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Defective gene linked to two inherited immune deficiencies

August 08, 2005

Defects in a single gene can result in two immune system disorders that leave affected individuals vulnerable to frequent or unusually severe infections, according to new findings reported in the August issue of Nature Genetics. The discovery may lead to new diagnostic tests for these two inherited conditions-immunoglobulin A (IgA) deficiency and common variable immunodeficiency (CVID) Currently, doctors diagnose the conditions by measuring immunoglobulin levels and excluding other causes for lowered immunoglobulin levels; there are no specific tests to detect the two disorders.

A deficiency of IgA-an important type of infection-fighting antibody found in tears, saliva and other secretions-affects 1 in 600 people in the western world; CVID is less common but more severe. Both conditions result in a person being more susceptible to pneumonia and to recurring infections of the ear, sinus and gastrointestinal tract. People with CVID also have an increased risk of developing cancers that affect B cells, cells that produce antibodies. Furthermore, IgA deficiency and CVID can predispose to autoimmune diseases, where the immune system turns against the body's own tissues and organs.

"Most cases of CVID and IgA deficiency are of unknown cause," notes Josiah Wedgwood, M.D., Ph.D., of the Clinical Immunology Branch of the National Institute of Allergy and Infectious Diseases (NIAID), the component of the National Institutes of Health that funded the study. "To find a specific molecular defect that is the apparent cause of illness in a substantial subset of individuals with these two diseases is extremely important. Not only will this finding enable us to better diagnose these patients, it provides clues to key biochemical pathways that can lead to immunodeficiencies."

The study was led by Raif Geha, M.D., and Emanuela Castigli, Ph.D., of the Children's Hospital Boston. The Boston team found specific mutations in a gene known as TACI, which plays a specific role in orchestrating the immune response. Defects in TACI were found in 4 of 19 unrelated patients with CVID and in 1 of 16 unrelated patients with IgA deficiency. None of 50 healthy people they studied had a TACI mutation. The scientists believe that it is likely that as yet unidentified genetic defects underlie CVID and IgA deficiency in those cases where TACI was not mutated.

When the scientists further examined four of the five individuals with TACI mutations, they found all four had relatives with the same mutations. Eleven of the 12 identified relatives with CVID or IgA deficiency reported a history of recurrent infections and were also found to have low levels of IgA and/or low levels of another type of antibody, immunoglobulin G (IgG).

TACI mutations interfere with two aspects of the immune response that involve maturation of B cells. Normally, TACI triggers B cells to switch from making immunoglobulin M (IgM), an antibody produced early in the immune response, to making other antibodies such as IgA and IgG. More important, TACI signals B cells to produce antibodies against specific invading bacteria and viruses.

Because TACI mutations are genetically dominant, a person with TACI mutations in one of the two TACI genes he or she inherits is unable to mount a strong antibody response. Each child of a person so affected has a fifty percent chance of inheriting the mutation and being predisposed to IgA deficiency and CVID.

"A test for TACI defects would enable the diagnosis of more children and their relatives with these immune deficiencies," says Dr. Geha, senior author of the study and the James Gamble Professor of Pediatrics at Harvard Medical School. "Many children who are sick with these disorders are now missed, because they can have normal IgA and IgG levels, yet they still have poor antibody responses and get the same bacterial and virus infections again and again."

But the gene discovery will not immediately change treatment strategies, notes Dr. Geha. "For the time being, therapy still consists of prophylactic antibiotics or intravenous immunoglobulin infusions every three weeks," he says.

NIH/National Institute of Allergy and Infectious D