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.