Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A T cell surface membrane-associated glycoprotein, Tp40 (40,000 mol wt), also designated as CD-7, was not expressed by the T cells of a patient with severe combined immunodeficiency. In addition to this abnormality, T cell proliferative responses to mitogens were defective and the IL-2 receptor expression was deficient on the patient's T lymphocytes. However, his T cells were found to provide help for the differentiation of normal B cells to Ig-secreting cells. Abundant circulating B cells were detected. These B cells proliferated normally in the presence of anti-mu antibodies and B cell growth factors, but did not differentiate into antibody-secreting cells when provided with the help of normal T cells. In addition, his activated B cells did not proliferate to IL-2 even though IL-2 receptors were expressed. A successful allogeneic histocompatible bone marrow transplantation resulting in T cell engraftment corrected both the T and B cell immunodeficiencies. These findings support the hypothesis that the Tp40 deficiency present in this patient is related to a defect of the T cell precursors, and that Tp40 plays important roles not only essential to T cell interactions but also to certain aspects of T-B cell interaction during the early lymphoid development.
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PMID:Defective expression of T cell-associated glycoprotein in severe combined immunodeficiency. 308 78

Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor gamma chain (IL2RG). For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing. Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226. This residue lies in the extracellular domain of the protein in a region not previously recognized to be significantly conserved in the cytokine receptor gene family, 11 amino acids upstream from the highly conserved WSXWS motif. Three additional instances of mutation at another CpG dinucleotide at cDNA 879 produced a premature termination signal in the intracellular domain of IL2RG, resulting in loss of the SH2-homologous intracellular domain known to be essential for signaling from the IL-2 receptor complex. Mutations at these two hotspots constitute > 20% of the X-linked SCID mutations found by our group and a similar proportion of all reported IL2RG mutations.
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PMID:Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency. 766 84

Interleukin-2 (IL-2) has various trophic and neuromodulatory actions in the mammalian central nervous system (CNS). The interleukin-2 receptor alpha (IL-2R alpha) is an accessory subunit of the IL-2 receptor heterotrimer complex which is essential for 'high' affinity IL-2 binding. Although an IL-2R alpha (or IL-2R alpha-like) epitope has been localized in brain by immunohistocytochemistry, it was unknown whether the IL-2R alpha subunit expressed in brain was derived from the same or a different gene than the lymphocyte IL-2R alpha. Therefore, in the present study, the cDNA comprising the full length coding region was cloned and sequenced from saline-perfused forebrain. The brain IL-2R alpha cDNA was found to be 100% homologous with the corresponding lymphocyte IL-2R alpha cDNA sequence. IL-2R alpha mRNA was expressed at very low levels in saline-perfused forebrain of non-challenged BALB/c mice as well as in saline-perfused forebrain from severe combined immunodeficiency (SCID) mice. The present data, demonstrating IL-2R alpha gene expression in both well-perfused normal and SCID mouse forebrain from which no CD3 gamma gene expression was detected by PCR, provides evidence that the IL-2R alpha clones isolated are from resident brain cells and not from blood lymphocytes (e.g. T lymphocytes). Thus, these findings demonstrate that the protein coding sequence of the mouse brain IL-2R alpha is derived from the same gene coding sequence as the lymphocyte IL-2R alpha, and indicate that previously reported differences in the size of their respective mRNA transcripts appear to be due to differences in untranslated regions.
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PMID:Molecular cloning of the coding sequence of an interleukin-2 receptor alpha subunit cDNA in murine brain. 779 14

Parallel genetic analysis of animal and human genetic diseases can facilitate the identification and characterization of the causative gene defects. For example, canine X-linked severe combined immunodeficiency (SCID) is characterized by clinical, pathological, and immunological manifestations similar to the most common form of human SCID. To derive a canine syntenic map including genes that in humans are located in proximal Xq, near human X-linked SCID, poly(TG) polymorphisms were identified at the canine phosphoglycerate kinase (PGK) and choroideremia (CHM) loci. These plus a polymorphic poly(CAG) sequence in exon 1 of the canine androgen receptor gene (AR) were used to genotype members of the colony informative for X-linked SCID. No recombinations among SCIDX1, AR, PGK, or CHM were observed. Fluorescence in situ hybridization localized PGK and CHM to proximal Xq in the dog, in the same chromosomal location occupied by the human genes. Somatic cell hybrid analysis and methylation differences at AR demonstrated that female dogs carrying X-linked SCID have the same lymphocyte-limited skewed X-chromosome inactivation patterns as human carriers. These genetic and phenotypic findings provide evidence that mutations in the same gene, now identified as the gamma chain of the IL-2 receptor, cause canine and human X-linked SCID. This approach is an efficient method for comparative gene mapping and disease identification.
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PMID:Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency. 782 3

X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the gamma chain of the IL-2 receptor (IL-2R gamma). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R gamma gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID.
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PMID:IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. 782 4

Human severe combined immunodeficiency (SCID) includes an X-linked SCID (XSCID) characterized by a complete absence of mature T cells, hypogammaglobulinemia and a normal or elevated number of B cells. XSCID results from mutation in the IL-2 receptor (IL-2R) gamma chain gene, which is thought to be involved in not only IL-2R but also IL-4R and IL-7R mediated signals. To investigate the VDJ recombination and Ig repertoire development in the absence of the IL-2R gamma chain, we intended to study the CDR3 junction in peripheral blood B cells of three XSCID patients. A total of 101 different CDR3 junctions were cloned following polymerase chain reaction amplification of polyclonal peripheral blood lymphocyte DNA. Sequence analysis of CDR3 junctions revealed that the primary antibody repertoire of the Ig H chain gene was assembled in a normal fashion. Among the JH segments, overexpression of JH3 segments was significant in XSCID patients compared with age-matched controls. D segment usage in XSCID was very similar to that in age-matched controls. All of the XSCID JH regions except for two clones were equal to germline JH genes, showing little or no evidence of somatic mutation. The results indicate that the immature JH segment is preferentially utilized and somatic mutation is absent in the CDR3 junction of the Ig H chain gene of XSCID patients.
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PMID:Preferential utilization of the immature JH segment and absence of somatic mutation in the CDR3 junction of the Ig H chain gene in three X-linked severe combined immunodeficiency patients. 786 64

A 4-y-old female with severe combined immunodeficiency disease had normal numbers of T cells in her circulation and normal T-cell subsets. However, her T cells proliferated poorly to mitogens and did not proliferate to antigens or to anti-CD3 MAb. IL-2 receptor expression was normal, but IL-2 synthesis was undetectable. The addition of recombinant IL-2 to a mitogen-stimulated culture resulted in normalization of the proliferative response. Northern blot analysis of total RNA derived from the patient's T cells revealed a weak or absent expression of mRNA coding for IL-2, IL-3, IL-4, and IL-5. In contrast, there were normal amounts of mRNA coding for granulocyte-macrophage colony-stimulating factor. Tumor necrosis factor and IL-6 production were also normal. Nuclear run-on transcriptional assays revealed markedly decreased levels of newly initiated nuclear transcripts coding for IL-2, IL-3, IL-4, and IL-5 and normal levels of granulocyte-macrophage colony-stimulating factor transcripts in the patient relative to control lymphocytes. Gel retardation assays suggest that the NFAT-1 nuclear transcription complex is abnormal in this patient. These results indicate that the patient suffers from a defect that affects the transcription of multiple T-cell lymphokines and suggest that abnormalities affecting the production of T-cell lymphokines may underlie some of the primary immunodeficiency diseases.
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PMID:Severe combined immunodeficiency with selective T-cell cytokine genes. 843 71

JAK3 is a protein tyrosine kinase that specifically associates with the common gamma chain (gammac), a shared subunit of receptors for interleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or gammac presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3-gammac interaction. Despite the key roles of JAK3 and gammac in lymphocytic development and function, the molecular basis of this interaction remains poorly understood. In this study, we have characterized the regions of JAK3 involved in gammac association. By developing a number of chimeric JAK3-JAK2 constructs, we show that the binding specificity to gammac can be conferred to JAK2 by transferring the N-terminal domains of JAK3. Moreover, those JAK3-JAK2 chimeras capable of binding gammac were also capable of reconstituting IL-2 signaling as measured by inducible phosphorylation of the chimeric JAK3-JAK2 protein, JAK1, the IL-2 receptor beta chain, and signal transducer and activator of transcription 5A. Subsequent deletion analyses of JAK3 have identified the N-terminal JH7-6 domains as a minimal region sufficient for gammac association. Furthermore, expression of the mutant containing only the JH7-6 domains effectively competed with full-length JAK3 for binding to gammac. We conclude that the JH7-6 domains of JAK3 are necessary and sufficient for gammac association. These studies offer clues toward a broader understanding of JAK-mediated cytokine signaling and may provide a target for the development of novel therapeutic modalities in immunologically mediated diseases.
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PMID:The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. 919 65

Signaling through the hematopoietic receptors requires activation of receptor-associated Janus (Jak) kinases. For example, Jak1 and Jak3 bind specifically to the IL-2 receptor beta (IL-2Rbeta) and common gamma (gammac) chains, respectively, and initiate biochemical signals critical in controlling immune responses. The region of Jak responsible for receptor interactions, however, is not well characterized. Here we describe a naturally occurring Jak3 mutation from a patient with autosomal severe combined immunodeficiency (SCID), where a single amino acid substitution, Y100C, in Janus homology domain 7 (JH7) prevents kinase-receptor interaction. This mutation also results in a loss of IL-2-induced signaling in a B-cell line derived from this patient. Using mutational analysis we have identified a region of Jak3, including portions of JH6 and JH7, that is sufficient for kinase-receptor contact and show that this segment interacts with the proline-rich Box1 region of the receptor. Furthermore, a Jak3-Jak1 chimera containing only the JH6 and JH7 domains of Jak3 interacts with gammac and can reconstitute IL-2-dependent responses, including receptor phosphorylation and activation of signal transducer and activator of transcription (STAT) 5b. Our results suggest that the N-terminus of Jak kinases is critical for receptor binding, and is therefore likely to determine specificity of Jak kinase-receptor interactions.
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PMID:Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. 1007 26

This review comments on basic and clinical immunology articles that were published in 2005, with a focus on those that appeared in the Journal of Allergy and Clinical Immunology. In the area of basic immunology, mechanisms of the innate immune system and its interaction with the adaptive immune system were described, with special consideration to applications in biodefense strategies. T regulatory cells were further characterized in their role for the control of allergic, autoimmune, and neoplastic disorders. The function of the thymus Hassall's corpuscles was reported to be the generation of T regulatory cells. Flavonoid molecules obtained from medicinal herbs, including astilbin and epigallocatechin gallate, were discovered to have immunomodulatory properties. Advances in clinical immunology resulted from efforts to develop a newborn screening test for severe combined immunodeficiency and the elucidation of the crystal structure of the IL-2 receptor gamma chain. Mutations in the membrane receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor were found in patients with common variable immunodeficiency. New therapeutic options are described, such as the use of infliximab for granulomas and GM-CSF for chronic ulcers in patients with common variable immunodeficiency. The importance of mucosal immunity in acute HIV infection is cited, as is the role of CD8+ T-cell activation in HIV disease progression in children.
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PMID:Advances in basic and clinical immunology. 1689 Jul 76


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