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
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. 1. Introduction Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections, hypogammaglobulinemia, and impaired antigen-specific antibody synthesis [1]. In approximately 10% of patients, a genetic defect has been identified. In addition, functional defects have been described, for example, in Toll-like receptor (TLR) signaling [2, 3]. The most prevalent genetic alterations are located in the TNFRSF13B gene encoding transmembrane activator, calcium modulator, and cyclophilin ligand (CAML) interactor (TACI) [4]. TACI is mainly expressed on B-cells and belongs to the tumor necrosis factor receptor (TNFR) family [4]. Two ligands for TACI have been described: B-cell activating factor (BAFF) [5] and a proliferation-inducing ligand (APRIL) [6, 7]. In addition, TACI may bind proteoglycans including syndecan-2 that stimulate TACI-mediated signaling [8, 9]. BAFF and APRIL also bind B-cell maturation antigen (BCMA) [10], and BAFF has a third receptor, BAFFR [11]. This versatility complicates studying the precise
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