The primary immunodeficiency disorders reflect abnormalities in the development and maturation of cells of the immune system. These defects result in an increased susceptibility to infection; recurrent pyogenic infections occur with defects of humoral immunity, and opportunistic infections with defects of cell-mediated immunity. These two broad categories of illness correspond roughly to defects in the two principal types of immunocompetent cells, B lymphocytes and T lymphocytes. Defective development of B cells results in abnormalities in humoral immunity, whereas defects in the development of T cells cause problems with cellular immunity. When pathogens are taken up by macrophages or dendritic cells, . . .

The Primary Immunodeficiencies

Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis

https://www.cell.com/molecular-cell/pdf/S1097-2765(12)00003-2.pdf

Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase

Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells

We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses of approximately 15 U per kilogram of body weight maintained plasma adenosine deaminase activity at two to three times the level of erythrocyte adenosine deaminase activity in normal subjects. The principal biochemical consequences of adenosine deaminase deficiency were almost completely reversed. In erythrocytes, adenosine nucleotides increased and deoxyadenosine nucleotides decreased to less than 0.5 percent of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of the cellular immune function of each patient showed marked improvement, along with an increase in circulating T lymphocytes. Clinical improvement was indicated by absence of infection and resumption of weight gain. We conclude that from the standpoints of efficacy, convenience, and safety, polyethylene glycol-modified adenosine deaminase is preferable to red-cell transfusion as a treatment for adenosine deaminase deficiency. Patients with other inherited metabolic diseases in which accumulated metabolites equilibrate with plasma could benefit from treatment with the appropriate polyethylene glycol-modified enzyme.

https://www.nejm.org/doi/pdf/10.1056/NEJM198703053161005?listPDF=true

Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase.

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.

https://www.nejm.org/doi/pdf/10.1056/NEJM197703242961203?listPDF=true

Purine Nucleoside Phosphorylase Deficiency Associated with Selective Cellular Immunodeficiency

A patient with the full clinical expression of the classical Lesch-Nyhan syndrome is presented with a residual hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity of 5–10% in erythrocyte lysate and about 30% in fibroblast lysate The activities of other erythrocyte enzymes of purine metabolism were typical for a classical Lesch-Nyhan patient The effects of allopurinol therapy on the excretion of urinary purine metabolites were studied by a newly developed isotachophoretic technique The unusually high residual activity of HGPRT in erythrodytes and fibroblasts of the patient enabled the enzymologic characterization of the mutant enzyme: in fibroblasts the affinities for the substrates hypoxanthine and guanine were normal However, there was an increased apparent K
m for phosphoribosylpyrophosphate (PRPP), a complete absence of product inhibition by IMP and GMP, and a decreased heat stability Addition of PRPP did not stabilize the mutant enzyme In addition to the altered properties of the fibroblast enzyme, the K
m of the erythrocyte enzyme for hypoxanthine was also increased Immunoprecipitation experiments revealed the presence of an approximately normal amount of material cross-reacting with anti-human HGPRT antiserum However, it appeared that this cross-reacting material had a decreased stability When intact erythrocytes were incubated with radiolabeled purine bases, no formation of IMP or GMP could be detected, despite the relatively high residual activity of HGPRT in the hemolysate The results fit the following hypothesis: as a consequence of a structural mutation affecting the PRPP-site of the enzyme and a decreased heat stability, the activity of the mutant enzyme under in vivo conditions is virtually zero In the erythrocytes of the patient's mother a normal HGPRT-activity was found However, the activity in her fibroblasts was lower than normal, while a decreased heat stability and an intermediate behavior towards IMP could be shown Hair root analysis of several members of the patient's family confirmed the heterozygosity of the mother, whereas no other heterozygotes could be detected The family anamnesis did not show other cases of Lesch-Nyhan syndrome These findings were taken as evidence that the patient described in this paper might represent a mutation orginating from the gametes in either of the maternal grandparents

Partial hypoxanthine-guanine phosphoribosyl transferase deficiency with full expression of the Lesch-Nyhan syndrome

An abnormal form of purine nucleoside phosphorylase in a family with a child with severe defective T-cell-and normal B-cell immunity.

Separation and characterization of hexokinase I subtypes from human erythrocytes.

There is ever-increasing literature pointing out that gene expression in tumour cells is different from that in normal cells from which or in which the tumour originates. In general, neoplasia is characterized by misprogramming of protein synthesis (16).

https://cancerres.aacrjournals.org/content/canres/39/10/4263.full.pdf

G. E. J. Staal

Papers

Purine Nucleoside Phosphorylase Deficiency Associated with Selective Cellular Immunodeficiency

Partial hypoxanthine-guanine phosphoribosyl transferase deficiency with full expression of the Lesch-Nyhan syndrome

An abnormal form of purine nucleoside phosphorylase in a family with a child with severe defective T-cell-and normal B-cell immunity.

Separation and characterization of hexokinase I subtypes from human erythrocytes.

L-α-Alanine Inhibition of Pyruvate Kinase from Tumours of the Human Central Nervous System