title: CTLA4Ig alters the course of autoimmune disease development in Lyn-/- mice.
abstract: Lyn-deficient (Lyn(-/-)) mice develop an age-dependent autoimmune disease similar to systemic lupus erythematosus, characterized by the production of IgG anti-nuclear Ab. To determine the extent to which this autoimmune phenotype is driven by T cell costimulation, we generated Lyn(-/-) mice expressing a soluble form of the T cell inhibitory molecule, CTLA4 (CTLA4Ig). Surprisingly, although CTLA4Ig prevented myeloid hyperplasia, splenomegaly and IgG anti-nuclear Ab production in Lyn(-/-) mice, it did not inhibit immune complex deposition and tissue destruction in the kidney. In fact, regardless of CTLA4Ig expression, Lyn(-/-) serum contained elevated titers of IgA anti-nuclear Ab, although generally IgA deposition in the kidney was only revealed in the absence of self-reactive IgG. This demonstrated that activation of autoreactive B cell clones in Lyn(-/-) mice can still occur despite impaired costimulation. Indeed, CTLA4Ig did not alter perturbed Lyn(-/-) B cell development and behavior, and plasma cell frequencies were predominantly unaffected. These results suggest that when self-reactive B cell clones are unimpeded in acquiring T cell help, they secrete pathogenic IgG autoantibodies that trigger the fulminant autoimmunity normally observed in Lyn(-/-) mice. The absence of these IgG immune complexes reveals an IgA-mediated axis of autoimmunity that is not sufficient to cause splenomegaly or extramedullary myelopoiesis, but which mediates destructive glomerulonephritis. These findings have implications for the understanding of the basis of Ab-mediated autoimmune diseases and for their treatment with CTLA4Ig.
authors: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors: Sarah A
authors: SA
authors: Oracki
authors: Evelyn
authors: E
authors: Tsantikos
authors: Cathy
authors: C
authors: Quilici
authors: Amanda
authors: A
authors: Light
authors: Thomas
authors: T
authors: Schmidt
authors: Andrew M
authors: AM
authors: Lew
authors: Joanne E
authors: JE
authors: Martin
authors: Ken G
authors: KG
authors: Smith
authors: Margaret L
authors: ML
authors: Hibbs
authors: David M
authors: DM
authors: Tarlinton
mesh_terms: D000069594:Abatacept; D000818:Animals; D000936:Antigen-Antibody Complex / Q000096:biosynthesis; D015703:Antigens, CD / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D002999:Clone Cells / Q000276:immunology; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007674:Kidney Diseases; D008180:Lupus Erythematosus, Systemic; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency*
chemical_list: D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000069594:Abatacept; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases