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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Yesterday's immunodeficiencies emphasized the clinical and familial associations of the syndromes and date from the 1920s (ataxia-telangiectasia, chronic mucocutaneous candidiasis), the 1930s (Wiskott-Aldrich syndrome), skipping the 1940s, but blossoming in the 15-y period from 1950 to 1965. In this period, primary immunodeficiencies affecting all the major limbs of the immune system were first described (1950: severe combined immunodeficiency; 1952: X-linked agammaglobulinemia; 1957: chronic granulomatous disease; 1965: C2 deficiency). Today's immunodeficiencies, as detailed in Stiehm's Immunologic Disorders in Infants and Children (Edition 1, 1973; Edition 2, 1980; and Edition 3, 1989) emphasize the immunologic and genetic aspects of immunodeficiency. These increased from 43 syndromes in the 1973 edition (34 primary, nine secondary) to 94 syndromes in the 1989 edition (66 primary, 28 secondary). This means that about two primary and one secondary immunodeficiencies have been uncovered annually. Tomorrow's immunodeficiencies, to be covered in Edition 4, will include new clinical and immunologic observations and molecular and biochemical studies that characterize some unique immunodeficiencies. These include the following six groups of defects: 1) neutropenic syndromes with hypogammaglobulinemia, including the WHIM syndrome; 2) phenotypic genetic syndromes with immunodeficiency including Bloom's syndrome and Schimke's immuno-osseous dysplasia; 3) natural killer cell defects associated with a) other primary immunodeficiencies, b) other nonimmunologic illness, and c) primary natural killer defects; 4) T-cell membrane defects; 5) IL defects; and 6) miscellaneous phagocytic illnesses including periodontitis and the asplenia syndrome.
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PMID:New and old immunodeficiencies. 843 70

This report reviews the clinicopathologic, immunologic, and molecular biological features of the congenital immunodeficiencies and their associated lymphoproliferative disorders (LPD) including cases presented at the Third Slide Workshop of the Society of Hematopathology, held in Duarte California, in October 1995. The congenital immunodeficiencies most commonly associated with LPD include Wiskott-Aldrich syndrome (WAS), common variable immunodeficiency (CVID), ataxia telangiectasia (AT), severe combined immunodeficiency (SCID), X-linked lymphoproliferative disorder (XLP), and hyper-IgM syndrome. Each form of immunodeficiency disorder is associated with its own risk factors, which affect the pattern of LPD encountered. AT is characterized by a defect in DNA repair. The lymphomas and leukemias in this syndrome resemble those seen in sporadic LPD, but tend to occur at an earlier age. Epstein-Barr virus (EBV) plays an important role in the LPD associated with many immunodeficiency disorders including WAS, CVID, SCID, and XLP. One should use a combination of clinical, histopathologic and molecular data in the evaluation of lymphoproliferative lesions in this group of patients. Immunophenotypic and molecular evidence of clonality does not necessarily imply an aggressive clinical course, an exemplified by some LPD in WAS, which may show evidence of monoclonality in serum and lymph nodes, and yet still behave in a benign or indolent fashion.
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PMID:Lymphoproliferative disorders associated with congenital immunodeficiencies. 904 8

Severe combined immunodeficiency (SCID) mice are defective in their ability to rearrange their variable (V), diversity (D) and joining (J) genetic elements to generate functional immunoglobulin (Ig) and T-cell receptor (TCR) molecules; as a result, they lack mature B and T cells. These mice are highly sensitive to ionizing radiation, suggesting that the product of the scid gene plays a critical role in both V(D)J recombination and DNA double-strand break repair. Recent studies suggest that the SCID defect lies in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PK; refs 6-8), a nuclear protein made up of the Ku 70 and Ku 86 subunits as well as the large catalytic subunit, DNA-PKcs. Other reports have implied that the SCID phenotype correlates with nonsense mutations at the extreme 3' end of Prkdc, the DNA-PKcs gene. The identity of the gene remains in doubt, however, because the consequences of genetic inactivation of Prkdc have not been determined. This study shows that complete inactivation of Prkdc in a novel insertional mouse mutant recapitulates the SCID phenotype and that Prkdc and scid are alleic. Significantly, DNA-PKcs null mice demonstrate complete penetrance of thymic lymphoblastic lymphomas, strongly suggesting that Prkdc functions in mice as a T-cell tumour suppressor and, by virtue of its association with DNA repair and recombination, belongs to the 'caretaker' class of tumour-suppressor genes that includes ATM, BRCA1 and BRCA2 (ref. 15).
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PMID:DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. 939 56

Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.
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PMID:Positional cloning of the gene for Nijmegen breakage syndrome. 962 Jul 77

Severe combined immunodeficiency (scid) mice are deficient in the enzyme DNA-PK (DNA-dependent protein kinase) as a result of the mutation in the gene encoding the catalytic subunit (DNA-PKcs) of this enzyme. DNA-PKcs is a member of the phosphatidylinositol 3-kinase superfamily, which includes the human protein ATM (ataxia telangiectasia mutated) and the yeast protein Tel1. Using Q-FISH (quantitative fluorescence in situ hybridization), we show here that scid mice from four different genetic backgrounds have, on average, 1.5-2 times longer telomeres than those of corresponding wild-type mice. Our results point to the possibility that DNA-PKcs may, directly or indirectly, be involved in telomere length regulation in mammalian cells.
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PMID:Elongated telomeres in scid mice. 1005 9

Expression of the cyclin kinase inhibitor, p21, is regulated both transcriptionally and posttranscriptionally by the ubiquitin-proteasome degradation pathway. Recently, we reported that DNA damage is required for efficient p21 expression by demonstrating that enhanced p21 mRNA expression induced by DNA damage results in increased p21 protein, but enhanced p21 mRNA without DNA damage does not. In addition, we demonstrated that DNA damage suppressed the ubiquitination of p21. In this study, we analyze the link between p21 stabilization and DNA damage. Enhanced p21 protein expression in ML-1 cells resulting from 15 Gy gamma-irradiation was diminished by Wortmannin or LY294002 pretreatment of cells. However, the levels of p21 mRNA were not affected by inhibitor pretreatment. Wortmannin or LY294002 pretreatment reduces p53 expression after gamma-irradiation to a lesser degree than that of p21. In addition, we examined the involvement of DNA-PK, whose activity is inhibited by Wortmannin or LY294002, in p21 stabilization using the SCID fibroblast cell line and a DNA-PK targeting ML-1 cell line. Accumulation of p21 protein by gamma-irradiation was similar to that of DNA-PK intact cells and was reduced by Wortmannin or LY294002 pretreatment. Involvement of another DNA damage detecting enzyme, the ATM gene product, whose activity is also inhibited by Wortmannin or LY294002, was evaluated. ATM deficient cells induced p21 after gamma-irradiation, gamma-irradiation-induced p21 protein was diminished by pretreatment of cells with Wortmannin or LY294002. We conclude that the p21 stabilization mechanism functions after gamma-irradiation, was sensitive to Wortmannin or LY294002, and required neither DNA-PK nor ATM gene product for activity.
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PMID:Phosphatidylinositol 3-kinase inhibitors, Wortmannin or LY294002, inhibited accumulation of p21 protein after gamma-irradiation by stabilization of the protein. 1077 Oct 89

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
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PMID:Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. 1239

Epidemiological studies have shown wide geographical and racial variation in the prevalence and patterns of immunodeficiency disorders. To determine the frequency of primary immunodeficiencies (PID) in Iran, the Iranian Primary Immunodeficiency Registry (IPIDR) was organized in 1999. We extracted the patient's data, by using a uniform questionnaire from their hospital records. The diagnosis of patients was based on WHO criteria. By now, 440 patients with PID, who were observed during a period of 20 years, have been registered in our registry. Among these patients, the following frequencies were found: predominantly antibody deficiency in 45.9% of patients (n = 202), phagocytic disorders in 29.09% (n = 128), T-cell disorders in 24.31% (n = 107), and complement deficiencies in 0.68% (n = 3). Common variable immunodeficiency was the most frequent disorder (n = 98), followed by chronic granulomatous disease (n = 86), ataxia telangiectasia (n = 48), x-linked agammaglobulinemia (n = 45), selective IgA deficiency (n = 42), combined immunodeficiency (n = 15), and severe combined immunodeficiency (n = 14). This study revealed that antibody deficiencies is the most frequently diagnosed primary immunodeficiency disorder in our patients, which is similar to that observed in other registries. A comparative study shows some differences between our results and other registries.
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PMID:Primary immunodeficiency in Iran: first report of the National Registry of PID in Children and Adults. 1246 37

There are various types of radiation in space including high energy particles. It is, therefore, becoming to be important to study the low dose and low dose-rate effects in space radiation biology. Radiation adaptive response (RAR) for cell growth and its mechanism were examined using cultured glial cells. The cells from hippocampus of Wistar rats were irradiated with a low dose (0.1 Gy) of X-rays and 3 h after with a high dose (2 Gy). Decrease in the rate of cell growth with 2 Gy was suppressed by the 0.1 Gy preirradiation, when cells were counted 2 days after irradiation. The inhibitors of protein kinase C (PKC) and DNA-dependent protein kinase (DNAPK) or phosphatidylinositol 3-kinase (PI3K) suppressed RAR. The treatment with the activators of PKC instead of 0.1 Gy-preirradiation also caused adaptive response to 2 Gy-irradiation. Moreover, glial cells cultured from severe combined immunodeficiency (scid) mice, which have lost DNAPK activity, and AT-2KY cells, fibroblasts of an ataxia-telangiectasia (AT) patient, showed no RAR. These results indicated that PKC, ATtM, DNAPK and/or PI3K were involved in RAR for growth of cultured glial cells. Proteomics [correction of preteomics] analysis of these cells exposed to low dose irradiation in now underway.
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PMID:Radiation adaptive response of glial cells. 1269 18

The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H , CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54-/-). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs-/-/-) failed to exhibit wortmannin radiosensitization. On the other hand, SCID mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM-/-) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ).
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PMID:DNA-PK: the major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway. 1367 45


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