Defective Gene Linked To Two Inherited Immune Deficiencies

A deficiency of IgA--an important type of infection-fighting antibodyfound in tears, saliva and other secretions--affects 1 in 600 people inthe western world; CVID is less common but more severe. Both conditionsresult in a person being more susceptible to pneumonia and to recurringinfections of the ear, sinus and gastrointestinal tract. People withCVID also have an increased risk of developing cancers that affect Bcells, cells that produce antibodies. Furthermore, IgA deficiency andCVID can predispose to autoimmune diseases, where the immune systemturns against the body's own tissues and organs.

"Most cases of CVID and IgA deficiency are of unknown cause," notesJosiah Wedgwood, M.D., Ph.D., of the Clinical Immunology Branch of theNational Institute of Allergy and Infectious Diseases (NIAID), thecomponent of the National Institutes of Health that funded the study."To find a specific molecular defect that is the apparent cause ofillness in a substantial subset of individuals with these two diseasesis extremely important. Not only will this finding enable us to betterdiagnose these patients, it provides clues to key biochemical pathwaysthat 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 foundspecific mutations in a gene known as TACI, which plays a specific rolein orchestrating the immune response. Defects in TACI were found in 4of 19 unrelated patients with CVID and in 1 of 16 unrelated patientswith IgA deficiency. None of 50 healthy people they studied had a TACImutation. The scientists believe that it is likely that as yetunidentified genetic defects underlie CVID and IgA deficiency in thosecases where TACI was not mutated.

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

TACI mutations interfere with two aspects of the immune response thatinvolve maturation of B cells. Normally, TACI triggers B cells toswitch from making immunoglobulin M (IgM), an antibody produced earlyin the immune response, to making other antibodies such as IgA and IgG.More important, TACI signals B cells to produce antibodies againstspecific invading bacteria and viruses.

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

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

But the gene discovery will not immediately change treatmentstrategies, notes Dr. Geha. "For the time being, therapy still consistsof prophylactic antibiotics or intravenous immunoglobulin infusionsevery three weeks," he says.

NIAID is a component of the National Institutes of Health, an agency ofthe U.S. Department of Health and Human Services. NIAID supports basicand applied research to prevent, diagnose and treat infectious diseasessuch as HIV/AIDS and other sexually transmitted infections, influenza,tuberculosis, malaria and illness from potential agents ofbioterrorism. NIAID also supports research on transplantation andimmune-related illnesses, including autoimmune disorders, asthma andallergies.

Reference: E Castigli et al. TACI is mutant in common variableimmunodeficiency and IgA deficiency. Nature Genetics 37:829-34 (2005).DOI:10.1038/ng1601.