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ISRN Immunology
Volume 2013 (2013), Article ID 365916, 10 pages
Research Article

Synergy in B-Cell Activation between Toll-Like Receptor 9 and Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor (TACI) in A181E/C104R Compound Heterozygous Siblings

1Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Lundlaan 6, P.O. Box 85090, KC.01.069.0, 3584 EA Utrecht, The Netherlands
2Department of Medical Immunology, University Medical Center Utrecht, Heidelberglaan 100, F03.821, P.O. Box 85500, 3508 GA Utrecht, The Netherlands

Received 21 April 2013; Accepted 26 May 2013

Academic Editors: S.-i. Fujii, F. Granucci, W. W. Leitner, and S. Sánchez-Ramón

Copyright © 2013 Annick A. J. M. van de Ven et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Purpose. Approximately 9% of common variable immunodeficiency (CVID) patients harbor variants in the transmembrane activator and CAML interactor gene, TACI, which contribute to CVID development. We found identical compound heterozygous TACI variants (C104R and A181E) in kindred of which one sibling had severe CVID with refractory auto immunity, and a second sibling remained asymptomatic. This study investigated possible differences in B-cell phenotype and function that could explain this divergent clinical expression. Methods. C104R and A181E TACI variants were identified through Sanger sequencing. Phenotypic evaluation of the lymphocyte compartment was performed by flow cytometry analyses. Lymphoblastoid cell lines (LCL) from the index patient, asymptomatic sibling, and controls were generated. Intracellular TACI expression was determined, and activation-associated calcium flux capacity was measured. In vitro stimulation assays and RT PCR were performed. Results. Both intracellular levels and surface expressed TACI protein were higher in the asymptomatic sibling than the CVID patient as were TACI-triggering-induced mRNA expression AID and production of Ig class-switched antibodies. In analogy, the asymptomatic sibling displayed enhanced Toll-like receptor 9 expression and signaling, suggesting a compensatory immune mechanism. Conclusions. Posttranscriptional regulation of TACI protein and cross-talk with TLR9 signaling may contribute to phenotypic diversity between individuals with TACI variants.