title: CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice.
abstract: OBJECTIVE
  Autoantibody immune complexes and cellular infiltrates drive nephritis in patients with systemic lupus erythematosus (SLE) and in murine lupus. The chemokine receptor CXCR3 is assumed to promote cellular infiltration of inflamed tissues. Moreover, CXCR3 deficiency ameliorates lupus nephritis in the MRL/MpJ-Fas(lpr)  (MRL/lpr) mouse model of SLE. Hence, CXCR3 blockade has been suggested as a novel therapeutic strategy for the treatment of lupus nephritis. We undertook this study to test the effect of CXCR3 in the (NZB × NZW)F(1)  (NZB/NZW) mouse model of SLE.
  
  
  METHODS
  CXCR3(-/-)  NZB/NZW mice were generated and monitored for survival, proteinuria, and kidney infiltration. Anti-double-stranded DNA (anti-dsDNA) and total IgG1, IgG2a, and IgG2b antibody levels were determined by enzyme-linked immunosorbent assay. T cell and plasma cell infiltrates in the kidneys and interferon-γ production were determined by flow cytometry. Plasma cell infiltrates were measured using enzyme-linked immunospot assay. Kidney tissue was evaluated for pathologic changes.
  
  
  RESULTS
  CXCR3(-/-)  NZB/NZW mice exhibited reduced production of total and anti-dsDNA antibodies of the IgG1 subclass, but had normal titers of IgG2a and IgG2b antibodies compared to CXCR3(+/+)  NZB/NZW mice. Cellular infiltrates and glomerulonephritis were not reduced in CXCR3(-/-)  mice.
  
  
  CONCLUSIONS
  CXCR3 has an effect on (auto)antibody production but is not essential for lupus pathogenesis in NZB/NZW mice, indicating that the effect of CXCR3 on the development of kidney disease varies between MRL/lpr and NZB/NZW mice. These results suggest that CXCR3-dependent and -independent mechanisms can mediate lupus nephritis. Hence, therapeutic CXCR3 blockade could be beneficial for only a subgroup of patients with SLE.
authors: University of Lübeck, Lübeck, Germany.
authors: Katrin
authors: K
authors: Moser
authors: Kathrin
authors: K
authors: Kalies
authors: Martin
authors: M
authors: Szyska
authors: Jens Y
authors: JY
authors: Humrich
authors: Kerstin
authors: K
authors: Amann
authors: Rudolf A
authors: RA
authors: Manz
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008814:Mice, Inbred NZB; D011507:Proteinuria / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D007074:Immunoglobulin G; D054367:Receptors, CXCR3