Begriffe, Krankheiten, Einrichtungen u.v.m., verknüpft mit dem zuständigen Bereich.
Im Menüpunkt "Übersicht" sind Einrichtungen unter verschiedenen Gesichtspunkten gruppiert: Kliniken, Abteilungen, Institute, Zentrale Einrichtungen und ähnliches.
TACI deficiency
Summary
Within the past few years BAFF, APRIL and their receptors BAFFR, TACI and BCMA where shown to be crucially involved in the regulation of B cell survival and differentiation. Both BAFF and APRIL were shown to be potent inducers of T cell independent class switch recombination in human B cells which is mediated through TACI and in part also BAFF-R. The recent identification of molecular genetic defects in the receptor TACI in patients with CVID suggest a pathogenetic mechanism by which impaired T cell independent CSR ultimately leads to antibody deficiency in the affected patients because they have mutated non-functional TACI receptors. However this assumption does not suffice to explain why some TACI deficient individuals are nearly agammaglobulinemic at time of diagnosis and why T cell dependent responses are also impaired. It is also not clear, why most of TACI deficient humans are depleted of terminally differentiated B cells (memory cells and plasma cells), because there is no evident functional role for TACI in the development of these cells in the murine model. Thus a pathogenetic effect of the mutated TACI protein itself is proposed, that goes beyond the loss of its biological function. Further, the most common mutations in the TACI gene are simple heterozygous changes including the C104R mutation. These changes have also been observed at low frequency in normal individuals hence questioning their role in disease pathogenesis. TACI is a surface receptor which trimerises to form a receptor complex and thus the functional consequences of a mutation in one allele are not clear. Generation of appropriate in vitro cellular models will enable further understanding of TACI ligand binding and downstream signalling consequences.
Cooperation Partners
- Bodo Grimbacher, Dept. of Clinical Immunology, Royal Free Hospital and University College London, UK.
- Lennart Hammarström and Quiang Pan-Hammarström, Division of Clinical Immunology, Karolinska University Hospital, Sweden
- Pascal Schneider, Department of Biochemistry, University of Lausanne, Switzerland
Funding
7. FP, EUROPADnet, Workpackage 3.1, European Union (HEALTH-F2–2008–201549)
Publications
Mohammadi J, C Liu, Aghamohammadi A, Bergbreiter A, Du L, Lu J, Rezaei N, Amirzargar AA, Moin M, Salzer U, Pan-Hammarström Q, Hammarström L. Novel Mutations in TACI (TNFRSF13B) Causing Common 5 Variable Immunodeficiency J Clin Immunol, DOI 10.1007/s10875-009-9317-5.
Salzer U*, Bacchelli C*, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, Hagena T, Birmelin J, Plebani A, Webster ADB, Peter HH, Suez D, Chapel H, Maclean-Tooke A, Spickett GP, Anover-Sombke S, Ochs HD, Urschel S, Belohradsky BH, Kumararatne DS, Lawrence TC, Holm AM, Franco JL, Schulze I, Schneider P, Hammarström L, Thrasher AJ, Gaspar HB, Grimbacher B Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease causing from disease modifying TNFRSF13B variants in common variable immunodeficiency. Blood 2009 113:1967-1976.
Zhang L, Radigan L, Salzer U, Behrens TW, Grimbacher B, Diaz G, Bussel J, Cunningham-Rundles C. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol. 2007, 120:1178-1185.
Salzer U, Birmelin J, Bacchelli C, Witte T, Buchegger-Podbielski U, Buckridge S, Rzepka R, Gaspar HB, Thrasher AJ, Schmidt RE, Melchers I, Grimbacher B. Sequence Analysis of TNFRSF13b, Encoding TACI, in Patients with Systemic Lupus Erythematosus. J Clin Immunol. 2007, 27:372-377.
Pan-Hammarström Q*, Salzer U*, Du L, Björkander J, Cunningham-Rundles C, Nelson DL, Bacchelli C, Gaspar HB, Offer S, Behrens TW, Grimbacher B and Hammarström L Reexamining the role of TACI coding variants in common variable immunodefiency and selective IgA deficiency Nat Genet. 2007, 39:429-430.
Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A,Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005, 37:820-828.
