Chun HJ, Zheng L, Ahmad M, et al. Nature. 2002;419:395–399
Purpose of the Study.
Defects in genes involved in the apoptosis (programmed cell death) of lymphocytes have been shown to cause disorders characterized by significant adenopathy and autoimmunity. This study defines a new defect in that category and characterizes the clinical presentation. Mutations in the caspase-8 gene not only affect apoptosis but also affect host defense. This article describes a heretofore unrecognized function of caspase-8 in lymphocyte activation.
The study relies on a single kindred with 2 affected children and the heterozygous parents and sibling. The carriers of the mutation were asymptomatic.
The authors carefully characterize the apoptosis of cells from the affected children as well as the activation of their lymphocytes. Traditional killing studies were performed to define the defect in apoptosis as well as flow cytometric determinations of T cell activation. Cytokine production and proliferation were also measured to delineate the defect in T cell function.
The 2 patients with defects in caspase-8 had significant adenopathy and splenomegaly. These 2 features have been observed in all patients with defects in genes involved in lymphocyte apoptosis. In addition, these patients had several features that appear to be specific for caspase-8 defects. The patients had diminished CD4 counts, elevated CD8 T cell counts, poor responses to immunization, failure to thrive, recurrent herpes infections, and other recurrent infections. Mechanistic studies revealed defective apoptosis attributable to Fas-mediated signals but preserved apoptosis in response to mitochondrial-mediated signals. Western blots suggested that the Fas signal was intact up to recruitment of Fas-associated death domain, but that subsequent recruitment of caspase-8 was defective. Sequencing revealed a homozygous caspase-8 mutation. In addition to the defect in apoptosis, the authors describe a very significant defect in lymphocyte activation that probably accounts for the immunodeficiency phenotype. B cells, T cells, and NK cells are all defective in this disorder.
Caspase-8 mutations lead to a disorder characterized by expansion of lymphocytes in secondary lymphoid organs and abnormal lymphocyte activation.
This article is significant for introducing us to a new immunodeficiency and for the demonstration that caspase-8 is involved in lymphocyte activation. The 3 known defects of lymphocyte apoptosis, Fas deficiency, FasL deficiency, and caspase 10 deficiency all have a similar phenotype: the early presentation of significant adenopathy, splenomegaly, and autoimmune disease. Caspase-8 is now known to have an undefined but integral function in lymphocyte activation and the phenotype of patients with caspase-8 deficiency reflects this, with both lymphoid expansion and immunodeficiency.