Description

The past year has seen an important advance in our understanding of the mechanism of Common Variable Immunodeficiency, with about 10% of these patients having mutations in the B cell receptor, TACI. An interesting facet is that patients can be either homozygous or heterozygous for disease associated mutations. This is a similar scenario to that seen in patients with mutations in the IFN-γ Receptor, where heterozygous mutations can cause susceptibility to mycobacterial infection. Like IFN-γR, TACI is a trimeric receptor, and it seems likely a mutation in one chain can disrupt the integrity of the complex. This has helped to explain the dominant inheritance of immunodeficiency in some families.
However, an increasing number of relatives of CVID patients with TACI mutations are clinically normal, having normal or only mild defects in immunity; the family reported in this Bulletin (page 51) is an example of this clinical heterogeneity. This is yet another example of redundancy in the human immune system, and creates a problem in how we approach and offer genetic counseling to apparently healthy family members who may pass on a more severe clinical phenotype to their offspring.

Given that over 80 different genetic defects causing immunodeficiency have been discovered in the last 15 years, it is likely that we will know the genetic basis of most cases of CVID before 2020. Meanwhile it will be the job of Immunologists to discover the co-factors that determine the severity of the immunodeficiency and complications, such as autoimmunity and granulomatous disease, that are common in CVID; such knowledge should lead to better treatments and prophylactic strategies for these problems.