Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine deaminase (ADA) deficiency is the cause of about one third of the autosomal recessively inherited cases of severe combined immunodeficiency. Disease severity in ADA deficiency is variable, presumably related in part to heterogeneity in the genotypes causing the disease. We now report on two children in a single family with ADA deficiency who presented with distinct clinical courses. One child presented with severe immunodeficiency and recurrent infections that led to the diagnosis of severe combined immunodeficiency and ADA deficiency at 7 months of age. The older child, who was diagnosed at 3 years of age (after the diagnosis of the younger child), did not have a history of serious or opportunistic infections. Although she was lymphopenic, immune responsiveness was intact, in terms of antibody production, delayed-type hypersensitivity, and in vitro T-cell function. The difference in clinical course in these two siblings is an important observation and demonstrates that the phenotypic expression of ADA deficiency can vary within a family, even in a situation in which protective isolation from infectious pathogens was not a factor in causing the milder course. These observations indicate that expression of disease severity in ADA deficiency may depend to a significant degree on environmental factors and/or on heterogeneity at other genetic loci, which may regulate or modify the expression of the ADA gene or the activity of its product. Furthermore, these observations highlight the importance of recognizing patients with ADA deficiency who present with less severe disease and support the impression that functional immunity in patients with the "late-onset" form of ADA deficiency can deteriorate over time.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Heterogeneity of phenotype in two siblings with adenosine deaminase deficiency. 812 Feb 81

Many applications of somatic gene therapy relate to the immune system. Several forms of inherited immunodeficiencies are candidates for treatment by gene transfer. Adenosine deaminase (ADA) deficiency causes a form of severe combined immunodeficiency. Stable gene transfer and expression of human ADA has now been obtained in hematopoietic stem cells of mice and, more recently, in large animals. The human ADA has also been introduced and expressed in the primitive human hematopoietic progenitor cells that initiate long-term bone marrow culture. Clinical trials of gene therapy for ADA deficiency have been initiated. The initial protocols were aimed at the correction of peripheral blood T lymphocytes, but recent strategies are attempting ADA gene transfer into peripheral blood or bone marrow stem cells. Other immunodeficiencies that may soon be amenable to somatic gene therapy include leukocyte adhesion deficiency and chronic granulomatous disease. Gene therapy may also be applied to the treatment of acquired disorders. In theory, the hematopoietic stem cells of a human immunodeficiency virus (HIV)-infected patient could be genetically modified and used to reconstitute an HIV-resistant hematopoietic system. Various strategies are currently being investigated to achieve this "intracellular immunization" against HIV. These include the transfer of genes encoding recombinant soluble CD4 molecules, suicide genes under the control of HIV-inducible promoter, and anti-HIV ribozymes. Gene transfer could also be used in the treatment of cancer to increase the immune response of the host, to activate prodrugs specifically in tumors, or to protect normal tissues against the toxicities of conventional treatment. Recent progress in all of these applications of gene therapy is reviewed here.
 ...
PMID:Gene therapy of the immune system. 847 64

Adenosine deaminase (ADA; EC 3.5.4.4) deficiency in humans is an autosomal recessive genetic disorder that results in severe combined immunodeficiency disease. ADA-deficient mice generated by targeted gene disruption die perinatally, preventing postnatal analysis of ADA deficiency. We have recently rescued ADA-deficient fetuses from perinatal lethality by expression of an ADA minigene in the placentas of ADA-deficient fetuses, thus generating postnatal mice admissible to analysis of ADA deficiency. The minigene used also directed ADA expression to the forestomach postnatally, producing adult animals that lacked ADA enzymatic activity in all tissues outside the gastrointestinal tract. Mice with limited ADA expression exhibited profound disturbances in purine metabolism, including thymus-specific accumulations of deoxyadenosine and dATP, and inhibition of S-adenosylhomocysteine hydrolase in the thymus, spleen, and, to a lesser extent, the liver. Lymphopenia and mild immunodeficiency were associated with these tissue-specific metabolic disturbances. These mice represent the first genetic animal model for ADA deficiency and provide insight into the tissue-specific requirements of ADA.
 ...
PMID:Metabolic and immunologic consequences of limited adenosine deaminase expression in mice. 866 40

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no. 1 (39 years of age) had combined immunodeficiency. She had frequent infections, lymphopenia, and recurrent hepatitis as a child but did relatively well in her second and third decades. Then she developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease; she died of viral leukoencephalopathy at 40 years of age. Patient no. 2, a healthy 28-year-old man with normal immune function, was identified after his niece died of SCID. Both patients lacked erythrocyte ADA activity but had only modestly elevated deoxyadenosine nucleotides. Both were heteroallelic for missense mutations: patient no. 1, G216R and P126Q (novel); patient no. 2, R101Q and A215T. Three of these mutations eliminated ADA activity, but A215T reduced activity by only 85%. Owing to a single nucleotide change in the middle of exon 7, A215T also appeared to induce exon 7 skipping. ADA deficiency is treatable and should be considered in older patients with unexplained lymphopenia and immune deficiency, who may also manifest autoimmunity or unexplained hepatobiliary disease. Metabolic status and genotype may help in assessing prognosis of more mildly affected patients.
 ...
PMID:Adenosine deaminase deficiency in adults. 910 4

Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis. The ADA gene has been sequenced and the ADA three-dimensional structure solved. The relationship between genotype and phenotype is being analysed, and ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy.
 ...
PMID:Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency. 921 Nov 90

Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency. The mechanisms involved in the lymphoid specificity of the disease are not fully understood due to the inaccessibility of human tissues for detailed analysis and the absence of an adequate animal model for the disease. We report the use of a two-stage genetic engineering strategy to generate ADA-deficient mice that retain many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T and B cell lymphopenia was accompanied by a pronounced accumulation of 2'-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in these organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathogenesis. These mice have provided in vivo information into the metabolic basis for the immune phenotype associated with ADA deficiency.
 ...
PMID:Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency. 947 61

Adenosine deaminase (ADA) deficiency causes lymphopenia and immunodeficiency due to toxic effects of its substrates. Most patients are infants with severe combined immunodeficiency disease (SCID), but others are diagnosed later in childhood (delayed onset) or as adults (late onset); healthy individuals with "partial" ADA deficiency have been identified. More than 50 ADA mutations are known; most patients are heteroallelic, and most alleles are rare. To analyze the relationship of genotype to phenotype, we quantitated the expression of 29 amino acid sequence-altering alleles in the ADA-deleted Escherichia coli strain SO3834. Expressed ADA activity of wild-type and mutant alleles ranged over five orders of magnitude. The 26 disease-associated alleles expressed 0.001%-0.6% of wild-type activity, versus 5%-28% for 3 alleles from "partials." We related these data to the clinical phenotypes and erythrocyte deoxyadenosine nucleotide (dAXP) levels of 52 patients (49 immunodeficient and 3 with partial deficiency) who had 43 genotypes derived from 42 different mutations, including 28 of the expressed alleles. We reduced this complexity to 13 "genotype categories," ranked according to the potential of their constituent alleles to provide ADA activity. Of 31 SCID patients, 28 fell into 3 genotype categories that could express <=0.05% of wild-type ADA activity. Only 2 of 21 patients with delayed, late-onset, or partial phenotypes had one of these "severe" genotypes. Among 37 patients for whom pretreatment metabolic data were available, we found a strong inverse correlation between red-cell dAXP level and total ADA activity expressed by each patient's alleles in SO3834. Our system provides a quantitative framework and ranking system for relating genotype to phenotype.
 ...
PMID:Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. 975 12

Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency characterized by severe T and B cell lymphopenia. ADA-deficient humans also display defective development of gut-associated lymphoid tissues (GALT). They lack lymphoid cells, and the Peyer's patches are without germinal centers. In mice, ADA-deficient fetuses die perinatally due to liver damage, but they also exhibit pathology in the thymus, spleen, and the small intestine. The GI phenotype associated with ADA-deficient humans prompted us to examine the effect of ADA-deficiency on mouse small intestine tissue. The work presented here focuses on understanding the physiological role of ADA in the GI tract, using ADA-deficient mice rescued from perinatal lethality by restoring Ada expression to trophoblast cells. Histologically and immunologically, the GALT was compromised at all sites in ADA-/- mice, with the most dramatic changes seen in the Peyer's patches. Profound disturbances in purine metabolism were detected in all the gastrointestinal tissues. In particular, adenosine and deoxyadenosine, the ADA substrates, increased markedly while the product inosine decreased. The activity of S-adenosylhomocysteine hydrolase decreased throughout the GI tract, indicating a possible disruption of cellular transmethylation and activation of apoptotic pathways. There were also disturbances in the purine metabolic pathway with a decrease in the production of downstream nucleosides hypoxanthine and xanthine.
 ...
PMID:Function of murine adenosine deaminase in the gastrointestinal tract. 1072 Apr 88

Adenosine deaminase (ADA) deficiency results in a combined immunodeficiency brought about by the immunotoxic properties of elevated ADA substrates. Additional non-lymphoid abnormalities are associated with ADA deficiency, however, little is known about how these relate to the metabolic consequences of ADA deficiency. ADA-deficient mice develop a combined immunodeficiency as well as severe pulmonary insufficiency. ADA enzyme therapy was used to examine the relative impact of ADA substrate elevations on these phenotypes. A "low-dose" enzyme therapy protocol prevented the pulmonary phenotype seen in ADA-deficient mice, but did little to improve their immune status. This treatment protocol reduced metabolic disturbances in the circulation and lung, but not in the thymus and spleen. A "high-dose" enzyme therapy protocol resulted in decreased metabolic disturbances in the thymus and spleen and was associated with improvement in immune status. These findings suggest that the pulmonary and immune phenotypes are separable and are related to the severity of metabolic disturbances in these tissues. This model will be useful in examining the efficacy of ADA enzyme therapy and studying the mechanisms underlying the immunodeficiency and pulmonary phenotypes associated with ADA deficiency.
 ...
PMID:The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice. Differential impact on pulmonary and immunologic abnormalities. 1090 69

Adenosine deaminase (ADA) deficiency in humans results in a severe combined immunodeficiency (SCID). This immunodeficiency is associated with severe disturbances in purine metabolism that are thought to mediate lymphotoxicity. The recent generation of ADA-deficient (ADA(-/-)) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from ADA deficiency. We demonstrate severe depletion of T and B lymphocytes and defects in T and B cell development in ADA(-/-) mice. T cell apoptosis was abundant in thymi of ADA(-/-) mice, but no increase in apoptosis was detected in the spleen and lymph nodes of these animals, suggesting that the defect is specific to developing thymocytes. Studies of mature T cells recovered from spleens of ADA(-/-) mice revealed that ADA deficiency is accompanied by TCR activation defects of T cells in vivo. Furthermore, ex vivo experiments on ADA(-/-) T cells demonstrated that elevated adenosine is responsible for this abnormal TCR signaling. These findings suggest that the metabolic disturbances seen in ADA(-/-) mice affect various signaling pathways that regulate thymocyte survival and function. Experiments with thymocytes ex vivo confirmed that ADA deficiency reduces tyrosine phosphorylation of TCR-associated signaling molecules and blocks TCR-triggered calcium increases.
 ...
PMID:Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. 1143 65


<< Previous 1 2 3 4 Next >>