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)

T lymphocytes cultured from a patient (T.D.) with adenosine deaminase (ADA) deficiency expressed ADA activity in the normal range, inconsistent with her severe immunodeficiency, metabolic abnormalities, and with the absence of ADA activity in her B lymphocytes and other nucleated hematopoietic cells. ADA from T.D. T cells had normal Km, heat stability, and sensitivity to ADA inhibitors. Examination of HLA phenotype and polymorphic DNA loci indicated that T.D. was neither chimeric nor a genetic mosaic. Amplified and subcloned ADA cDNA from ADA+ T.D. T cells was shown by allele-specific oligonucleotide hybridization to possess the same mutations (Arg101----Trp, Arg211----His) previously found in the ADA-T.D. B cell line GM 2606 (Akeson, A. L., D. A. Wiginton, M. R. Dusing, J. C. States, and J. J. Hutton. 1988. J. Biol. Chem. 263:16291-16296). Our findings suggest that one of these mutant alleles can be expressed selectively in IL-2-dependent T cells as stable, active enzyme. Cultured T cells from other patients with the Arg211----His mutation did not express significant ADA activity, while some B cell lines from a patient with an Arg101----Gln mutation have been found to express normal ADA activity. We speculate that Arg101 may be at a site that determines degradation of ADA by a protease that is under negative control by IL-2 in T cells, and is variably expressed in B cells. Il-2 might increase ADA expression in T cells of patients who possess mutations of Arg101.
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PMID:Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency. 197 54

We have investigated the effects of graft-versus-host disease on T cell differentiation in the murine thymus. We previously reported that GVH-induced thymic dysplasia results in a T cell immunodeficiency associated with a lack of IL-2 production. This deficiency in IL-2 production may be the result of a reduction in the number of L3T4+Lyt-2- IL-2-producing cells or of a functional defect in this population. To test these two alternatives, flow cytometry analysis of L3T4 and Lyt-2 antigen expression on thymocytes along with immunofluorescence microscopy were employed to assess T cell phenotypes in thymuses of GVH mice. GVH reactions were induced by injecting 40 x 10(6) C57BL/6 (B6) or A strain lymphoid cells into C57BL/6xAF1 (B6AF1) mice. Thymocyte populations were quantitated on different days after GVH induction. In the normal thymus, the ratio of L3T4/Lyt-2 single positive cells was greater than 2:1. In contrast, such a ratio was less than 1:1 in the atrophic GVH thymus, owing to a selective reduction in the number of L3T4+Lyt-2- cells. Following cortisone treatment the ratio of L3T4/Lyt-2 single positive thymocytes in normal F1 mice was approximately 3:1, whereas in GVH animals this ratio was reversed (1:2). This reversal was due to a selective reduction in the absolute numbers of L3T4+Lyt-2- cells. In adrenalectomized GVH animals, thymic cortical atrophy was prevented and normal ratios of L3T4/Lyt-2 single positive cells were observed. However, when these animals were treated with cortisone, the L3+T4/Lyt-2- population was more sensitive than was the L3T4- Lyt2+ population, thereby resulting in a 1:2 L3T4/Lyt-2 ratio. These results demonstrate that single positive L3T4 cells are present in the murine GVH thymus, yet they have not acquired cortisone resistance, a trait normally attributed to this mature thymic subset. It appears that the GVH dysplastic thymus can support the differentiation of L3T4+Lyt-2- cells--however, such a thymus is unable to confer cortisone resistance upon this population. Consequently, these cells appear to be eliminated when exposed to corticosteroids in peripheral lymphoid tissue.
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PMID:T cell subsets in the thymus of graft-versus-host immunosuppressed mice. Sensitivity of the L3T4+Lyt-2- subset to cortisone. 198 97

We have used limiting dilution culture methods to determine the frequency of mitogen-responsive T cells in peripheral blood of patients after bone marrow autotransplantation, and have compared their responsiveness to that of allotransplant recipients and normal controls. Autotransplant patients were found to have low responder cell frequencies in tests for lymphokine-secreting helper function, and for IL-2 dependent proliferator and cytotoxic function. Multiple regression analysis showed that function was lower in autotransplant patients than in allorecipients, and lower in male patients for all three functional assays. Patients with clinically significant infection tended to have lower proliferative function in both transplant groups and lower cytotoxic function in the allotransplant population. Graft-versus-host disease was associated with lower T-cell function, but was present only in the allotransplant group; therefore, it cannot account for the even lower levels of function observed in the autotransplant population. Because we observe deficits in T-cell regeneration in autotransplant recipients that are even more severe than in allorecipients, we postulate that cellular immunodeficiency after bone marrow transplantation may reflect limitations in thymic-dependent repopulation rather than an effect of genetic disparity between host and donor (eg, clinical or subclinical graft-versus-host).
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PMID:Clonal analysis of T-cell deficiencies in autotransplant recipients. 201 8

7,8-Disubstituted guanine ribonucleosides represent a class of B lymphocyte agonists that utilize a protein kinase C-independent signaling pathway. These compounds provide an alternate T helper signal for B cells and enhance antigen-specific humoral responses in the murine model and in an IL-2-dependent human model in vitro. They effectively restore high level immune responses in a variety of murine models of immunodeficiency both in vivo and in vitro. In this study we examined the potential of these compounds to improve antibody responses generated by cultured cells from patients with common variable immunodeficiency (CVI). The inability to mount normal humoral responses to antigen was confirmed in nine patients with diagnosed CVI (CVI: 37 +/- 16, normal 653 +/- 116 plaque-forming cells (PFC)/culture; P less than 0.001). In cultured lymphocytes from eight of the nine patients studied, a normal level or greater responses to nominal antigen could be elicited by antigen in the presence of the immunostimulatory nucleoside 7-methyl-8-oxoguanosine (7m8oGuo). The average response to antigen increased from 37 +/- 16 without nucleoside to 1733 +/- 488 PFC/culture in its presence (P less than 0.002). Restoration of specific immune responses was an antigen-dependent and nucleoside dose-dependent event. Signaling by 7m8oGuo rendered the response to antigen protein kinase C independent in cultures of cells from normal donors as well as from CVI patients. These data substantiate (i) that a non-C-kinase signaling pathway for antigen-dependent differentiation exists, (ii) that this pathway can function normally in B cells from patients with CVI when triggered appropriately, and (iii) that 7,8-disubstituted guanine ribonucleosides can convert a C-kinase-dependent signaling event to a C-kinase-independent signaling event. Substituted guanine ribonucleosides may have potential as immunotherapeutic agents for patients with CVI.
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PMID:Protein kinase C independent restoration of specific immune responsiveness in common variable immunodeficiency. 201 9

T cell lines with a novel phenotype (CD3+ TCR-alpha/beta+ CD4- CD8-) were developed from the peripheral blood of a patient with a combined immunodeficiency and tissue injury resembling graft-vs-host disease. One of these IL-2-dependent T cell lines demonstrated non-MHC-restricted cytolytic function against tumor targets, syngeneic and allogeneic fibroblasts, and PHA blasts from allogeneic donors. The other cell line only became cytotoxic in the presence of lectin or anti-CD3 antibody. The two cell lines also differed in their expression of the T-200 gene products CD45RO (gp180) and CD45RA (gp220). Both cell lines produced tumor necrosis factor-alpha and -beta and IFN-gamma activity when activated with mitogens or PMA and IL-1. The in vitro functions of these T-cell lines suggest a potential role for alpha/beta double-negative T lymphocytes in tissue injury resembling graft-vs-host disease.
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PMID:Double-negative (CD4- CD8-) T cells with an alpha/beta T cell receptor. Non-MHC-restricted cytolytic activity and lymphokine production. 214 Oct 37

The T-cell receptor (TCR) for antigen is a complex consisting of at least seven polypeptides chains. Two chains form the clonotypic heterodimer, which determines antigen-specificity. The other five constitute the monomorphic CD3 components, which are thought to be involved in signal transduction. We have reported a familial defect in the surface expression of the TCR/CD3 complex on otherwise phenotypically normal T lymphocytes. As a consequence of the surface defect, an impaired T-lymphocyte activation through the TCR and CD3 complex by both antigens and mitogens is observed in this type of immunodeficiency (ID) for which we propose the name TCR ID. In contrast, normal proliferative responses were recorded to TCR-independent activation or proliferation signals (i.e: anti-CD2, phorbol esters and IL-2). We believe that other ID with similar clinical and immunological characteristics, described before the general availability of monoclonal antibodies, may have also been TCR ID. Severe and mild clinical phenotypes of the disease exist which correlate with differences in the levels of TCR surface expression and of T-cell function in vitro. The biochemical basis of the defect in one of the cases thus far studied is an impaired association of CD3-zeta chain with the other chains of the complex. This defect prevented the maturation and transport of the incomplete complex to the cell surface. Due to the multi-subunit nature of the TCR/CD3 complex it is possible that other biochemical defects in TCR assembly may also give rise to TCR ID. The description of mild as well as a severe phenotype in TCR ID points to a threshold effect of TCR/CD3 expression necessary for normal T cell function in vivo since mild TCR ID is clinically asymptomatic. In contrast, severe TCR ID behaves as a clinical SCID, with clear autoimmune features and profound lymphoid tissue depletion. TCR ID and other naturally occurring SCID variants may shed light on fundamental questions of the development, function and biochemistry of the in vivo immune system. Their study and characterization also opens the door to somatic gene therapy in this kind of disorder, which is an obvious goal in ID research.
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PMID:Congenital T-cell receptor immunodeficiencies in man. 214

The simian immunodeficiency virus of macaques (SIVmac) is a lentivirus which induces an AIDS-like disease in rhesus monkeys. We have explored the virus-specific cellular immune response in SIVmac-infected rhesus monkeys. Con A-activated, IL-2 expanded PBL of some SIVmac-infected rhesus monkeys lyse autologous B lymphoblastoid cell lines infected with a recombinant vaccinia virus that carries the SIVmac gag gene. This lysis is mediated by CD8+ lymphocytes and is MHC class I restricted. Moreover, these effector lymphocytes do not express the NK cell-associated molecules NKH1 or CD16. These cells are, therefore, CTL. In a limited prospective study of SIVmac-infected rhesus monkeys, the presence of the SIVmac gag-specific CTL activity in PBL correlated with both a reduced efficiency in isolating SIVmac from PBL of these monkeys and their extended survival. This method for assessing SIVmac gag-specific cellular immunity in rhesus monkeys will be important not only in investigating the immunopathogenesis of SIVmac-induced disease, but also in evaluating the capacity of candidate AIDS vaccines to elicit a cell-mediated immune response in this animal model.
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PMID:The gag-specific cytotoxic T lymphocytes in rhesus monkeys infected with the simian immunodeficiency virus of macaques. 215 61

We have classified patients with common variable immunodeficiency (CVI) on the basis of the ability of their B cells to respond to anti-IgM and interleukin (IL)-2 in vitro. Group A had cells unable to secrete IgM or IgG, Group B secreted IgM alone, and Group C secreted both IgM and IgG. A separate small group of patients lacked peripheral B cells. Where Ig secretion was present with anti-IgM and IL-2, EBV increased it, but where it was absent, EBV only induced IgM secretion in two out of eight Group A patients and IgG in one out of five Group B patients. These classifications are related to the sex of the patient and may represent different loci of the block in B-cell differentiation in CVI.
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PMID:Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2. 216 80

The development of acute graft-vs-host disease (GVHD) is a common outcome after the injection of fully MHC disparate parental T cells into unirradiated F1 mice. Murine cytomegalovirus (MCMV) infection has been previously shown to augment the development of acute GVHD in the parent-into-F1 (P----F1) model, such that 10-fold fewer parental cells are required. In the present study, we have investigated the effect of MCMV infection on the induction of non-lethal GVHD that occurs in P----F1 combinations involving MHC class I only or class II only differences. Using P----F1 combinations involving either an H-2K only difference or an H-2D only difference, MCMV infection of F1 mice 3 days before the injection of parental spleen cells led to a profound T cell immunodeficiency that strongly resembled that observed in acute GVHD. Further studies examining the H-2K disparate P----F1 combination, C57Bl/6---- (C57Bl/6xB6.C-H-2bm1) F1 and combined MCMV infection showed that the immunodeficiency is characterized by a profound loss of in vitro Th cell production of IL-2 and an intrinsic defect in T effector function as shown by an inability of rIL-2 to restore defective CTL responses. Additional experiments in these mice revealed the presence of suppressor cells as well as significant parent-anti-F1 CTL activity possibly accounting for the suppressor effect. This pattern of immunodeficiency was not seen after the administration of either MCMV or MHC class I disparate parental cells alone. MCMV infection did not detectably alter the immunodeficiency observed in a P----F1 combination involving a MHC class II difference only. These results indicate that MCMV infection can alter the pattern of GVHD in the setting of an MHC class I disparity, but not in the setting of class II disparity, such that it resembles acute GVHD. These results may have relevance to the human transplant setting where intercurrent CMV infection has been associated with an adverse clinical outcome.
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PMID:Synergistic effect of murine cytomegalovirus on the induction of acute graft-vs-host disease involving MHC class I differences only. Analysis of in vitro T cell function. 217 81

Natural killer (NK) cells have long been known to aid in the control of viral infections by killing virus-infected cells, including those infected with human immunodeficiency virus (HIV). Among the possible NK-susceptible target cells in an infected individual, the monocyte/macrophages are of special significance since they may serve as both a reservoir of HIV and aid in dissemination of the virus throughout the body. A new technique for the enrichment and cultivation of large numbers of recombinant interleukin 2 (rIL-2)-stimulated NK cells has been developed which provides cells with high cytotoxic activity. These IL-2-activated NK cells, adherent lymphokine-activated killer cells (A-LAK), can kill monocytes infected with HIV for 24 h to 7 days, with optimal target sensitivity between 3 and 7 days. Recognition and killing of the infected monocytes did not appear to be restricted by the major histocompatibility complex (MHC) antigens and could be cold-target inhibited by tumor cell lines. A-LAK cells may be useful in newer therapeutic approaches to treatment of HIV infection.
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PMID:Cytotoxic activity against HIV-infected monocytes by recombinant interleukin 2-activated natural killer cells. 222 37


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