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

Bloom's syndrome is a genetic disorder characterized by increased incidence of cancer and an immunodeficiency of unknown origin. The BLM gene mutated in Bloom's syndrome encodes a DNA helicase involved in the maintenance of genomic integrity. To explore the role of BLM in the immune system, we ablated murine Blm in the T-cell lineage. In the absence of Blm, thymocytes were severely reduced in numbers and displayed a developmental block at the beta-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) beta genes normally yet failed to survive and proliferate in response to pre-TCR signaling. Furthermore, peripheral T cells were reduced in numbers, manifested defective homeostatic and TCR-induced proliferation, and produced extensive chromosomal damage. Finally, CD4(+) and CD8(+) T-cell responses were impaired upon antigen challenge. Thus, by ensuring genomic stability, Blm serves a vital role for development, maintenance, and function of T lymphocytes, suggesting a basis for the immune deficiency in Bloom's syndrome.
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PMID:The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage. 1721 Jun 42

Human immunodeficiency virus (HIV)-induced immunodeficiency and immune-system aging share some analogies. Since Werner (WRN) and Bloom (BLM) helicases are crucial in cell repair and aging, their peripheral blood mononuclear cells (PBMC) mRNA levels were compared in HIV-1 infected patients and in normal donors. The mean levels of WRN mRNA were 3.7-fold higher in PBMCs from HIV-1 infected individuals in comparison to healthy donors, whereas BLM mRNA mean levels were slightly higher, although not significantly. WRN increase was positively correlated to CD4 and CD8 T-cell numbers, and also the percentage of naive T lymphocytes, and was observed also in T-cell subsets. Interestingly, a general trend toward increased WRN mRNA levels in individuals with lower viral load was observed, without association with patient age, time of seroconversion, and on/off antiretroviral therapy regimen. On the whole, this study shows that WRN and BLM are differentially modulated in HIV infection, as WRN--but not BLM--is significantly increased, suggesting that mechanisms different from defect or loss of helicase function, observed in WRN and BLM syndromes, may be at the basis of T-cell aging in HIV infection.
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PMID:Differential expression of Werner and Bloom syndrome genes in the peripheral blood of HIV-1 infected patients. 1732 98

Bloom syndrome is an autosomal recessive disorder characterized by proportionate short stature, photosensitivity, immunodeficiency, hypogonadism and a tendency to develop various malignancies. The greatly increased frequency of sister chromatid exchanges (reciprocal exchange of homologous segments between the two sister chromatids of a chromosome) is regarded as pathognomonic for BS. We describe an 18-year old girl who presented with short stature. She was diagnosed with BS based on an extremely increased frequency of sister chromatid exchanges. Ophthalmological examination revealed mild lens opacities bilaterally, which, to our knowledge, has not been previously reported to be associated with BS.
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PMID:Lens opacities in Bloom syndrome: case report and review of the literature. 1789 17

A number of immunodeficiency states--both inherited (such as agammaglobulinaemia, Bloom's syndrome, hereditary telangiectasia) and acquired (e.g. immunosuppressive therapy) have been associated with varieties of cancers. HIV induces more profound immunodeficiency state and it should not be difficult to imaging why cancer diagnosis is made in over 40% of HIV infected patients. Impairment of normal function of natural killer cells as a result of lack of helper signals from CD4+ T-lymphocytes may be a major mechanism of increased susceptibility to cancer development in HIV infected patients. Although many neoplastic diseases could occur at a frequency not higher than would be expected by chance alone, the biological behaviour of such malignancies tend to be more aggressive. Three neoplastic diseases are associated so commonly with HIV infection that each of them has become recognized as an AIDS defining illness. These are Kaposi's Sarcoma (KS), Non-Hodgkin's Lymphoma (NHL) and Cervical Carcinoma. Both KS and NHL were recognized as AIDS associated cancers from the onset of the epidemic in 1981 but carcinoma of the cervix became AIDS defining in 1993. The epidemiology, aetiopathogenesis, clinical manifestation, diagnostic tools and modalities of therapeutic intervention for KS and NHL form the subject of this review.
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PMID:AIDS-associated malignancies. 1805 Jul 76

Patients with Bloom syndrome (BS) show an immunodeficiency, an enhanced sister chromatid exchanges (SCEs), a strong genetic instability and an increased predisposition to all. In order to investigate the differential expression of BLM protein in hematopoietic tumor cell strains and study the effects of BLM gene on ultraviolet (UV)-or hydroxyurea (HU)-induced apoptosis, Western blot was used to detect the expression of BLM protein in normal human bone marrow mononuclear cells and 4 kinds of hematopoietic tumor cell strains. The 4 kinds of hematopoietic tumor cells were exposed to UV light with a germicidal UV lamp or treated with 2 mmol/L hydroxyurea and the apoptotic rate was detected by using AnnexinV-FITC. The results showed that these tumor cells expressed BLM protein higher than the normal human bone marrow mononuclear cells (P<0.01). In the 4 hematopoietic tumor cells, BLM protein was all specially cleaved in response to UV-or HU-induced apoptosis. The increase of BLM protein expression may play an important role in the development of these tumors, and BLM proteolysis is likely to be a general feature of the apoptotic response.
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PMID:Protein expression of BLM gene and its apoptosis sensitivity in hematopoietic tumor cell strains. 1827 55

Flap endonuclease-1 (FEN1) is a structure specific endonuclease. The natural substrates of FEN1 are 5'-flap structures formed by three DNA chains one of them has unannealed flapped 5'-end (flap). Flap structures are the intermediates of different processes of DNA metabolism, such as DNA recombination, Okazaki fragment maturation during replication of lagging strand, as well as strand displacement DNA synthesis in base excision repair. FEN1 also possesses 5'-exonuclease activity and newly discovered gap endonuclease activity. FEN1 is known to interact physically and functionally with a number of DNA replication and repair proteins such as the proliferating cell nuclear antigen, helicase/nuclease Dna2, WRN and BLM proteins, replication protein A, apurinic/apyrimidinic endonuclease 1, DNA polymerase beta, poly(ADP-riboso) polymerase 1, high mobility group protein 1, integrase of human immunodeficiency virus, transcription coactivator p300, chromatin proteins, cyclin-dependent kinases (Cdk1, Cdk2, Cyclin A). FEN1 activity is significant for maintaining the integrity of repeat sequences in genome. Recent data suppose the correlation between the abnormality of hFEN1 activity and arising/progression of neurodegenerative and cancer diseases. FEN1 has the dramatic effect on cell growth and development thereby attracting the interest to this enzyme.
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PMID:[Flap endonuclease-1 and its role in the processes of DNA metabolism in eucaryotic cells]. 1870 99

The RecQ family helicase BLM is critically involved in the maintenance of genomic stability, and BLM mutation causes the heritable disorder Bloom's syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum Ab titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naive mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG Ab responses upon immunization were poor and mutant B cells exhibited a generally reduced Ab class switch capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift toward microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts were identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.
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PMID:Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage. 1910 66

Mutations in the BLM gene cause human Bloom syndrome (BS), an autosomal recessive disorder of growth retardation, immunodeficiency and cancer predisposition. Homozygous null Blm(m3/m3) mice are cancer prone with a 5-fold increased risk of cancer compared with Blm(m3/+) and Blm(+/+) mice. Irradiation of Blm(m3/m3) mice increased the risk to 28-fold. Tumors occurred mainly in the hematopoietic system and were similar to those in BS based on detailed histologic and immunohistochemical analyses. Irradiated Blm-deficient mice thus provide a novel model for understanding accelerated malignancies in BS and a new platform for investigating the molecular basis for a wide range of hematopoietic neoplasms.
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PMID:Irradiated Blm-deficient mice are a highly tumor prone model for analysis of a broad spectrum of hematologic malignancies. 1970 44

Bloom syndrome (congenital telangiectatic erythema) is a rare autosomal recessive disorder characterized by telangiectasias and photosensitivity, growth deficiency of prenatal onset, variable degrees of immunodeficiency, and increased susceptibility to neoplasms of many sites and types. We are reporting Bloom syndrome in two brothers from Kashmir (India), 8 and 6 years of age, who presented with erythematous rashes on the face, photosensitivity, and growth retardation.
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PMID:Bloom syndrome in two siblings. 2053 70

All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the heteromeric RTR complex consists of RMI1, RMI2, the Bloom's syndrome gene product (BLM), and topoisomerase 3A (TOP3A) proteins. Here, we describe the identification and characterization of two deleterious mutations in the zebrafish top3a gene that reveal an unexpected tissue-specific requirement of top3a function in developing thymocytes. Deficiency in top3a activates a p53-dependent check-point but does not affect VDJ recombination. Our results suggest that TOP3A could be a candidate gene involved in human primary immunodeficiency syndromes.
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PMID:Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha. 2062 52


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