title: IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression.
abstract: Systemic lupus erythematosus is a complex autoimmune disease characterized by dysregulated interactions between autoreactive T and B lymphocytes and the development of anti-nuclear Abs. The recently described pleiotropic cytokine IL-21 has been shown to regulate B cell differentiation and function. IL-21 is produced by activated T lymphocytes and its interactions with IL-21R are required for isotype switching and differentiation of B cells into Ab-secreting cells. In this report, we studied the impact of blocking IL-21 on disease in the lupus-prone MRL-Fas(lpr) mouse model. Mice treated for 10 wk with IL-21R.Fc fusion protein had reduced proteinuria, fewer IgG glomerular deposits, no glomerular basement membrane thickening, reduced levels of circulating dsDNA autoantibodies and total sera IgG1 and IgG2a, and reduced skin lesions and lymphadenopathy, compared with control mice. Also, treatment with IL-21R.Fc resulted in a reduced number of splenic T lymphocytes and altered splenic B lymphocyte ex vivo function. Our data show for the first time that IL-21 has a pathogenic role in the MRL-Fas(lpr) lupus model by impacting B cell function and regulating the production of pathogenic autoantibodies. From a clinical standpoint, these results suggest that blocking IL-21 in systemic lupus erythematosus patients may represent a promising novel therapeutic approach.
authors.affiliation: Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. dherber@wyeth.com
authors.forename: Deborah
authors.initials: D
authors.lastname: Herber
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Brown
authors.forename: Spencer
authors.initials: S
authors.lastname: Liang
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Young
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Kyri
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000276:immunology / Q000473:pathology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D000974:Antibodies, Antinuclear; C508118:Il21r protein, mouse; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D011993:Recombinant Fusion Proteins; D000098546:Interleukin-21