Title: The role of TACI mutations in common variable immunodeficiency
Description: CVID (Common Variable Immunodeficiency) is the most prevalent human primary immunodeficiency requiring medical attention. CVID is characterized by recurrent bacterial infections, and is complicated by autoimmune manifestations, lymphoproliferation and increased risk of selected cancers. Most cases of CVID are sporadic, but at least 10% are familial, with a predominance of autosomal dominant inheritance. Recently, we reported that mutations in TNFR (tumor necrosis factor receptor) family member called TACI ( TNFRSF13B ), were present in patients with CVID. TACI is a receptor for BAFF and APRIL and plays an important role in B cell isotype switching and antibody production to type II T independent antigens. We were able to demonstrate that B cells from CVID patients with TACI mutations did not produce IgG and IgA in response to the TACI ligand, APRIL, reflecting impaired signaling. One of the most common TACI mutations found in CVID patients is the C104R mutation, which is located in the extracellular domain and it abolishes ligand binding. Interestingly, most CVID patients are heterozygous with respect to TACI mutation. It is unknown whether C104R heterozygous patients have CVID because of haploinsufficiency or because the mutant might be dominantly interfering with WT TACI function. My work has revealed that this mutation (C104R) behaves similarly in the murine TACI receptor. In addition, when coexpressed with WT TACI the mutant is able to dominantly interfere with WT TACI signaling.

This effect was found to be due to the ability of the mutant TACI to preassociate with WT TACI in a ligand independent manner. Using a novel in vitro assembly system we showed that TACI forms ligand-independent preassociated homotypic complexes. The existence of preassociated TACI receptor complexes was confirmed in living cells by means of fluorescence resonance energy transfer (FRET). Our work provides new insight into structure of TACI receptor by showing that it preassociates prior to ligand binding, but more importantly it provides a mechanistic explanation for how a very common heterozygous mutation in TACI found in CVID patients can potentially causes disease. Finally, I have started developing an in vivo model of mice carrying the human TACI mutations in the murine TACI gene. We hope that these mouse models will allow us to understand the relationship of TACI mutations and B cell dysfunction found in CVID patients.