The multiple causes of human SCID

Abstract

SCID, a syndrome characterized by the absence of T cells and adaptive immunity, can result from mutations in multiple genes that encode components of the immune system. Three such components are cytokine receptor chains or signaling molecules, five are needed for antigen receptor development, one is adenosine deaminase--a purine salvage pathway enzyme, and the last is a phosphatase, CD45. In this issue of the JCI, a report describes how complete deficiency of the CD3epsilon chain of the T cell antigen receptor/CD3 complex causes human SCID.

Figure 1

Relative frequencies of the various molecular defects found in 174 consecutive cases of human SCID evaluated at Duke University Medical Center over the past 3 decades. The most common type is X-linked SCID, due to mutations in the gene encoding the common γ chain for multiple cytokine receptors; the second most common cause is adenosine deaminase deficiency (ADA def.), and the third most common cause is IL-7Rα–chain deficiency. In 25 cases the molecular defect remains unknown (those in the groups labeled autosomal recessive and unknown). No cases of CD45 deficiency have been seen at this institution. Def., deficiency.

Figure 2

Schematic of the T cell receptor/CD3 (TCR/CD3) complex on the surface of a normal CD4^–CD8^– double-negative thymocyte. All but one of the normal chains of the CD3 complex, including the β chain, are present, but instead of the CD3α chain, the pre–T cell receptor α gene is expressed at this stage. It is postulated, based on the CD3ε murine knockout studies, that the block in T cell development caused by mutations in CD3ε occurs at or just after this stage. In their study in this issue, de Saint Basile and colleagues (13) report histologic data which suggests that, in the case of mutations in the CD3δ gene, the block in T cell maturation occurs at the next stage, i.e., at the intermediate single-positive stage.