Splice variants in apoptotic pathway

Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis, and deregulation of apoptotic signaling pathways contributes to oncogenesis. 40 years have passed since the term “apoptosis” was introduced by Kerr et al. in 1972; among the programmed cell death, a variety of therapeutic strategies especially targeting apoptotic pathways have been investigated. Alternative precursor messenger RNA splicing, by which the process the exons of pre-mRNA are spliced in different arrangements to produce structurally and functionally distinct mRNA and proteins, is another field in progress, and it has been recognized as one of the most important mechanisms that maintains genomic and functional diversity. A variety of apoptotic genes are regulated through alternative pre-mRNA splicing as well, some of which have important functions as pro-apoptotic and anti-apoptotic factors. In this article we summarized splice variants of some of the apoptotic genes including BCL2L1, BIRC5, CFLAR, and MADD, as well as the regulatory mechanisms of alternative splicing of these genes. If the information of the apoptosis and aberrant splicing in each of malignancies is integrated, it will become possible to target proper variants for apoptosis, and the trans-elements themselves can become specific targets of cancer therapy as well. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Regulated T cell pre-mRNA splicing as genetic marker of T cell suppression

Includes abstract. Includes bibliographical references

Exploring the germinal centre and peripheral roles of CD21

Secondary lymphoid organs (SLOs), including lymph nodes, tonsils and Peyer’s patches, contain highly organised microenvironments in which adaptive and innate immune cells interact with stromal fibroblasts. It is within these organs that germinal centres (GCs) form; structures that function to permit the development of high affinity antigen-specific humoral immune responses. Follicular dendritic cells (FDCs) and B cells are the cells primarily responsible for driving formation and function of the GC. B cells scan FDC stromal cell networks for antigen complement complexes bound to the CD21 receptor through the complement component C3dg. CD21 is expressed on both cell types, permitting transfer of antigen complexes from B cells to FDCs where it is retained and presented permitting antigen-specific B cell activation and initiating a cyclical cycle of selection and expansion leading to high affinity antibody selection. Human FDCs are reported to express a long isoform of the CD21 receptor (CD21L), whereas B cells express a short isoform (CD21S). In this thesis I utilised a flow cytometry-based assay to investigate the different potential mechanism of CD21 isoform function in B cells and FDCs; revealing that FDC express a significantly higher number of CD21 molecules on their cell surface and provide evidence that this may be a mechanism of antigen transfer between the two cells types. CD21 and the complement pathway, including C3 and its derivatives, have been implicated in autoimmune diseases, including Rheumatoid Arthritis (RA). Soluble CD21 (sCD21) concentration is consistently decreased within the serum of RA patients compared with age-matched healthy control samples. Here I show that lower sCD21 concentrations correlate with increased disease phenotype. Additionally, I show that sCD21 can block C3dg complex binding to peripheral B cells and consequently prevent co-activation through the CD19/CD21 complex on the surface of B cells. Together these results suggest a role for sCD21 in suppressing human immune responses