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Long-lived clonal T cells deficient in CD28 expression are commonly found in patients with inflammatory syndromes and persistent infections. Considering that CD28 loss is the most consistent immunological marker of aging, we propose that, in pathological states, CD28(null) T cells represent prematurely senescent cells resulting from persistent immune activation. These unusual lymphocytes have aberrant functions that contribute to disease-related immune abnormalities, and the degree of accumulation of CD28(null) T cells predicts the severity of clinical manifestations. We suggest that understanding of the biological properties of T cells that have reached replicative senescence will influence the future management of certain diseases. Indeed, studies on the molecular basis for the loss of CD28 are already providing information on methods to functionally rescue senescent T cells. 相似文献
74.
One of the major challenges in the post-genome era is the correlation between genes and function or phenotype. We have pioneered a strategy for screening of cDNA libraries, which is based on sequential combination of lentiviral and oncoretroviral expression systems and can be used to identify proliferation-modulating genes. Screening of a lentiviral expression library derived from adult human brain cDNA resulted in cloning of the potent proliferation-inducing determinant termed pi1 (proliferation inducer 1). Transduction experiments using GFP-expressing oncoretroviruses to target proliferation-competent cells suggested that overexpression of pi1 initiates proliferation of human umbilical vein endothelial cells (HUVECs). Growth induction of HUVECs as well as Swiss3T3 fibroblasts was confirmed by Brd-uridine incorporation assays, which correlated increased DNA synthesis with expression of pi1. The identified pi1 cDNA is 297 bp long and encodes a 10 kDa polypeptide. Since deregulation of proliferation control accounts for a number of today’s untreatable human diseases such as neurodegenerative disorders and cancer, discovery of novel proliferation-modulating genes is essential for developing new strategies for gene therapy and tissue engineering. 相似文献
75.
Vallejo AN Yang H Klimiuk PA Weyand CM Goronzy JJ 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(4):1732-1740
Fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis elicit spontaneous proliferation of autologous T cells in an HLA-DR and CD47 costimulation-dependent manner. T cell costimulation through CD47 is attributed to specific interaction with thrombospondin-1 (TSP1), a CD47 ligand displayed on FLS. CD47 binding by FLS has broad biological impact that includes adhesion and the triggering of specific costimulatory signals. TSP1(+) FLS are highly adhesive to T cells and support their aggregation and growth in situ. Long-term cultures of T cells and FLS form heterotypic foci that are amenable to propagation without exogenous growth factors. T cell adhesion and aggregate formation on TSP1(+) FLS substrates are inhibited by CD47-binding peptides. In contrast, FLS from arthroscopy controls lack adhesive or T cell growth-promoting activities. CD47 stimulation transduces a costimulatory signal different from that of CD28, producing a gene expression profile that included induction of ferritin L chain, a component of the inflammatory response. Ferritin L chain augments CD3-induced proliferation of T cells. Collectively, these results demonstrate the active role of FLS in the recruitment, activation, and expansion of T cells in a CD47-dependent manner. Because TSP1 is abundantly expressed in the rheumatoid synovium, CD47-TSP1 interaction is proposed to be a key component of an FLS/T cell regulatory circuit that perpetuates the inflammatory process in the rheumatoid joint. 相似文献
76.
Spycher C Klonis N Spielmann T Kump E Steiger S Tilley L Beck HP 《The Journal of biological chemistry》2003,278(37):35373-35383
Using a stage-specific cDNA library from Plasmodium falciparum we have identified a gene coding for a novel histidine-rich protein (MAHRP-1). The gene is exclusively transcribed during early erythrocyte stages and codes for a small transmembrane protein. The C-terminal region contains a polymorphic stretch of histidine-rich repeats. Fluorescence microscopy studies using polyclonal mouse sera revealed that MAHRP-1 is located at the Maurer's clefts, which represent parasite-induced structures within the cytosol of infected erythrocytes. Biochemical studies showed that recombinant MAHRP-1 binds the toxic hemoglobin degradation product, ferriprotoporphyrin (FP) with a submicromolar dissociation constant and a stoichiometry determined by the number of DHGH motifs. The bound FP has increased peroxidase-like activity and is 10-fold more susceptible to H2O2-induced degradation compared with unbound FP. These properties of MAHRP-1 suggest it may play a protective role against oxidative stress, and its location at the Maurer's clefts suggests a function in promoting the correct trafficking of exported proteins, such as P. falciparum erythrocyte membrane protein-1. 相似文献
77.
The relationship between form and function in the lumbar vertebral column has been well documented among platyrrhines and especially catarrhines, while functional studies of postcranial morphology among strepsirrhines have concentrated predominantly on the limbs. This morphometric study investigates biomechanically relevant attributes of the lumbar vertebral morphology of 20 species of extant strepsirrhines. With this extensive sample, our goal is to address the influence of positional behavior on lumbar vertebral form while also assessing the effects of body size and phylogenetic history. The results reveal distinctions in lumbar vertebral morphology among strepsirrhines in functional association with their habitual postures and primary locomotor behaviors. In general, strepsirrhines that emphasize pronograde posture and quadrupedal locomotion combined with leaping (from a pronograde position) have the relatively longest lumbar regions and lumbar vertebral bodies, features promoting sagittal spinal flexibility. Indrids and galagonids that rely primarily on vertical clinging and leaping with orthograde posture share a relatively short (i.e., stable and resistant to bending) lumbar region, although the length of individual lumbar vertebral bodies varies phylogenetically and possibly allometrically. The other two vertical clingers and leapers, Hapalemur and Lepilemur, more closely resemble the pronograde, quadrupedal taxa. The specialized, suspensory lorids have relatively short lumbar regions as well, but the lengths of their lumbar regions are influenced by body size, and Arctocebus has dramatically longer vertebral bodies than do the other lorids. Lumbar morphology among galagonids appears to reflect a strong phylogenetic signal superimposed on a functional one. In general, relative length of the spinous processes follows a positively allometric trend, although lorids (especially the larger-bodied forms) have relatively short spinous processes for their body size, in accordance with their positional repertoire. The results of the study broaden our understanding of postcranial adaptation in primates, while providing an extensive comparative database for interpreting vertebral morphology in fossil primates. 相似文献
78.
Franzke CW Tasanen K Schäcke H Zhou Z Tryggvason K Mauch C Zigrino P Sunnarborg S Lee DC Fahrenholz F Bruckner-Tuderman L 《The EMBO journal》2002,21(19):5026-5035
Collagen XVII, a type II transmembrane protein and epithelial adhesion molecule, can be proteolytically shed from the cell surface to generate a soluble collagen. Here we investigated the release of the ectodomain and identified the enzymes involved. After surface biotinylation of keratinocytes, the ectodomain was detectable in the medium within minutes and remained stable for >48 h. Shedding was enhanced by phorbol esters and inhibited by metalloprotease inhibitors, including hydroxamates and TIMP-3, but not by inhibitors of other protease classes or by TIMP-2. This profile implicated MMPs or ADAMs as candidate sheddases. MMP-2, MMP-9 and MT1-MMP were excluded, but TACE, ADAM-10 and ADAM-9 were shown to be expressed in keratinocytes and to be actively involved. Transfection with cDNAs for the three ADAMs resulted in increased shedding and, vice versa, in TACE-deficient cells shedding was significantly reduced, indicating that transmembrane collagen XVII represents a novel class of substrates for ADAMs. Functionally, release of the ectodomain of collagen XVII from the cell surface was associated with altered keratinocyte motility in vitro. 相似文献
79.
The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample 下载免费PDF全文
Dermaut B Theuns J Sleegers K Hasegawa H Van den Broeck M Vennekens K Corsmit E St George-Hyslop P Cruts M van Duijn CM Van Broeckhoven C 《American journal of human genetics》2002,70(6):1568-1574
Nicastrin regulates gamma-secretase cleavage of the amyloid precursor protein by forming complexes with presenilins, in which most mutations causing familial early-onset Alzheimer disease (EOAD) have been found. The gene encoding nicastrin (NCSTN) maps to 1q23, a region that has been linked and associated with late-onset Alzheimer disease (LOAD) in various genome screens. In 78 familial EOAD cases, we found 14 NCSTN single-nucleotide polymorphisms (SNPs): 10 intronic SNPs, 3 silent mutations, and 1 missense mutation (N417Y). N417Y is unlikely to be pathogenic, since it did not alter amyloid beta secretion in an in vitro assay and its frequency was similar in case and control subjects. However, SNP haplotype estimation in two population-based series of Dutch patients with EOAD (n=116) and LOAD (n=240) indicated that the frequency of one SNP haplotype (HapB) was higher in the group with familial EOAD (7%), compared with the LOAD group (3%) and control group (3%). In patients with familial EOAD without the APOE epsilon4 allele, the HapB frequency further increased, to 14%, resulting in a fourfold increased risk (odds ratio = 4.1; 95% confidence interval 1.2-13.3; P=.01). These results are compatible with an important role of gamma-secretase dysfunction in the etiology of familial EOAD. 相似文献
80.