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.

Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease

“…This is highlighted in Lyn À/À IL-6 À/À mice, who show a reduced inflammatory environment, a normal T cell compartment and a failure to produce pathogenic IgG or IgA autoantibodies without affecting B cell autoreactivity per se [16,56]. Interestingly, when T celleB cell interactions are inhibited in Lyn À/À mice with a soluble form of the T cell inhibitory molecule CTLA4, IgG ANA production is repressed, but the mice instead develop an IgA-mediated glomerulonephritis [56]. However, Lyn À/À p110d þ/KD mice show no tendency toward IgA overproduction, rather, IgA levels were decreased in comparison to Lyn-deficient mice.…”

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

“…We hypothesize that the role of IgA deposition in kidney pathology in the original BAFF-Tg colony may have been mixed with or obscured by more conventional IgG-driven autoimmunity. Such interplay was recently described in the autoimmune-prone Lyn -/-mice, in which IgA glomerular deposition was observed only in the absence of IgG antinuclear antibodies (44).…”

Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus

“…Antinuclear antibodies (ANAs) were measured as described 35. For identification of antibody specificities, the FIDIS Connective Profile MX 117 kit (Theradiag) was used as per manufacturer's instructions, except using a PE-conjugated antimouse IgG F(ab′)2 antibody (eBioscience).…”