Primary Immune Deficiency Diseases
NIH Scientists Identify a New Immunodeficiency Disease
Condition May be Treatable with Anti-Rejection Drug
The NIAID Primary Immune Deficiency Clinic is located in the NIH Mark O. Hatfield Clinical Research Center. Credit: NIH.
BackgroundPrimary immune deficiency diseases (PIDDs) are rare, genetic disorders that impair the immune system. Without a functional immune response, people with PIDDs may be subject to chronic, debilitating infections, such as Epstein-Barr virus (EBV), which also can increase the risk of developing cancer. PIDDs may be diagnosed in infancy, childhood, or adulthood, depending on disease severity. They are estimated to affect more than 500,000 people in the United States.
PIDDs usually are treated with therapies that broadly boost the immune response, such as regular infusions of antibodies from healthy blood donors. These therapies may not be completely effective or even target the underlying cause of disease. However, identification of the mutated gene responsible for a PIDD allows researchers to address the specific cause and test therapies that directly target the problem.
NIAID runs a primary immune deficiency (PID) clinic, which operates on a referral basis. The goal of the clinic is to provide patients with an accurate disease diagnosis, particularly from a genetic standpoint, and help referring specialists improve patient care.
Results of StudyNIAID researchers and their collaborators identified a novel PIDD called PASLI disease, named after the mutated gene and its symptoms (p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency). PASLI disease was initially detected in 6 patients who were referred to the NIAID PID Clinic. Upon further screening of the patients’ relatives, the disease was confirmed in 14 patients from 7 unrelated families of different ethnic and racial backgrounds. The patients have experienced recurring infections, including bacterial infections of the respiratory system and chronic viral infections with EBV, since childhood, and some have developed EBV-associated lymphoma.
By studying this group, the researchers found that the patients have a mutation in their PIK3CD gene, resulting in an overactive protein called PI3K-p110 delta. PI3K proteins are essential for directing the growth and activity of many types of immune cells, and p110 delta is specifically involved in B and T cells, which make antibodies and recognize and eliminate infected cells, respectively. The mutated, overactive p110 delta protein causes a chain reaction of problems. By sending the wrong signals at the wrong times, it disrupts the normal development of B and T cells, increasing susceptibility to infection.
The genetic information allowed the researchers to identify and target mTOR, an important signal that is excessively activated by p110 delta in PASLI patients. Drugs that block mTOR are already FDA-approved for the prevention of transplant rejection. One patient was treated with the drug rapamycin daily, which restored T cells to normal levels after 4 months. While the patient is not cured, normalization of T cells was adequate to improve disease symptoms.