Common variable immunodeficiency (CVID) encompasses a varied group of immunodeficiency syndromes characterized by B cell defects, low immunoglobulin levels, and recurrent bacterial infections.
Recently, Raif Geha and colleagues from Harvard Medical School reported that the gene TNFRSF13B, which encodes a protein known as TACI, is mutated (a C104R missense mutation) in about 10% of CVID patients. However, just how this TACI mutation causes CVID remained unknown.
In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, these same authors provide insight into the molecular mechanisms of how TACI mutations cause CVID.
TACI is a cell surface receptor and is mainly expressed on B cells. The authors examined mice carrying a C76R TACI mutation (the equivalent of the human C104R mutation) and found that mutated TACI is unable to bind ligand. Both the human and mouse TACI mutants were shown to pre-associate with normal TACI, independent of ligand, indicating that the mutation was acting in a dominant-negative manner. More importantly, the human TACI mutant can interfere with signaling by normal TACI without interfering with the surface expression of normal TACI or its ability to bind ligand.
Thus, ligand-independent preassociation of C104R TACI mutants with normal TACI mutants provides a potential explanation for how the C104R mutation may disrupt TACI signaling in B cells and impair the ability of B cells from CVID patients to produce immunoglobulin.