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.
CD154 (CD40 ligand) is a protein on the surface of T cells that is a potent mediator of the immune response. This protein plays a key role in autoimmune disease, graft rejection and tumor immunity. Unfortunately, while blocking the activity of this protein with an antibody was effective, this treatment caused adverse events that will probably limit its clinical application for the foreseeable future. We have discovered two pathways that regulate the expression of CD154 in T cells. One of these is highly novel and has profound biological significance. These findings potentially account for the overexpression of CD154 seen in diseases like SLE and RA. Understanding these pathways of CD154 overexpression may be crucial in developing therapies that alter the basic mechanisms of autoimmune diseases such as SLE and RA.
|Jones, Jonathan D; Hamilton, B JoNell; Rigby, William F C (2012) Rituximab mediates loss of CD19 on B cells in the absence of cell death. Arthritis Rheum 64:3111-8|
|Rigby, William F C; Wu, Yee Ling; Zan, Moe et al. (2012) Increased frequency of complement C4B deficiency in rheumatoid arthritis. Arthritis Rheum 64:1338-44|
|Nichols, Ralph C; Botson, John; Wang, Xiao Wei et al. (2011) A flexible approach to studying post-transcriptional gene regulation in stably transfected mammalian cells. Mol Biotechnol 48:210-7|
|Hamilton, B JoNell; Wang, Xiao-Wei; Collins, Jane et al. (2008) Separate cis-trans pathways post-transcriptionally regulate murine CD154 (CD40 ligand) expression: a novel function for CA repeats in the 3'-untranslated region. J Biol Chem 283:25606-16|
|Rigby, William F C; Roy, Kristen; Collins, Jane et al. (2005) Structure/function analysis of tristetraprolin (TTP): p38 stress-activated protein kinase and lipopolysaccharide stimulation do not alter TTP function. J Immunol 174:7883-93|