title: IL-21 promotes the production of anti-DNA IgG but is dispensable for kidney damage in lyn-/- mice.
abstract: The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn-deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B-cell and myeloid cell activation. This results in B-cell hyper-responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL-21 is associated with autoimmunity in mice and humans and promotes B-cell differentiation and class switching. Here, we explore the role of IL-21 in the autoimmune phenotypes of lyn(-/-)  mice. We find that IL-21 mRNA is reduced in the spleens of lyn(-/-) IL-6(-/-)  and lyn(-/-) Btk(lo)  mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL-21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn(-/-)  mice, it is required for anti-DNA IgG antibodies and some aspects of T-cell activation. Surprisingly, GN still develops in lyn(-/-) IL-21(-/-)  mice. This likely results from the presence of IgG autoantibodies against a limited set of non-DNA Ags. These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn(-/-)  mice.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.
authors.forename: Toni
authors.initials: T
authors.lastname: Gutierrez
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mayeux
authors.forename: Sterling B
authors.initials: SB
authors.lastname: Ortega
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000276:immunology*; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007074:Immunoglobulin G; D015850:Interleukin-6; D007378:Interleukins; D004247:DNA; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000098546:Interleukin-21