Systemic Lupus Erythematosus is an incurable disease. Complement C4 deficiency predisposes both to SLE and to impaired humeral responses. We propose to restore C4 protein in C4-deficient mice with an ongoing anti-chromatin response to test the hypothesis that C4 reconstitution can ameliorate active autoimmunity. Specifically, several approaches will be tested to study the potential of C4 reconstitution to induce tolerance to nuclear antigens in adult mice with developed lupus: 1) bone marrow transfer to reconstitute myeloid-derived C4; 2) in vivo transfection of murine hepatocytes with C4 expression plasmid DNA; 3) conditional Cre/IoxP gene repair of C4 locus. The proposed experiments will directly address the role of complement C4 in functional silencing of autoreactive B cells specific to chromatin in the context of an ongoing autoimmune response. The proposed studies could provide a proof of the concept that systemic autoimmune responses directed against chromatin and possibly other nuclear antigens can be tuned down by specific repair of molecules and mechanisms that normally maintain immune tolerance to those antigens.
