The “Bubble Boy” Paradox: An Answer That Led to a Question

In the late 1970s the world witnessed the heart-wrenching tale of David Vetter, the "bubble boy."Born with X-linked SCID (XSCID), 2 a complete deficiency of T cells and NK cells, David lived his entire life inside a plastic bubble, deprived of all human contact.Sadly, David Vetter died in 1984, as a result of complications following an allogeneic bone marrow transplant designed to cure his disease.Nearly 10 years later, the genetic defect responsible for XSCID was identified by Warren Leonard and colleagues and was reported in a landmark paper published in Cell (1) that is reprinted in this issue of The Journal of Immunology.Published in April of 1993, this paper used genetic linkage analysis to demonstrate that the gene encoding the IL-2 receptor ␥-chain (IL-2R␥) mapped to the same chromosomal location as the gene responsible for XSCID.Further, Noguchi et al. showed that three unrelated patients with XSCID had three different nonsense mutations in the IL-2R␥ gene, resulting in premature translational termination of the predicted IL-2R␥ protein in these individuals (1).Together, these data provided compelling evidence supporting the conclusion that XSCID is caused by the absence of a functional IL-2R ␥-chain protein.However, despite this important breakthrough, the true underlying cause of XSCID remained a mystery.This congenital disease is characterized by a complete absence of circulating T cells and NK cells but normal numbers of B cells, although the B cells in these individuals are nonfunctional (2).Before the discovery of the underlying genetic basis of the disease, a diagnosis of XSCID also entailed a thymic biopsy, which would reveal a small underdeveloped organ with little evidence of developing T cells (3).Successful treatment of XSCID infants by bone marrow transplantation demonstrated that the observed structural defects in the thymus were secondary to the hematopoietic defects, as donor-derived T cells would develop normally and reconstitute the recipient's immune system (2).Additional studies on the B cells from XSCID infants indicated that at least some of the impaired B cell function was due to the absence of T cells, as addition of normal T cells to in vitro assays with XSCID B cells could promote B cell activation and Ab secretion (2).Yet, there remained some lingering sense that all was not completely right with the XSCID B cells.Some clarity regarding these issues came from an unexpected source.