CD154 overexpression is a hallmark of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The etiology of the overexpression of this critical immune molecule is not understood. Second, the targeting of CD154 by antibody?based approaches is limited by toxicity. These two issues underscore the need for better understanding of the regulation of CD154 biosynthesis. We have established the role of polypyrimidine tract binding (PTS) proteins in mediating CD154 mRNA turnover through binding to a 3'UTR CU?rich element (CURE). These studies uncovered a novel pathway of translational regulation through a polymorphic CA repeat found in the CD154 3'UTR which regulates CD154 mRNA polyadenylation. We refer to this novel cis?acting element, consisting of CA dinucleotide repeats, as the CA?rich element (CARE). Importantly, the CD153'UTR CA repeats are polymorphic with certain alleles associated with CD154 overexpression and the development of RA and SLE.
C0154 constitutes one of the central molecules of the immune response and plays a critical role in autoimmunity. It also appears to be regulated through unique pathways that possibly afford selective targeting and therapeutics. One of these pathways appears to have a direct genetic relationship to the development of Rheumatoid Arthritis. We plan to understand the basic science of these pathways as well as rlp.finp.
