Common variable immune deficiency (CVID) is the most important primary antibody deficiency disease due to prevalence, complications, and requirement for lifelong replacement immune globulin therapy. CVID B cells lack the capacity to differentiate into plasma cells leading to reduced levels of serum IgG, IgA and/or IgM. A recent classification system, based on the numbers of peripheral blood isotype-switched memory B cells, divides patients into those with few if any of these cells, and those with higher numbers. Lower numbers of these cells is correlated with restricted VH gene families and reduced somatic hyper-mutation of variable heavy chain genes, loss of antibody production in vitro and in vivo. While the genetic causes of B cell dysfunction in CVID are unknown for most subjects, two pathways contributing to the block in B cell development are known: 1) 8% of subjects have mutations in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and 2) there is defective activation of Toll Like Receptors (TLR) 7, 8 and 9, pathways. Both CVID patients with TACI mutations and subjects with lowest numbers of switched memory B cells and poorest responses to TLR ligands, have a significantly higher likelihood of developing massive lymphoid hyperplasia, splenomegaly and autoimmunity. These observations suggest that the normal function of TACI and its ligands, B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL, is to initiate and control B cell growth and differentiation. We hypothesize that mutations in TACI lead to uncontrolled proliferation, autoimmunity and defective B cell apoptosis in CVID, potentially due to the excess serum BAFF and APRIL found in CVID. We also hypothesize that that loss of function of TLR pathways in CVID prevents normal B cell growth and regulation and permits retention of autoreactive B cells This project permits the exploration of two important themes in B cell biology: how TACI and related TNF ligands control growth and differentiation, and the role of external microbial signals on B cell competence in a human system. RELEVANCE (See instructions): CVID is the most important primary antibody deficiency disease due to prevalence, complications, and requirement for lifelong replacement immune globulin. The failure of B cells to develop normally leads to infections, organ damage, autoimmunity and in some, lymphoma. Here we investigate two main pathways to B cell maturation that are defective in CVID, with a view to better understanding of normal B cell biology.