CTLA4 deficiency is a rare disorder that severely impairs the normal regulation of the immune system, resulting in conditions such as intestinal disease, respiratory infections, autoimmune problems, and enlarged lymph nodes, liver, and spleen. NIAID scientists and their collaborators identified the disease in 2014. NIAID supports research to learn more about the genetic cause of CTLA4 deficiency and to investigate therapies for alleviating symptoms and related conditions.

CTLA4 deficiency is a primary immune deficiency disease (PIDD).

CTLA4 deficiency is caused by mutations in a gene called CTLA4, which gives cells instructions for making the CTLA4 protein. This protein functions as a brake to slow down and control the action of the immune system.

Each person has two copies of the CTLA4 gene, one from each parent. In 2014, NIAID scientists found that people with only one functional copy of CTLA4 experience abnormal T-cell activity; lower levels of healthy, antibody-producing B cells; higher levels of autoimmune B cells; and the disruption of organs by infiltrating immune cells. The researchers determined that having a single working copy of CTLA4 is not sufficient to produce enough CTLA4 protein for a normal immune system.

CTLA4 deficiency is characterized by infiltration of immune cells into the gut, lungs, bone marrow, central nervous system, kidneys, and possibly other organs. Most people with CTLA4 deficiency experience diarrhea or intestinal disease. Enlarged lymph nodes, liver, and spleen also are common, as are respiratory infections. People with CTLA4 deficiency often experience autoimmune problems that can affect various organs and tissues, including the blood, thyroid, skin, and joints. The disease also may slightly increase the risk of lymphoma, a type of immune-cell cancer.

CTLA4 deficiency is diagnosed based on clinical symptoms, laboratory findings, and genetic testing.

Treatment for CTLA4 deficiency may include standard therapies for autoimmune problems and immunoglobulin deficiencies. A potential new therapy is the drug called CTLA-4-Ig, also known as abatacept, which mimics the action of the CTLA4 protein and reduces immune activity. Abatacept is used to treat autoimmune diseases such as rheumatoid arthritis, but its effectiveness for treating CTLA4 deficiency requires further study. In 2019 NIAID investigators launched a small clinical trial to test the safety and efficacy of intravenous infusions of abatacept for correcting or improving numbers of blood cells in people with CTLA4 deficiency. Bristol-Myers Squibb, which manufactures abatacept, is donating the drug to the study.