DIFFERENTIAL REQUIREMENTS FOR CD28 AND CD40 LIGAND IN THE INDUCTION OF EXPERIMENTAL AUTOIMMUNE MYASTHENIA-GRAVIS

The interactions of CD28-B7 and CD40-CD40 ligand (CD40L) pathways in T cell costimulation and autoimmune disease are incompletely understood . We sought to address this issue by investigation of the genesis of a cetylcholine receptor (AChR)-induced antibody-mediated experimental au toimmune myasthenia gravis (EAMG) in CD28- and CD40L-deficient mice (C D28(-/-), CD40L(-/-)). Compared to wild-type mice, the CD28(-/-) mice became less susceptible, and CD40L(-/-) mice were completely resistant to EAMG induction. Analysis of T helper functions, reflected by cytok ine responses, revealed a switch to a Th1 profile in CD28(-/-) mice. C onsistently, levels of serum AChR-specific antibodies of the IgG1 isot ype were decreased in CD28(-/-) mice. In the CD40L(-/-) mice, both Th1 and Th2 cytokine responses were diminished, and T cell-dependent AChR -reactive B cell responses were more severely impaired than in the CD2 8(-/-) mice. Thus, CD28 and CD40L are differentially required for indu ction of EAMG.