Researchers Discover Cause Of A Human Immunodeficiency

The protein, called BLNK (B cell linker protein, pronounced blink), is important for the development of B lymphocytes, white blood cells that help the body fight infections. A group led by Andrew C. Chan, M.D., Ph.D., who discovered BLNK in 1998, report their findings about BLNK and B cell development in mice in the Dec. 3 issue of Science.

Chan is an associate professor of pathology and medicine in the Division of Rheumatology at Washington University School of Medicine in St. Louis, and an assistant investigator at the Howard Hughes Medical Institute. His laboratory also previously determined that BLNK brings together molecules that transmit signals for B cell function and development.

He also is co-author of an accompanying Science article about a human immunodeficiency study that was based on his suspicion that a defect in BLNK could produce human disease. Mary Ellen Conley, M.D., Ph.D., at St. Jude Children's Research Hospital in Memphis, Tenn., was the principal investigator for the human study, which included colleagues from the University of Tennessee, Memphis, and Johns Hopkins Hospital in Baltimore.

In the first Science article, Chan's group analyzed the tissue and blood of mice that lacked BLNK. Lead author Rajita Pappu, a graduate student in Chan's laboratory, generated and analyzed the mice with Alec M. Cheng, Ph.D., an assistant professor of pathology and medicine at the School of Medicine. The researchers determined that most of the animals' progenitor B cells failed to pass through a key developmental stage. As a result, the cells do not develop into mature B lymphocytes required to ward off infection throughout the body.

"We detected a 50-fold reduction in the number of peripheral B lymphocytes in these mice," Chan says, noting that the mice were kept in a germ-free environment.

The few B cells that had reached the peripheral parts of the body had not passed through a final stage of maturation. These cells were also abnormal in size and secreted few antibodies. Chan's laboratory is studying these unusual cells further and determining whether their development involves a signaling pathway that doesn't include BLNK.

The other Science article revealed that the BLNK-deficient patient had no detectable B cells or antibodies in his body, though other components of his immune system still functioned. He has a history of ear infections and sinusitis despite monthly injections of antibodies since he was less than 2 years old.

The researchers determined that his immunodeficiency resulted from a mutation in the gene for BLNK that prevented the protein from being produced. Chan notes that future improvements in gene therapy may one day allow such patients to receive a normal copy of the gene for BLNK to overcome the defect.

"Understanding the molecular basis of this disease was the first step," Chan says. "Now you can consider the second step."

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Pappu R, Cheng AM, Li B, Gong Q, Chiu C, Griffin N, White M, Sleckman BP, Chan AC. Requirement for B Cell Linker Protein (BLNK) in B Cell Development. Science, 286 (5445), 1949-1954, Dec. 3, 1999.

This study was funded by grants from the Human Frontiers Program in Biomedical Sciences, the Pew Scholars Program in Biomedical Sciences, the National Institutes of Health and the Burroughs Wellcome Fund.

Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D, Chan AC, Conley ME. An Essential Role for BLNK in Human B Cell Development. Science, 286 (5445), 1954-1957, Dec. 3, 1999.

This study was funded by grants from the National Institutes of Health, the March of Dimes, by the Assisi Foundation, the American Lebanese Syrian Associated Charities, the Human Fronteiers Scientific Organization, and by funds from the Federal Express Chair of Excellence.