increase in renal expression for PC survival factors (BAFF, a proliferation-inducing ligand, and IL-6) and PC attracting chemokines (CXCL12). Short-term treatment with anti-CD20 (4 wk) neither decreased anti-dsDNA nor IgG ASCs in different anatomical locations. However, long-term treatment (12 wk) significantly reduced both IgG- and dsDNA-specific ASCs. In addition, long-term treatment substantially decreased splenic germinal center and PC generation, and unexpectedly reduced the expression for PC survival factors in the kidney. These results suggest that prolonged B cell depletion may alter the PC survival niche in the kidney, regulating the accumulation and maintenance of autoreactive PCs.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wang
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: Teresa
authors.initials: T
authors.lastname: Owen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barnard
authors.forename: Sarah
authors.initials: S
authors.lastname: Nevarez
authors.forename: H Travis
authors.initials: HT
authors.lastname: Ichikawa
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000974:Antibodies, Antinuclear; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D054377:Chemokine CXCL12; D015850:Interleukin-6; C505720:Tnfsf13b protein, mouse; D000069283:Rituximab