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Protein amplification in melanoma is possible drug target

A newly discovered gene mutation may account for many cases of immune deficiency, in particular two syndromes known as immunoglobulin A (IgA) deficiency and Common Variable Immunodeficiency (CVID), report researchers in the July issue of Nature Genetics. The discovery may lead to a new diagnostic test for these conditions, which make people highly susceptible to infections and often go unrecognized because of a lack of good tests.

IgA deficiency affects 1 in 600 people; CVID is less common but more severe. Children and adults with either condition suffer relentlessly recurring ear infections, sinus infections, bronchitis, pneumonias and gastrointestinal infections. IgA deficiency and CVID can occur in the same family, and also predispose people to autoimmunity, particularly affecting the thyroid gland and resulting in thyroid hormone insufficiency. Finally, people with CVID are susceptible to B-cell lymphomas.

The researchers, led by Raif Geha, MD, and Emanuela Castigli, PhD, in the Division of Immunology at Children's Hospital Boston, found mutations in a gene known as TACI in 4 of 19 unrelated patients with CVID and in 1 of 16 unrelated patients with IgA deficiency. None of 50 healthy people tested had a TACI mutation. Four of the 5 patients with TACI mutations were studied further, and all 4 had relatives with the same mutations. Eleven of the 12 identified relatives with TACI or IgA deficiency reported a history of recurrent infections and were found to have low levels of immunoglobulin A (IgA), immunoglobulin G (IgG) or both.

TACI mutations interfere with two aspects of the immune response that involve maturation of B cells, the white blood cells that make immunoglobulins, which function as antibodies, to fight infections. Normally, TACI triggers B cells to switch from making immunoglobulin M (IgM), an antibody produced early in the body's immune response, to making other immunoglobulins like IgA and IgG. More important, TACI signals B ce
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