Analyzing rare human patients with inborn errors of immunity may shed light on critical genes and pathways controlling differentiation and/or function of the innate and adaptive immune system.
We performed genetic and cellular immunologic analyses involving two patients from unrelated families with shared phenotypes of immunodeficiency with defective lymphocytic responses, autoimmunity and malignancy
We identified two distinct homozygous mutations in the gene encoding CD137, leading to reduced or loss of protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, cytotoxicity and differentiation were impaired. Genetic reconstitution of CD137 reversed these defects.
CD137 deficiency is a novel inborn error of human immunity characterized by combined immunodeficiency associating autoimmunity and Epstein-Barr virus (EBV)-induced lymphomagenesis. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and surveillance.