The role of TACI in the molecular pathogenesis of Common Variable immunodeficiency

Common variable immunodeficiency (CVID) is a condition which affects the immune system and results in an inability to fight infection, problems with autoimmunity and in some cases development of lymphoma. The gene defect in CVID has only recently been identified. The gene, TACI, is abnormal in CVID but we do not as yet understand why TACI defects leads to the development of the disease. We will first check over 400 CVID patients for abnormalities in TACI so that we can understand how frequent these abnormalities are. Next we plan to look at how abnormal TACI protein works and functions when placed in combination with normal TACI proteins. We also plan to create a mouse model where the TACI gene has been made defective in a way similar to the human condition. This will provide us with a living system where we can examine the effects of TACI defects on the immune system. A greater understanding of these TACI defects will allow us to develop ways of treating CVID in the future.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterised by abnormalities of humoral immunity. The molecular basis of CVID is only now being unravelled and arises from mutations in a number of different genes controlling B cell function and homeostasis. Homozygous and heterozygous mutations in the TNF superfamily receptor TACI (transmembrane calcium modulator and cyclophilin ligand) result in approximately 10% of all cases of CVID although the exact frequency of mutations and the molecular mechanisms by which mutations cause disease are unknown. We have already identified novel missense mutations in a cohort of patients and have developed techniques for high throughput analysis of patient samples. In this study we plan to: 1) study a further 200 patients for TACI mutations usng a combination of screening by heteroduplex analysis and direct screening 2) analyse the consequenses of mutant TACI forms by expression in heterologous cell lines and study the binding to putative ligands and downstream signalling changes 3) generate and study mutant murine models which contain heterozygous mutations in TACI and thereby more closely mimic human defects than previous null mutant strains.