Purine Nucleoside Phosphorylase Deficiency Associated with Selective Cellular Immunodeficiency

Abstract

We studied a 15-month-old girl who had normal T-cell and B-cell immunity at birth, after which a gradual decrease in T-cell immunity developed. This selective cellular immunodeficiency was inherited as an autosomal recessive trait: two older sisters had the same immunodeficiency. Adenosine deaminase activity was present in erythrocytes and lymphocytes of the patient, parents and a healthy brother. Purine nucleoside phosphorylase activity was not found in the patient's erythrocytes and lymphocytes (the parents and brother had intermediate values, indicating that the enzyme deficiency too was inherited as an autosomal recessive trait). Analysis of serum and urine from the patient and of serum from her two deceased sisters showed high levels of inosine and guanosine in addition to hypouricemia and hypouricosuria. The bone marrow was megaloblastic, and the blood hypochromic microcytic. The patient had spastic tetraparesis. Intoxication of the T lymphocytes after birth by metabolic products may explain the progressive cellular immunodeficiency.

Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes

“…Human genetic deficiency of PNP provides unequivocal evidence that loss of this enzymatic activity causes suppression of T cell function with minimal effects on B cells or other tissues (1). The challenge of inhibitor design for PNP arises from the abundance of the enzyme in human tissues.…”

“…Although PNP is present in all mammalian cells, T cells are especially sensitive to deficiencies of this enzyme. A rare genetic deficiency of PNP results in a gradual specific loss of T cell function after birth and is associated with significant cellular immunodeficiency (1). DNA synthesis in other lymphoid and nonlymphoid cells of affected individuals is usually normal, suggesting that inhibition of PNP may provide an effective mechanism for selectively targeting T cells.…”

A New Case of Purine Nucleoside Phosphorylase Deficiency: Enzymologic, Clinical, and Immunologic Characteristics

“…Since the first description of PNP deficiency associated with cellular immunodeficiency (I), about 20 patients from more than 10 families have been described (2)(3)(4)(5). Clinically, PNP deficiency may manifest itself later in life than ADA deficiency, which affects cellular immune function and also humoral immunity.…”

“…PNP deficient patients show an extreme susceptibility to viral infections such as varicella, measles, and cytomegalovirus. In addition neurologic abnormalities such as spastic tetraparesis often are part of the clinical syndrome (4,5). T lymphocyte function is impaired in vivo and in vilro, whereas B lymphocyte function, as determined by the synthesis of specific antibodies, is usually intact in these patients.…”

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

“…Mutations in the locus encoding for purine nucleoside phosphorylase (PNP) cause gradual decrease in Tcell immunity, though keeping B-cell immunity normal as well as other tissues (Stoop et al 1977). The activation of helper T cells requires that they recognize a complex formed between an antigen and a class II MHC (Major Histocompatibility Complex) protein on the surface of antigen-presenting cells with appropriate costimulation.…”