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

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

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.

Technical Summary

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.
 
Description role of TACI in CVID
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description EC FP7 funding
Amount £84,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start  
 
Title DNA from patients with CVID 
Description DNA collected from patients with CVID 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2007 
Provided To Others? Yes  
Impact PUBLICATION 18981294 
 
Title Murine model of TACI defect 
Description We created a knock-in mouse model whereby the most common human TACI variant has been replicated in a murine strain. Rather than study a complete TACI knockout, this now allows us to study the effect of a specific mutation 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact to be published in 2010 
 
Description Collaboration with European groups as part of a EU consortium on antibody deficiency 
Organisation European Commission
Country European Union (EU) 
Sector Public 
PI Contribution Analysis of immunodeficient mouse models of antibody deficiency namely the murine TACI deficient model
Collaborator Contribution Collobaration and exchange of information with other groups in Europe working on Antibody deficiency
Impact 1) Awarding of FP7 grant 2) research work ongoing at present
Start Year 2008
 
Description Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Lecturing at a patient awareness day

n/a
Year(s) Of Engagement Activity 2009
 
Description Royal Society Christmas lecture 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Invitation to Royal Society Lecture to talk about gene therapy
Year(s) Of Engagement Activity 2018