Systemic lupus erythematosis (SLE) is a relatively common and incurable autoimmune disorder that affects women 10 fold more than men. The etiology is unknown, but the disease is characterized by autoantibodies specific for nuclear antigens, such as dsDNA histones and ribonuclear proteins. Genetic studies support a critical protective role for the innate immune system, as humans deficient in complement components C1q or C4 almost always develop this disease. To dissect the importance of self-antigen and the complement system in negative regulation of self-reactive B cells, mice bearing a targeted deletion in complement proteins C1q, C4 or the receptor C42 will be examined alone, or in combination with immunoglobulin (Ig) transgenes (tg), in three interrelated aims described below.
The first aim will test the hypothesis that self-antigen alters the development of B-lymphocytes. Two sub-aims will explore the questions: (i) What is the relative importance of antigen concentration and affinity on B cell receptor (BCR) editing and apoptosis? (ii) Does receptor editing represent re- initiation of RAG gene expression (induction), or is it a dye product of selection or continued expression of the rearrangement complex? The second aim will test the hypothesis that complement C1q, C4 and CD21/CD35 participate in negative selection of developing B cells. The two sub-aims will address: (i) Does deficiency in C1q, C4 or CD21/CD35 alter negative selection? (i) Is CD21/CD35 expression on stroma or B cells important in negative selection? The third aim will test the hypothesis that complement protects from autoimmunity by enhancing clearance of apoptotic material. The two sub-aims will address the questions: (ii) Does expression of C4 in adult C4-/- mice restore clearance and protect against auto-antibodies? The overall significance of this project is that it directly addresses a fundamental question regarding the role of complement in protection against autoimmune disease. The results should distinguish whether complement protects by enhancing negative selection of self-reactive B-lymphocytes; or if its importance is more in sequestration and clearance of lupus antigens.
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