Exposing the human nude phenotype Frank, Jorge; Pignata, Claudio; Panteleyev, Andrei A ...
Nature (London),
04/1999, Letnik:
398, Številka:
6727
Journal Article
Recenzirano
Odprti dostop
The recent discovery of the human counterpart of the hairless mouse phenotype has helped our understanding of the molecular genetics of hair growth. But there are no reports of a defect in the human ...homologue of the best known of the 'bald' mouse phenotypes, the nude mouse. This may be because affected individuals are so gravely ill from the accompanying immunodeficiency that their baldness goes unnoticed. We have carried out a genetic analysis that reveals a human homologue of the nude mouse.
Human Nude/SCID (severe combined immunodeficiency) is the first severe combined immunodeficiency caused by mutation of the winged-helix-nude (WHN) gene, which is expressed in the thymus but not in ...the hematopoietic lineage. The disease is characterized by a T-cell defect, congenital alopecia, and nail dystrophy. A Nude/SCID patient who underwent bone marrow transplantation from the human leukocyte antigen-identical heterozygote brother was studied to investigate, in this unique model, the role of the thymus in immunologic reconstitution. Despite an increase in CD3(+), CD4(+), and CD8(+) cells, CD4(+) CD45 RA naive lymphocytes were not regenerated. Conversely, naive CD8(+) cells were normal. After an initial recovery, lymphocyte proliferation to mitogens progressively declined compared with controls and genotypically identical donor cells grown in the WHN(+/-) environment. Analysis of the T-cell receptor (TCR) repertoire of CD4(+) cells revealed that only 3 of 18 Vbeta families had an altered CDR3 heterogeneity length profile. Conversely, CD8(+) lymphocytes showed an abnormal distribution in most Vbeta families. These data indicate that the thymus is differentially required in the reconstitution of CD4(+) and CD8(+) naive subsets and in the maintenance of their TCR repertoire complexity. Taken together, these findings suggest that bone marrow transplantation is ineffective in the long-term cure of this form of SCID.
Dipeptidyl peptidase IV (CD26/DPP‐IV) is an ectoenzyme expressed on different cell types. Signaling properties and functional consequences of the CD26 triggering have been elucidated mostly on T ...cells, where the molecule delivers a costimulatory signal that potentiates T‐cell activation through the T‐cell receptor. We conducted studies in the human hepatocarcinoma–derived PLC/PRF/5 cell line to examine the signal transduction through CD26 and its functional properties in the absence of other T‐cell–specific membrane molecules. Engagement of CD26 in PLC/PRF/5 cells through a specific antibody induces tyrosine phosphorylation of several proteins with maximal intensity 15 minutes after the stimulation. This effect was under the negative regulatory control of CD45 tyrosine phosphatase, in that the addition of orthovanadate clearly enhanced the phosphorylation events. Using in vitro kinase assays with CD26 immunoprecipitates, we observed that a protein or proteins with kinase activity are coprecipitated with the CD26 molecule. In addition, unlike Jurkat T cells, in which CD26 expression exerts a protective effect against apoptosis, in PLC/PRF/5 cells CD26 occupancy delivers a potent apoptotic signal. This effect was also observed in HepG2 cells, thus indicating that it represents a more general phenomenon occurring in different liver neoplastic cell lines.
Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self-mutilating behaviour, anhidrosis and recurrent ...hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.
Viral infections may induce an acquired form of immunodeficiency, generally lasting a few weeks. In the more severe form, such as HIV infection, the immunodeficiency is permanent. Programmed death of ...T cells represents one of the mechanisms by which HIV determines the T cell functional impairment, finally resulting in the destruction of T cells. In this study, we evaluated whether an altered regulation of apoptosis was also implicated in the anergy associated with the common measles or varicella-zoster virus (VZV) infections in infancy. A spontaneous apoptosis of peripheral blood mononuclear cells was observed in children who had suffered from these infections as long as 6 mo after the acute disease. Apoptosis was demonstrated through analysis of cellular DNA content, morphologic evidence of cell nuclei shrinkage, and by analysis of DNA degradation. Stimulation of T cells through anti-CD4 MAb increased the number of apoptotic cells with a maximal effect 72 h after the stimulation. Our results suggest that apoptosis may account for the anergy that follows acute viral infections in infancy.
Children affected by Down's syndrome (DS) have an increased susceptibility to viral or bacterial infections and leukemia, associated with several abnormalities of the immune system. We investigated ...whether the T cell defect was qualitative in nature and associated with abnormalities of the early events occurring during cell activation. The proliferative response of lymphocytes from DS individuals after CD3 cross-linking was clearly depressed, as already reported. In contrast, phorbol ester and ionomycin were able to induce cell cycle progression in DS, suggesting a defect in the early stages of the signal transduction through a T cell receptor/CD3 (TCR/CD3) complex upstream of protein kinase C activation. The functional impairment in DS was not related either to a decrease of circulating mature-type CD3+ cells, which express high levels of surface of CD3 molecules, or to a decrease of the CD4+ subpopulation. The analysis of phosphotyrosine-containing proteins after the cross-linking of CD3 molecules in DS lymphocytes revealed a partial signaling, characterized by increased phosphorylation of proteins of 42-44 kD, comparable to that observed in control subjects, but not of proteins of 70 and 21 kD. Moreover, although the "anti-anergic" gamma element of IL-2, IL-4, IL-7, and IL-15 receptors was normally tyrosine-phosphorylated during cell activation, the CD3 zeta-associated protein kinase (ZAP-70) was not. Our results indicate that in DS there is a T cell activation defect, characterized by partial signal transduction through a TCR/CD3 complex, and associated with a selective failure of ZAP-70 tyrosine phosphorylation.
Chronic hepatitis B (CHB) virus infection is associated with functional abnormalities of cell-mediated immunity, defective interferons alpha and gamma synthesis, and interleukin-2 receptor ...expression. In this study, interleukin-2 (IL-2) production and the role of adherent cells was evaluated in 25 children chronically infected with hepatitis B virus.
IL-2 activity was measured by bioassay in supernatants of phytohemoagglutinin-stimulated peripheral blood mononuclear cells. In a few patients, IL-2 concentration was also immunochemically determined. Coculture experiments using a mixture of adherent cells and lymphocytes from healthy children and patients with CHB were also performed.
Children with CHB showed lower IL-2 production than healthy controls. In patients, IL-2 activity was 34.7 +/- 22.5 U/ml as compared to 152.6 +/- 78.5 U/ml of controls. Immunochemical quantitation of IL-2 confirmed a lower IL-2 production in patients. No correlation was found between the functional T-cell defect and the severity of liver damage, degree of viral replication, and duration of the disease. In co-culture experiments, adherent cells from HBsAg-positive patients inhibited IL-2 production following mitogen stimulation of control non-adherent cells by 67%. The inhibitory effect, mediated by patients adherent cells, was abolished by blocking with indomethacin prostaglandins, that are potent local immunomodulators released by adherent cells.
Our results further support the observation that in children with CHB virus infection adherent cells play an important role in the inappropriate regulation of immune response, an effect being likely mediated by prostaglandins.
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