Variants of autosomal recessive SCID that arise from defects in enzymes of the salvage pathway of purine synthesis include adenosine deaminase (ADA) deficiency (see Fig. 13.2) and purine nucleotide phosphorylase (PNP) deficiency. ADA catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively, and its deficiency results in the accumulation of deoxyadenosine and its precursor, Sadenosylhomocysteine, which are toxic to developing T and B cells. PNP catalyzes the conversion of inosine and guanosine to hypoxanthine and guanine, respectively. PNP deficiency, which is a rarer form of SCID, also causes the accumulation of toxic precursors but affects developing T cells more severely than B cells. In both diseases, the development of lymphopenia, or decreased numbers of lymphocytes, is progressive after birth, resulting in profound lymphopenia within the first few years of life. Because both enzymes are housekeeping proteins expressed by many cell types, the immune deficiency associated with each of these inherited defects is part of a broader clinical syndrome.
13-5 Defects in antigen receptor gene rearrangement can result in SCID.
Another group of autosomally inherited defects leading to SCID is caused by failures of DNA rearrangement in developing lymphocytes. Mutations in either the RAG1 or RAG2 gene that result in nonfunctional proteins cause arrest of lymphocyte development at the pro to preTcell and Bcell transitions because of a failure of V(D)J recombination (see Fig. 13.2). Thus, there is a complete lack of both T cells and B cells in these patients. Because the effects of RAG deficiencies are limited to lymphocytes that undergo antigen gene rearrangement, NKcell development is not impaired. There are other children with hypomorphic mutations (which cause reduced, but not absent, function) in either RAG1 or RAG2 who can make a small amount of functional RAG protein, allowing limited V(D)J recombination. This latter group includes patients with a distinctive and severe disease called Omenn syndrome, which, in addition to increased susceptibility to multiple opportunistic infections, has clinical features very similar to graftversushost disease characterized by rashes, eosinophilia, diarrhea, and enlargement of the lymph nodes (see Section 1536). Normal or increased numbers of activated T cells are found in these children. An explanation for this phenotype is that low levels of RAG activity allow some limited Tcell receptor gene recombination. No B cells are found, however, suggesting that B cells have more stringent requirements for RAG activity. Due to the limited number of Tcell receptors that are successfully rearranged, the repertoire of T cells is highly restricted in patients with Omenn syndrome, and there is activation and clonal expansion of the limited number of specificities present. The clinical features strongly suggest that these peripheral T cells are autoreactive and are responsible for the graftversushost phenotype. In addition to Omenn syndrome, which is manifested very early in life, other forms of immunodeficiency have also been associated with reduced but not absent RAG activity, and are often characterized by granulomatous disease that is not evident until late childhood or adolescence.