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A Single-Gene Mutation May be Cause Some Immunodeficiencies; Genetic Test May Guide Therapy


In a discovery that may guide the treatment of two immunodeficiency syndromes, researchers led by Emanuela Castigli and Raif Geha of the Division of Immunology at Children's Hospital in Boston have identified mutations in the TNFRSF13B gene as an important contributing cause.

Immunoglobulin A deficiency and common variable immunodeficiency affect approximately 1 person in 600 and 1 person in 50,000, respectively. Sufferers of both conditions endure recurrent bronchitis and pneumonia, as well as infections of the ears, sinuses, gastrointestinal tract, and other areas of the body. Both diseases also predispose their victims to autoimmune reactions and B-cell lymphomas.

The TNFRSF13B gene encodes the TACI protein, a member of the transmembrane activator and calcium-modulator and cyclophilin ligand interactor family.

It is not difficult to see how diagnostics detecting TNFRSF13B mutations might impact future patient care. "Many children who are sick are now missed, because they can have normal IgA and IgG levels, yet they still have poor antibody responses and get the same bacteria and viruses again and again," Castigli said in a statement.

Changes in patient care would likely not impact people already known to suffer from these immunodeficiencies, but it would allow those not currently diagnosed, as well as many of their relatives, to adopt standard treatment for the two conditions. "For the time being, [treatment consists of] prophylactic antibiotic or IV-immunoglobulin infusions every three weeks," said Castigli.

The effects of TNFRSF13B mutations are often overlooked, according to the study. Of 12 TNFRSF13B mutation-harboring relatives of immunodeficiency patients studied by Castigli and colleagues, 11 reported a history of recurrent infections and were found to have low levels of IgA, IgG, or both, the statement said. In 19 unrelated CVID patients tested for TNFRSF13B mutations, four carried them, while one of 16 IgA-deficiency patients were found to carry a mutation. None of the 50 normal subjects tested carried a TNFRSF13B mutation.

When functioning normally, the TACI protein, TNFRSF13B's product, aids the maturation of B cells as the body mounts a response to infection. The wild-type gene modulates the shift of B cells from IgM production to IgA or IgG production, and it influences B cells to produce especially specific antibodies. Individuals carrying even one TNFRSF13B mutation can have an abnormal B-cell maturation process.

Wild-type TACI protein was previously demonstrated by Castigli and colleagues to bind proteins called APRIL and BAFF in the process of B-cell maturation. According to the current study, B cells from individuals with TACI mutations expressed the protein, but did not produce IgG and IgA in response to its ligand, APRIL — a response typical to properly functioning cells. The lack of response probably reflects impaired isotype switching, the study said.

Castigli suspects that mutations in either APRIL or BAFF, which are produced by cells in the gastrointestinal lining and respiratory tract, may also cause immunodeficiencies, according to the statement.

— Chris Womack ([email protected])

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