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Characterization of novel genetic defects in patients with antibody deficiency

Summary

Primary human antibody deficiencies such as CVID may result from mutations and epigenetic changes that interfere with normal development and activation of B cells. We recently found that homozygous mutations in the BAFF-R gene correlate with CVID and prevent the formation of a normal B cell compartment. In addition, we and others were recently able to demonstrate that mutations in TACI and CD19 resulted in a CVID like phenotype. Although the B cell compartment was less severely affected in these patients, they also represent genuine B cell defects, which ultimately lead to disturbance of terminal B cell differentiation. However, For most of the other CVID patients the primary cause of the immunodeficiency remains unknown. We propose to screen for undiscovered B cell defects by phenotypic analysis of B cells and functional assays that allow the in vitro development of antibody secreting cells, plasmablasts and memory-like B cells. The combined evaluation of these results will enable us to set up a plausible list of candidate genes for each observed defect. The molecular nature of the effects will then be further studied by direct genetic analysis and expression analyses.

Cooperation Partners

• Hermann Eibel, Klinische Forschergruppe für Rheumatologie, Universitätsklinikum Freiburg.
• Klaus Warnatz, Abteilung für Rheumatologie und klinische Immunologie, CCI Universitätsklinikum Freiburg

Funding

BMBF, CCI Tandemprojekt 1 "Primary human antibody deficiencies caused by B cell defects"

Publications

Warnatz K*, Salzer U*, Rizzi M, Fischer B, Gutenberger S, Böhm J, Pan-Hammarström Q, Hammarström L, Rakhmanov M, Schlesier M, Grimbacher B, Peter HH, Eibel H. BAFF-R deficiency is associated with an adult onset antibody deficiency syndrome in humans. Proc Natl Acad Sci U S A., in press.

SLitzman J, Freiberger T, Grimbacher B, Gathmann B, Salzer U, Pavlík T, Vlček J, Postránecká V, Travnickova Z, Thon V. Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency. Clin Exp Immunol 2008, 153:324-330.

Salzer U, Hagena T, Webster ADB and Grimbacher B. Sequence analysis of XIAP in male patients with common variable immunodeficiency. Int Arch Allergy Immunol 2008, 147:147-151.

Salzer U, Neumann C, Thiel J, Woellner C, Pan-Hammarstrom Q, Lougaris V, Hagena T, Jung J, Birmelin J, Du L, Metin A, Webster ADB, Plebani A, Moschese V, Hammarstrom L, Schaffer AA, Grimbacher B. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunology 2008, 9:3.

Losi CG, Salzer U, Gatta R, Lougaris V, Cattaneo G, Meini A, Soresina A, Grimbacher B, Plebani A. Mutational Analysis of Human BLyS in Patients with Common Variable Immunodeficiency. J Clin Immunol. 2006, 26:396-399.

Roscioli T, Cliffe ST, Bloch DB, Bell CG, Mullan G, Taylor PJ, Sarris M, Wang J, Donald JA, Kirk EP, Ziegler JB, Salzer U, McDonald GB, Wong M, Robert Lindeman R, Buckley MF. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nat Genet. 2006, 38:620-622.

Warnatz K, Bossaller L*, Salzer U*, Skrabl-Baumgartner A, Schwinger W, van der Burg M, van Dongen JJ, Orlowska-Volk M, Knoth R, Durandy A, Draeger R, Schlesier M, Peter HH, Grimbacher B. Human ICOS-deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006, 107:3045-3052.

Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH,Litzman J, Holm A, Franco JL, Plebani A, Hammarstrom L, Skrabl A, Schwinger W, Grimbacher B. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol. 2004, 113:234-240.