Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy.
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PMID:Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene. 892 Aug 91

Gene modification of hematopoietic stem cells (HSC) with antigen-specific, chimeric, or "universal" immune receptors (URs) is a novel but untested form of targeted immunotherapy. A human immunodeficiency virus (HIV) envelope-specific UR consisting of the extracellular domain of human CD4 linked to the zeta chain of the T cell receptor (CD4 zeta) was introduced ex vivo into murine HSC by retroviral transduction. After transplantation into immunodeficient SCID mice, sustained high level expression of CD4 zeta was observed in circulating myeloid and natural killer cells. CD4 zeta-transplanted mice were protected from challenge with a lethal dose of a disseminated human leukemia expressing HIV envelope. These results demonstrate the ability of chimeric receptors bearing zeta-signaling domains to activate non-T cell effector populations in vivo and thereby mediate systemic immunity.
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PMID:Systemic T cell-independent tumor immunity after transplantation of universal receptor-modified bone marrow into SCID mice. 897 81

Late-stage HIV-1 disease in humans has been associated with perturbations of the T cell receptor (TCR) Vbeta repertoire. It is not known if the observed loss of certain Vbeta families is attributable directly to HIV-1 infection or whether this is a consequence of multiple opportunistic infections. Putative HIV-1-associated superantigens have been postulated to be the cause of the perturbed TCR Vbeta repertoire and the subsequent CD4+ T cell depletion in HIV-1-infected humans. In this study, we examined the human TCR Vbeta repertoire in SCID-hu mice, housed in a pathogen-free environment and infected with a molecularly cloned virus strain, to ascertain directly the effect of HIV-1 on the human TCR Vbeta repertoire in the absence of other infectious agents. We demonstrate that mock-infected human thymus/liver (Thy/Liv) implants in SCID-hu mice have complete TCR Vbeta repertoires, reflective of a normal human thymus. However, HIV-1-infected implants in SCID-hu mice had depleted TCR Vbeta repertoires, corresponding with thymocyte depletion. These results indicate that HIV-1-specific mechanisms are the cause of the TCR Vbeta repertoire depletion in infected implants. However, these thymocyte depletions were not restricted to specific TCR Vbeta subsets. These results are not consistent with the hypothesis that HIV-1 acts as a superantigen in vivo. The disruption of the TCR Vbeta repertoire in the human Thy/Liv implants of the SCID-hu mice suggests that HIV-1 infection may be influencing T cell development in the thymus, contributing to both the overall CD4+ T cell depletion in AIDS and limited TCR repertoire diversity.
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PMID:Loss of T cell receptor Vbeta repertoires in HIV type 1-infected SCID-hu mice. 900 98

Jak3 mediates growth signals through cytokine receptors such as interleukin-2 (IL-2), IL-4, and IL-7, and its deficiency results in autosomal recessive SCID in mice and humans. In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age. However, we found that self-reactive T cells were not deleted in the thymus and the peripheral tissues in Jak3-deficient mice. All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation. From the analysis of TCR-transgenic Jak3-deficient mice, only self-reactive T cells appeared to be in the activated state and anergic. These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.
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PMID:Crucial role of Jak3 in negative selection of self-reactive T cells. 901 83

Although expression of the Jak3 tyrosine kinase in T lymphocytes has been thought to be restricted to mature, activated cells, mutations of Jak3 can lead to the development of a human severe combined immunodeficiency (SCID) characterized by an absence of peripheral T lymphocytes. We therefore examined in detail the expression of Jak3 throughout human T cell differentiation and show that Jak3 is in fact present throughout the entire developmental process, with high levels expressed in thymocytes. Jak3 is highly expressed in double negative (CD4- CD8-) cells, one of the earliest stages of thymocyte differentiation, and can be activated via the IL-7 receptor. IL-7 is known to stimulate thymocyte proliferation and initiate re-arrangement of the T cell receptor (TCR) beta gene, suggesting that the failure of mutated Jak3 proteins to transduce this signal may be responsible for failures in T cell development. While Jak3 SCID patients possess mature peripheral B cells, we demonstrate that the Jak3 tyrosine kinase is also expressed in human pre-B cells and can be activated by the pre-B cell growth factor IL-7.
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PMID:Jak3 activation in human lymphocyte precursor cells. 918 6

Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, "signaling" mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)-triggered effector functions of T lymphocytes including the TCR-triggered FasL mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado-exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The "memory" of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A2A adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A2A receptors are identified as the predominantly expressed subtype of Gs-coupled Ado receptors in T cells. The demonstration of cross-talk between the A2A receptors and TCR in both directions support the possible role of A2A receptors in mechanisms of extAdo-mediated immunosuppression in vivo under adenosine deaminase deficiency and hypoxic conditions in, e.g., solid tumors.
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PMID:Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. 932 20

One of the most common human immunodeficiencies is an X-linked condition arising from mutations of the gamma subunit of the interleukin-2 receptor (IL-2Rgamma). The IL-2Rgamma protein is one chain of the heterotrimeric (alpha, beta, gamma) IL-2 receptor, but also participates in the formation of the IL-4, 7, 9, and 15 receptor complexes. The diagnosis of X-linked SCID is usually relatively simple due to the distinctive immunological presentation; IL-2Rgamma-deficient patients typically lacking mature T lymphocytes (T-B+). However, it is becoming clear that this merely represents one extreme of a potential range of clinical presentations. We describe here a novel mutation of the human IL-2Rgamma chain (R222C) resulting in an unusual immunological phenotype. Although clinically immunodeficient, this patient has normal numbers of peripheral T and B cells, responds normally to mitogenic stimuli, and unusually, has a normal thymus gland. This IL-2Rgamma mutation is distinctive in that the protein is sufficiently stable to be expressed at the cell surface. While the T cell receptor repertoire appears complete, suggesting normal T cell differentiation occurs, patient T cells demonstrate a reduced ability to bind IL-2 and this appears sufficient to cause a deficiency in their ability to participate in antigenic responses. Early clinical recognition of this phenotype is critical as a delay in diagnosis may result in a fatal infection.
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PMID:An interleukin-2 receptor gamma chain mutation with normal thymus morphology. 939 50

Rotavirus infection was studied in adult nude mice (BALB/c background), alpha beta or gamma delta and alpha beta/gamma delta T cell receptor (TCR) knockout (-/-) mice (C57BL/6 and C57BL/6 x 129 backgrounds), and SCID mice (C57BL/6 background). The gamma delta TCR -/- mice cleared infection just like control mice. All of the nude mice, alpha beta, and alpha beta/gamma delta TCR -/- mice cleared primary rotavirus infection, with a short delay, compared to immunocompetent control mice and developed a rotavirus-specific intestinal IgA measured by ELISA. Elispot analysis with spleen and lamina propia cells showed that the virus-specific intestinal IgA response in immunocompetent C57BL/6 mice was similar to the gamma delta TCR -/- mice and 7- to 60-fold higher than in the alpha beta TCR -/- and alpha beta/gamma delta TCR -/- mice. Likewise, the response of nude +/- mice was 20 times greater than that of nude -/- littermates. While the intestinal IgA antibodies of C57BL/6 mice, gamma delta TCR -/- mice, and nude +/- mice recognized insect cells infected with recombinant baculovirus expressing rotavirus VP6 and VP4 proteins, those of the alpha beta TCR -/-, alpha beta/gamma delta TCR -/-, and nude -/- mice recognized only VP6. Immunocompetent C57BL/6 mice depleted of CD4+ T cell developed similar levels of rotavirus-specific intestinal IgA as the alpha beta TCR -/- mice, suggesting that this T cell-independent IgA response is present in normal mice. In contrast to previously published results with BALB/c SCID and RAG 2 -/- (C57BL/6 x 129 background) mice, all of which become chronically infected with murine rotavirus, 40% of the C57BL/6 SCID mice cleared primary rotavirus infection. These results suggest that both a T cell-independent antibody response and innate mechanisms can contribute to immunity to murine rotavirus and show that gamma delta T cells are not necessary for efficient clearance of primary rotavirus infection in mice.
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PMID:Immunity to rotavirus in T cell deficient mice. 940 May 90

T cell receptor (TCR) genes are rearranged and expressed in an ordered manner during T cell development. The basic mechanism regulating this stepwise DNA alteration is poorly understood. To address this issue, we explored the presence of a stage-specific element for germ-line transcription of the TCR alpha gene which is closely associated with gene rearrangement. First, germ-line transcription of the TCR alpha gene including the first segment of the J alpha locus, J alpha49, was delayed compared to that of the TCR beta gene in both normal and TCR-transgenic (Tg) mice. Furthermore, expression of this transcript could be induced by CD3epsilon-mediated signals in recombination-activating gene (RAG)-2-deficient mice. In TCR-Tg mice, the endogenous J alpha49 germ-line transcript could not yet be observed at the CD25+ double-negative (DN) stage when the TCR alpha transgene was expressed. Of immature T cell hybridomas derived from either scid thymocytes (CD25+ DN) or immature CD8-single positive (ISP) thymocytes, only the latter hybridoma expressed the J alpha49 germ-line transcript. These data indicate that the J alpha49 germ-line transcription occurs only at a specific developmental stage. Second, to determine which elements may be regulating stage specificity, we performed transient transfection analysis with a reporter gene and demonstrated that the upstream region of the J alpha49 locus possesses promoter activity in correlation with germ-line transcription in ISP-derived but not in SCID-derived hybridomas. These results indicate that the expression of TCR alpha germ-line transcripts is regulated in a stage-specific manner by a cis-element located within the J alpha locus.
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PMID:Evidence of stage-specific element for germ-line transcription of the TCR alpha gene located upstream of J alpha49 locus. 956 77

To evaluate the long-term reconstitution of the T cell immune repertoire in recipients of an allogeneic Bone Marrow Transplantation (allo-BMT), we have analyzed the T cell receptor (TCR) repertoire in the periphery and the T cell response against tetanus toxoid in two T- B+ Severe Combined Immunodeficiency Disease (SCID) patients more than 11 years after HLA haplo-identical allo-BMT. Our studies demonstrate that in the periphery of allo-BMT recipients, on the basis of TCR V-gene segment usage, the T cell immune repertoire long after allo-BMT is diverse, as is that of the donor. However, when donor and allo-BMT recipient were compared, differences were noted in the TCR Complementarity Determining Region 3 (CDR3) size distributions and in the T cell response against tetanus toxoid. In particular, the tetanus toxoid specific T cell clones differed in their use of HLA restriction elements, and expressed different T cell receptors. Moreover, we have uncovered donor-type tetanus toxoid specific T cell clones which were established from allo-BMT recipient derived peripheral blood lymphocytes and were found to be restricted by the non-shared recipient allele. This observation suggests a role for recipient-mediated T cell selection processes, in the thymus or at extra-thymic sites.
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PMID:Long-term T cell immune reconstitution in 2 SCID patients after BMT. 956 98


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