The thymus and rheumatology: should we care?

Purpose of review: The purpose of this review is to discuss the mechanisms of central and peripheral tolerance in relation to T-cell mediated autoimmunity in rheumatoid arthritis (RA). Recent findings: The well established association between major histocompatibility complex class II and RA has led us to understand that T cells, and the adaptive immune response, are important in the pathogenesis of disease. In order for autoimmune disease to develop, there is a breach of tolerance to self antigen and the mechanisms of both central and peripheral tolerance aim to prevent this. Here, we review evidence from mouse models indicating that alterations in T-cell receptor signalling thresholds during thymic selection may be linked to the escape of T cells that mediate autoimmune arthritis. In addition, we summarize the role of dendritic cells and Foxp3+ regulatory T cells in both peripheral and thymic tolerance, and highlight their relevance to what we know about the aetiology of RA. Summary: Mechanisms of central tolerance in the thymus and peripheral tolerance are in place to control autoreactive T cells and to prevent the development of autoimmune disease. We anticipate that a better understanding of these mechanisms will lead to the development of better, antigen-specific therapeutics to restore tolerance

Analysis of the canonical initiation and trans-acting factor requirements of 5'TOP containing mRNAs

All eukaryotic mRNAs process a cap structure (m7G(5')ppp(5')N) at the S' end of their message and most have an A as the first nucleotide after the cap. However, 30% of messages within eukaryotic cells have a C (m7G(t')ppp(5')C) as the first nucleotide followed by a short polypyrimidine tract. These mRNAs are termed TOP (Tenninal Oligopyrimidine tract) messages and are co-ordinately regulated by mitogenic, growth and nutritional stimuli. This work describes the construction of a reporter vector that encodes mRNA containing the TOP motif, and its use in a series of systematic experiments to further investigate the translational regulation of TOP messages. Given that TOP containing mRNAs are known to encode proteins involved in the translational machinery, these findings have important implications with regard to translational control and translation related disease. In this study, reporter vectors have been used to investigate the role of the mTOR and PI3K signalling pathways, which have previously been implicated in the translational regulation of TOP containing mRNAs. The data obtained suggests that the mTOR signalling pathway may be involved in the regulation of TOP containing mRNAs. The canonical initiation and frans-acting factor requirements of TOP mRNAs were also investigated using a combination of protein over-expression and affinity purification of TOP-containing-mRNA:protein complexes. The data obtained raises the possibility that eIF4E may not be required in the initiation of TOP containing mRNA translation. The candidate trans-acting factors that were identified include La, ILF2 and EBPl, the latter of which has previously been shown to associate with mature ribosomes in the cytoplasm. Finally, affinity purification of TOP-containing-mRNA:microRNA complexes was carried out. Candidate microRNAs which may be involved in the regulation of TOP containing mRNAs were identified. The data obtained was consistent with a previous study, which suggested that microRNA-IOa may bind to the S'UTR of TOP containing mRNA