Complete deficiencies of C4A and C4B are among the strongest genetic risk factors associated with SLE or lupus-like diseases, across all HLA haplo-types and racial backgrounds. However, the age of disease onset and the disease severity vary substantially among the C4-deficient subjects, which underscores the importance of other genetic and environmental factors contributing to disease pathogenesis and progression. In contrast to the rarity of complete C4A and C4B deficiencies, partial and homozygous deficiencies of C4A are present in 32-55% of SLE patients from all races studied except Spanish, Mexican, and Australian Aborigines who had increased frequencies of C4B deficiency instead of C4A deficiency. This phenomenon underscores the relevance of C4A and C4B proteins in the fine control of autoimmunity. Different racial genetic backgrounds could change the thresholds and the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. An important unanswered issue is the identification of a specific receptor or a chaperone that would link C4A and/or C4B proteins to the regulation of systemic autoimmunity.
In many lupus patients serum or plasma C4 levels fluctuate widely. Sometimes such fluctuations correlate with disease activity, especially in lupus nephritis. Consumption of C4 and activation of the complement pathways are involved in complement-mediated tissue injuries during the disease flares. Therefore, while a deficiency of C4A or C4B appears to be a genetic susceptibility factor for SLE (Atkinson and Schneider, 1999; Tsao, 2003; Yang et al, 2003), in about half of the lupus patients who have no apparent complement C4A or C4B deficiency, higher basal levels of C4A and/or C4B could instead increase their disease severity and vital organ involvement.
Another important aspect that has not been accurately addressed is the polygenic and gene size variations of C4A and C4B in the disease susceptibility and disease progression of SLE. A systematic analysis of C4A and C4B gene dosage and gene size, protein polymorphism and functional diversity, different basal plasma protein levels in various ethnic groups, and possible sex differences in extrahepatic tissue expression such as those in subcutaneous adipose tissue would refine our knowledge of the roles of C4A and C4B in the disease process.
After the establishment of the role(s) of heterozygous and/or homozygous deficiency of either C4A or C4B in SLE, a great challenge lies in how to use this information to help patients by developing more effective treatments or even a potential cure. In reality, the gap between knowledge and treatment is still great, and sustained multidisciplinary efforts will be needed to reach these ultimate goals. Perhaps innovative strategies for therapeutic interventions could include manipulation C4A and/or C4B protein expression in patients. Examples might include direct delivery of nonimmunogenic C4A or C4B proteins, creation of autologous or chimeric hepatocytes or adipocytes with high expression capability of C4A or C4B proteins, and prolongation of half-life of activated C4 proteins by site-directed mutagenesis of C4 or by manipulating specific complement regulatory proteins through soluble competitors (Weisman et al., 1990; Morgan and Harris, 1999), inhibitory RNA or specific antibodies. Characterization of the immunologic and physiologic functions of C4A and C4B polymorphic variants will be fundamental to provide insights for development of therapeutic strategies. This research would be facilitated by the development of nonhuman primate and transgenic mouse models to validate research hypothesis and to allow pharmaco-logic testing of new therapies.
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