Missing Genetic Link Discovery May Lead to New Treatments for RA, Diabetes

Gene may help identify clue to separation of overactive and underactive immune activity.

The identification of a gene that may be a link between overactive and underactive immune activity may lead to more effective treatments for autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, and diabetes.

In a study published online April 20, 2015 in Nature Communications, researchers evaluated common variable immunodeficiency disorder (CVID), which involves weak antibody responses that can lead to recurrent and frequently severe bacterial respiratory tract infections.

"Although this finding does not lead to immediate clinical applications, it raises new opportunities for understanding underlying causes of different immune disorders, and eventually developing more effective diagnostic tests and therapies," co-study lead Hakon Hakonarson, MD, PhD, said in a press release.

CVID is found in approximately one in 25,000 individuals of all ages in European populations. The condition involves defective B cells in the immune system that lead to a low level of antibodies and can cause patients to be vulnerable to recurrent infections, some of which can cause permanent lung damage.

Approximately 25% of CVID patients have various autoimmune disorders, including rheumatoid arthritis, stomach and bowel disorders, and autoimmune thrombocytopenia. Defective B-cells can also increase the risk for a type of lymphoma.

During the study, the researchers discovered a novel candidate for a CVID risk gene in the CLEC16A gene region on chromosome 16p13.13.

"This is the first risk susceptibility gene for CVID identified by a genome-wide association study that does not code for the HLA complex," Dr. Hakonarson said.

The study found that mice with reduced activity in the corresponding animal gene had lower B-cell levels, which are the immune cells decreased in human disease. Furthermore, prior genetic studies established that changes in CLEC16A increased the risk of type 1 diabetes, inflammatory bowel disease, and other autoimmune disorders.

"The biological mechanisms that cause disease symptoms in CVID are still unclear, but this study may suggest that altered function in CLEC16A and its associated proteins may represent a 'missing link' between immunodeficiency and autoimmunity in CVID,” Hakonarson said. “This may offer new opportunities for eventually designing more effective treatments."