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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

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

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

Mutations in Artemis in both humans and mice result in severe combined immunodeficiency due to a defect in V(D)J recombination. In addition, Artemis mutants are radiosensitive and chromosomally unstable, which has been attributed to a defect in nonhomologous end joining (NHEJ). We show here, however, that Artemis-depleted cell extracts are not defective in NHEJ and that Artemis-deficient cells have normal repair kinetics of double-strand breaks after exposure to ionizing radiation (IR). Artemis is shown, however, to interact with known cell cycle checkpoint proteins and to be a phosphorylation target of the checkpoint kinase ATM or ATR after exposure of cells to IR or UV irradiation, respectively. Consistent with these findings, our results also show that Artemis is required for the maintenance of a normal DNA damage-induced G2/M cell cycle arrest. Artemis does not appear, however, to act either upstream or downstream of checkpoint kinase Chk1 or Chk2. These results define Artemis as having a checkpoint function and suggest that the radiosensitivity and chromosomal instability of Artemis-deficient cells may be due to defects in cell cycle responses after DNA damage.
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PMID:Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. 1545 91

Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs). A defect in Artemis causes human radiosensitive-severe combined immunodeficiency. Cells from Artemis-deficient patients and mice display increased chromosomal instability, but the precise function of this factor in the response to DNA damage remains to be elucidate. In this study, we show that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)- and Nijmegen breakage syndrome 1 (Nbs1)-dependent manner in response to ionizing radiation (IR), and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. The hyperphosphorylation of Artemis is markedly reduced in ATM- and Nbs1-null cells. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in ATM- or Nbs1-deficient cells, respectively. In support of this functional link, hyperphosphorylated Artemis was found to physically associate with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DNA double strand breaks (DSB). Since deficiency of either DNA-Pkcs or ATM leads to defective repair of IR-induced DSB, our finding places Artemis at the signaling crossroads downstream of DNA-PKcs and ATM in IR-induced DSB repair.
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PMID:Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. 1572 59

The Artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced DNA double-strand breaks (DSBs) in an ATM and DNA-PK dependent process. Here, we show that Artemis phosphorylation by ATM and DNA-PK in vitro is primarily attributable to S503, S516 and S645 and demonstrate ATM dependent phosphorylation at serine 645 in vivo. However, analysis of multisite phosphorylation mutants of Artemis demonstrates that Artemis phosphorylation is dispensable for endonuclease activity in vitro and for DSB repair and V(D)J recombination in vivo. Importantly, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) autophosphorylation at the T2609-T2647 cluster, in the presence of Ku and target DNA, is required for Artemis-mediated endonuclease activity. Moreover, autophosphorylated DNA-PKcs stably associates with Ku-bound DNA with large single-stranded overhangs until overhang cleavage by Artemis. We propose that autophosphorylation triggers conformational changes in DNA-PK that enhance Artemis cleavage at single-strand to double-strand DNA junctions. These findings demonstrate that DNA-PK autophosphorylation regulates Artemis access to DNA ends, providing insight into the mechanism of Artemis mediated DNA end processing.
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PMID:DNA-PK autophosphorylation facilitates Artemis endonuclease activity. 1687 98

Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%), combined T- and B-cell immunodeficiencies (11.0%), complement deficiencies (2.4%), and diseases of immune dysregulation (2.3%). Common variable immunodeficiency was the most frequent disorder (20.8%), followed by chronic granulomatous disease, ataxia-telangiectasia, btk deficiency, selective IgA deficiency, and T-B-severe combined immunodeficiency. The frequency of other PID disorders was less than 50 in number (<5%). There is an increasing trend in recognition of more PID in the recent years. Construction of such registry is not only important for its epidemiological aspect but also for its role in increasing the physician's knowledge about such disorders.
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PMID:Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry. 1702 64

Primary immunodeficiency disorders (PID) are a heterogeneous group of disorders, characterized by an unusual increased susceptibility to various infections. In order to study the frequency of PID in Turk ethnic group of northwestern Iran, this study was performed. Fifty-nine PID patients (36 male and 23 female) with a mean age of 5.3 years (median: 3 years; range: <1 to 22 years) were diagnosed in a 5-year period. The estimated occurrence of PID is about 24 per 100,000 live births in this region. Combined T- and B-cell immunodeficiencies were the most common form of PID in this region, including severe combined immunodeficiency (32.2%), followed by ataxia-telangiectasia (22.0%) and common variable immunodeficiency (18.6%). Recurrent infections were found in almost all our patients, particularly in the respiratory and gastrointestinal systems. Fifteen patients died (25.4%) because of recurrent and severe infections. All dead patients belong to the group of combined T- and B-cell immunodeficiencies. Although PID was previously considered as a group of rare disorders, these is an increased trend in recognition of PID. The high incidence of severe combined immunodeficiency and ataxia-telangiectasia could be due to the genetic backgrounds in the Turk ethnic group.
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PMID:Distribution of primary immunodeficiency diseases in the Turk ethnic group, living in the northwestern Iran. 1758 43


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