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PubMed1969

Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection.

The neutrophils and monocytes of a patient with disseminated candidiasis were found to lack detectable levels of the lysosomal enzyme myeloperoxidase (MPO), although they had normal levels of other granule-associated enzymes. Leukocytes from one of the patient's sisters also lacked detectable MPO; leukocytes from his four sons contained approximately one-third of mean normal peroxidase levels. Neither the patient nor his affected relatives had experienced frequent or unusual bacterial infections. The phagocytic activity of the patient's MPO-deficient neutrophils was intact, and the cells displayed normal morphologic and metabolic responses to phagocytosis. In contrast to normal leukocytes which killed 30.5+/-7.3% of ingested Candida albicans in 1 hr, however, the patient's neutrophils killed virtually none. His leukocytes also failed to kill the strain of C. albicans recovered from his lesions, as well as other Candida species. These MPO-deficient neutrophils killed Serratia marcescens and Staphylococens aureus 502A at an abnormally slow rate, requiring 3-4 hr to achieve the bactericidal effect attained by normal leukocytes after 45 min. No other abnormalities in his cellular or humoral immune responses were demonstrated. These findings suggest that hereditary MPO deficiency is transmitted as an autosomal recessive characteristic, that the homozygous state conveys enhanced susceptibility to disseminated candidiasis, and that MPO is necessary for candidacidal activity in human neutrophils. Although lending support to the suggested bactericidal role of MPO in leukocytes, the data indicate that alternative bactericidal mechanisms, effective in the absence of MPO, are functionally dominant in the human neutrophil.

Blood Bactericidal Activity↗

PubMed1985

A molecular hypothesis concerning the pathogenesis of myasthenia gravis.

The purine enzyme, adenosine deaminase, is essential for the maturation of lymphocytes, cell growth and normal immune function. Since adenosine deaminase has the highest activity in the thymus and in T lymphocytes, it is hypothesized that a defective or altered enzyme may be a cause of myasthenia gravis, a lymphoid dyscrasia. It is proposed that the alteration is on the non-catalytic portion of adenosine deaminase concerned with the normal immune function of T lymphocytes. Lymphocytes, particularly suppressor T lymphocytes containing a defective adenosine deaminase will function improperly. They will lose their normal immune regulatory function, allowing immunoglobulin-producing B lymphocytes to produce autoantibodies against the nicotinic acetylcholine receptor, with resultant induction and perpetuation of the autoimmune state. In an attempt to compensate for the defect, there may be hypertrophy of the thymus and lymphoid system, with overproduction of a defective adenosine deaminase. Since many of the functions of thymosin, the alleged active principle in thymus are identical to those of adenosine deaminase, it is postulated that thymosin may be a subunit of adenosine deaminase.

Adenosine Deaminase↗

PubMed2004

Novel mutations and hot-spots in patients with purine nucleoside phosphorylase deficiency.

Purine nucleoside phosphorylase (PNP) deficiency results in severe immune dysfunction and early death from infections. Lymphopenia, reduced serum uric acid, and abnormal PNP enzymatic activity assist in the diagnosis of PNP-deficient patients. Analysis of the gene encoding PNP in these patients reveals several recurring mutations. Identification of these hot-spots for mutation may allow faster confirmation of the diagnosis in suspected cases.

CpG Islands↗

PubMed1993

Diagnosis of the carbohydrate-deficient glycoprotein syndrome by analysis of transferrin in filter paper blood spots.

Carbohydrate-deficient glycoprotein syndrome is a recently identified recessively inherited, multisystemic disease with severe nervous system involvement. It is characterized biochemically by carbohydrate-deficient serum glycoproteins, and can be diagnosed by analysis of abnormal isoforms of serum transferrin. Using stored, neonatally collected filter paper blood spots from such patients, it was shown that neonatal diagnosis was possible by immune-isoelectric focusing of transferrin eluted from up to 14-year-old samples. Freshly collected blood on filter paper was readily analyzed quantitatively for carbohydrate-deficient isotransferrins by a rapid microchromatographic assay, revealing highly elevated values in all patients. The presently described methods thus provide a means for early diagnosis of the carbohydrate-deficient glycoprotein syndrome in microliter volumes of capillary blood. Sampling on filter paper offers an important simplification in sample collection, storage and transport, and may make population studies possible.

Blood Specimen Collection↗

PubMed2005

The genetic and molecular bases of monogenic disorders affecting proteolytic systems.

Complete and limited proteolysis represents key events that regulate many biological processes. At least 5% of the human genome codes for components of proteolytic processes if proteases, inhibitors, and cofactors are taken into account. Accordingly, disruption of proteolysis is involved in numerous pathological conditions. In particular, molecular genetic studies have identified a growing number of monogenic disorders caused by mutations in protease coding genes, highlighting the importance of this class of enzymes in development, organogenesis, immunity, and brain function. This review provides insights into the current knowledge about the molecular genetic causes of these disorders. It should be noted that most are due to loss of function mutations, indicating absolute requirement of proteolytic activities for normal cellular functions. Recent progress in understanding the function of the implicated proteins and the disease pathogenesis is detailed. In addition to providing important clues to the diagnosis, treatment, and pathophysiology of disease, functional characterisation of mutations in proteolytic systems emphasises the pleiotropic functions of proteases in the body homeostasis.

Animals↗

PubMed1997

In vivo infusion of anti-LFA-1 and anti-CD2 antibodies prevents graft failure after HLA partially incompatible bone marrow transplantation in children with high risk acute lymphoblastic leukaemia.

Bone marrow transplantation (BMT) from matched sibling donors is the therapy of choice for children with high-risk acute lymphoblastic leukaemia in children. It is however not available to more than two-thirds of patients who lack a matched donor. Here, we review the outcome of 28 patients with high-risk ALL who were transplanted in France with alternative marrow sources such as HLA-phenoidentical unrelated volunteers and HLA-partially incompatible relatives. For these patients, we tested the possibility to prevent T-depleted marrow graft rejection by infusing in vivo two monoclonal antibodies directed against adhesion receptors i.e., LFA-1 and CD2. Two previous multicenter trials in children transplanted with partially incompatible bone marrow for inborn errors of metabolism showed their efficacy in this setting. Twenty eight patients were enrolled in this study and followed for a median of 4.4 years. Bone marrow engraftment occurred in 81% of the evaluable patients. Post-transplantation leukaemic relapse was the most frequent cause of death in this group of patients, and occurred in 39% of patients. The second most frequent complication was infectious disease, while an EBV-induced B-lymphocyte proliferative disorder occurred in four patients. In conclusion, T-cell-depletion combined with infusion of anti-LFA-1 and anti-CD2 antibodies is efficient in preventing graft failure and GVHD in this group of children with high-risk leukaemia undergoing partially incompatible BMT. The overall DFS is not improved in contrast to what has been previously observed in patients with immunodeficiencies transplanted with a similar rejection prophylaxis. Other approaches are therefore needed aiming either at preserving donor T-cell mediated immunity or accelerating immune reconstitution.

Antibodies, Monoclonal↗

PubMed2006

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice.

Defects in purine nucleoside phosphorylase (PNP) enzyme activity result in abnormal nucleoside homeostasis, severe T cell immunodeficiency, neurological dysfunction, and early death. Protein transduction domain (PTD) can transfer molecules into cells and may help restore PNP activity in cases of PNP deficiency. However, long-term use of PTD to replace enzymes in animal models or patients has not previously been described. We fused human PNP to the HIV-TAT PTD and found that the fusion with TAT changed the retention and distribution of PNP in PNP-deficient mice. TAT induced rapid intracellular delivery of PNP into tissues, including the brain, prevented urinary excretion of PNP, and protected PNP from neutralizing antibodies, resulting in significant extension of the enzyme's biological activity in vivo. Frequent TAT-PNP injections in PNP-deficient mice corrected the metabolic disorder and immune defects with no apparent toxicity. TAT-PNP remained effective over 24 weeks of treatment, resulting in continued improvement in immune function and extended survival. Our data demonstrate that TAT changes the properties of PNP in vivo and that long-term intracellular delivery of PNP by TAT corrects PNP deficiency in mice. We provide evidence to promote further use of PTD to treat diseases that require repeated intracellular enzyme or protein delivery.

Animals↗

PubMed1975

[Sea-blue histiocytes and Gaucher-like cells. Occurrence and significance].

Sea-blue histiocytes (SBH) and Gaucher-like cells are macrophages containing a pigment related to or identical with ceroid or lipofuscin. While an occasional cell may be found in the normal bone marrow, large numbers of SBH can be observed in various conditions mainly associated with increased cellular breakdown or with disturbances of lipoid metabolism. We have examined smears and/or sections of bone marrow and spleens of 722 patients with various hematological disorders. In only four instances large numbers of SBH could be found, twice in the bone marrow, once in the spleen and once in both organs. Two of these patients were suffering from immune thrombocytopenia. Gaucher-like cells have a different morphologic appearance although the pigment shows the same cytochemical characteristics as in SBH. Gaucher-like cells are mainly found in patients with chronic myeloid leukaemia and are thought to be related to the increased breakdown of granulocytes. The exact mechanisms responsible for the formation of these pigment macrophages are not yet known. In the author's view it does not seem justifiable to speak of a special "syndrome of the blue macrophages".

Adult↗

PubMed1987

Synopsis and prospectives on fetal liver transplantation.

Over 300 individuals have received fetal liver transplants for a spectrum of disorders including immunodeficiencies, aplastic anemia, leukemia and genetic disorders. In some instances, the objective has been to reconstitute the immune system from fetal liver-derived lymphoid stem cells. In aplastic anemia and leukemia two distinct approaches have been used: engraftment of fetal liver-derived hematopoietic stem cells or attempts to stimulate recovery of autologous hematopoiesis via factors produced by fetal liver. In genetic disorders, partial engraftment of fetal liver-derived hematopoietic and hepatic cells has been investigated. This report critically reviews data presented at a symposium on fetal liver transplantation in New-Delhi, 1-5 February 1986.

Anemia, Aplastic↗

PubMed1995

Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies.

Medium chain acyl-CoA dehydrogenase deficiency (MCAD) is a defect in the mitochondrial oxidation of fatty acids. The disorder typically presents with episodes of vomiting and hypoglycemia, sometimes with changes in mental status and hepatic failure. These Reye's-like features may culminate in coma and death. Stress, intercurrent illness, and reaction to childhood immunization have been shown to precipitate acute metabolic episodes in MCAD patients. All cases are caused by mutations of the single MCAD gene on chromosome 1. Most clinically ascertained cases are caused by an A985G transition in exon 11. Here we report the preliminary findings of MCAD patients detected prospectively through a supplemental newborn screening program in Pennsylvania using tandem mass spectrometry. From the first 80,371 newborns screened we prospectively found nine babies with MCAD (1/8930) plus two additional newborns screened because of a previously known family history. Molecular analysis showed 56% of the detected patients to be compound heterozygotes for the A985G and a second mutation. This is in contrast to clinical retrospective studies which have found only 20% to be compound heterozygotes. We have identified two of the other mutations including a novel mutation (DG91/C92, 6-bp deletion) in one of our patients by using single-stranded conformation polymorphism (SSCP) and sequence analysis of conformers. Our results confirm that MCAD is one of the more common inborn errors of metabolism. The different mutation frequencies observed between retrospective clinical studies and our prospective newborn screening study suggest that clinical ascertainment may lead to preferential identification of the A985G mutation.

Acyl-CoA Dehydrogenase↗

PubMed1979

Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function.

A role for the enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyl-transferase, EC 2.4.2.1) in the functional maturation of lymphoid cells has been revealed by the association of inherited deficiencies of these enzymes and profound immune deficiency. Previous studies have suggested that the selective toxicity for lymphocytes may be mediated by the accumulation of toxic deoxynucleoside metabolites, likely through the action of specific kinases enriched in lymphoid cells. In order to study possible mechanisms whereby lymphocyte function may be impaired in these disorders, we have studied the effect of nucleosides and their deoxy analogues on both T and B lymphocyte growth and function. In the presence of deoxyguanosine, there was marked inhibition of T lymphoblast growth, phytohem-agglutinin-induced cell proliferation, and T suppressor cell activity. T helper cell activity and the differentiation of B cells to an antibody-secreting stage were unaffected. Deoxyadenosine was much less inhibitory, but in the presence of an inhibitor of adenosine deaminase, its effects on lymphocyte growth and function were markedly potentiated. The addition of deoxycytidine prevented deoxyadenosine toxicity in all assays, whereas it only interfered with deoxyguanosine effects on T lymphoblast growth. These studies provide some initial understanding for the selective loss of specific lymphocyte functions in individuals with inborn errors of purine metabolism.

B-Lymphocytes↗

PubMed1983

Enzymological aspects of disorders in purine metabolism.

Congenital enzyme defects of purine synthesis de novo and the salvage pathway are responsible for excessive uric acid production and are often associated with hyperuricemia and gout. On the other hand, defects of enzymes essential for the purine nucleotide cycles are the biochemical basis of dysfunction of the immune system. The influence of several congenital enzyme deficiencies on the regulation of biosynthesis de novo, on the regulation of purine nucleotide concentrations, and on adenosine concentration, as well as the effect on purine transport through cell membranes are discussed. The determination of enzymes involved in purine metabolism in noncongenital diseases seems to be of diagnostic importance. As examples, enzyme activities in lymphocytes of leukemic patients, and the determination of serum guanase activity in patients with liver dysfunction are described.

Adenosine↗

PubMed1994

Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients.

Lysinuric protein intolerance is an autosomal recessive disease caused by defective transport of cationic amino acids. Of the 38 lysinuric protein intolerance patients diagnosed in Finland since 1965, four pediatric patients have died. We describe the clinical courses and autopsy findings for these patients. All patients developed acute respiratory insufficiency. In addition to pulmonary hemorrhages, three of the patients had pulmonary alveolar proteinosis and one had cholesterol granulomas. Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis. The patients also developed hepatic insufficiency with fatty degeneration or cirrhosis. All patients showed anemia, thrombocytopenia, and a severe bleeding tendency. The bone marrow of three patients was hypercellular, but the amount of megakaryocytes was decreased in two cases. Amyloid was present in the lymph nodes and the spleen. Bone specimens showed osteoporosis. We conclude that pediatric patients with lysinuric protein intolerance are predisposed to develop pulmonary alveolar proteinosis and glomerulonephritis. They are also at risk of protein malnutrition in the active growth phase, probably due to higher requirements for total nitrogen and amino acids.

Adolescent↗

PubMed1992

Congenital deficiency of alpha-fetoprotein.

Although alpha-fetoprotein may play a role in fetal immune function or in maintenance of osmotic pressure, its exact function is unknown. We report two infants documented to have congenital deficiency of alpha-fetoprotein. One infant had cord blood levels less than 0.5 ng/ml. The second infant had a neonatal level of 120 ng/ml, which is about 2% of the usual concentration for a term newborn. These infants document the existence of congenital deficiency of serum alpha-fetoprotein. Because it is homologous to albumin, congenital deficiency of alpha-fetoprotein may be analogous to analbuminemia, a benign genetic trait.

Adult↗

PubMed1998

Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency.

There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy with an adenoviral vector. Using the partially OTC-deficient sparse fur mouse we found transduction and expression could be achieved using an intravenous infusion of a recombinant adenovirus containing the OTC cDNA. The results were transient as a result of immune activation in response to the vector and vector-transduced cells. By modifying the adenoviral construct, creating an E1 deletion-E2 temperature-sensitive mutation, we blunted the cytotoxic T lymphocyte immune response and achieved correction of biochemical abnormalities for 2-3 months. We also found that transduction and expression following gene transfer occurred sufficiently rapidly to protect against acute hyperammonaemia within 24 h. Subsequent preclinical studies in mice and non-human primates demonstrated that E1-E4-deleted vectors had a substantially improved safety profile and similar efficacy. With this evidence of efficacy and safety of adenoviral vectors, we are embarking on a phase I trial of intravascular gene transfer using an E1-E4-deleted vector in adults with partial OTC deficiency.

Adenoviruses, Human↗

PubMed1992

Recurrent transient hyperphosphatasemia of infancy in an adult.

We report a case of recurrent transient hyperphosphatasemia in a 29-year-old man with immune deficiency. He had serum alkaline phosphatase (ALP; EC 3.1.3.1) activity 16.9- and 4.8-fold greater than the upper reference limit on two occasions; the activity returned to normal within 2 months on the first and within 1 month on the second. On both occasions we observed the typical electrophoretic pattern for ALP isoenzymes seen in transient hyperphosphatasemia of infancy. We noted no evidence of liver or bone disease. Recognition of the occurrence of transient hyperphosphatasemia of infancy in adults, although rare (it is the fifth case reported), seems as important as in children so that unnecessary extensive investigations are avoided.

Adult↗

PubMed1983

Therapy in adenosine deaminase and purine nucleoside phosphorylase deficient patients.

The discovery of the causal association of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency with some forms of primary immunodeficiency disease had led to new approaches to therapy, such as enzyme replacement. In ADA deficiency, bone marrow transplantation remains the primary method of choice. If no suitable bone marrow donor is available, enzyme replacement with irradiated erythrocyte transfusions should be considered. The latter therapy may be sustained by treatment with thymic factors. In ADA deficiency, bone marrow transplantation and, in about 50% of the cases, also enzyme replacement, may result in clinical and neurological improvement with concurrent (partial) restoration of immune function and (partial) disappearance of the metabolic abnormalities present before treatment. In PNP deficiency, enzyme replacement has been evaluated carefully in only two patients. The results disclose profound changes in the purine excretion patterns after each transfusion, and a slow but partial restoration of in vitro T cell function. Treatment of ADA and PNP deficiency with continued enzyme replacement by erythrocyte transfusions has certain risks which hopefully can be overcome in the near future by loading the patient's own blood cells with the missing enzyme.

Adenosine Deaminase↗

PubMed1978

A role for purine metabolism in the immune response: Adenosine-deaminase activity and deoxyadenosine catabolism.

We have investigated a new hypothesis for the association between adenosine deaminase (A.D.A.) deficiency and immunodeficiency--namely, that deoxyadenosine rather than adenosine (an equally effective A.D.A. substrate) is toxic to proliferating cells of lymphoid origin. This possibility was explored in mitogen-stimulated lymphocytes cultured with a potent A.D.A. inhibitor, E.H.N.A. (erythro-9[2-hydroxy-3-nonyl] adenine) to simulate A.D.A. deficiency. In this in-vitro system deoxyadenosine was inhibitory at much lower and more physiological concentrations (1 mumol/1), compared with adenosine (100 mumol/1).

Adenosine↗