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PubMed1981

Autologous mixed lymphocyte reactions in NZB mice: analysis in recombinant inbred lines shows a T cell defect unrelated to autoantibody production.

The autologous mixed lymphocyte reaction (AMLR) has been examined in the AMLR-deficient strain, NZB, in C58 mice, which have normal AMLR responses, and in the (NZB x C58) recombinant inbred (NX8 RI) lines. Half of the NX8 RI lines had deficient AMLR and half were comparable in reactivity to the C58 parent strain. AMLR unresponsiveness did not correlate in the NX8 RI lines with H-2 or any other marker known to affect immune recognition. Non-T cells from H-2k NX8 RI lines which had deficient AMLR were able to stimulate an MLR when cultured with T cells of C58 origin. AMLR-positive H-2d lines responded to NZB stimulators, whereas NZB T cells did not respond to any of the H-2d NX8 RI lines but did exhibit strong alloreactivity. Thus, the AMLR defect in NZB mice is due to a T cell lesion. Furthermore, since AMLR deficiency in the NX8 RI lines did not correlate with a positive Coombs test or the production of naturally occurring thymocytotoxic antibody, we conclude that autoimmunity in NZB mice is a complex disease resulting from the inheritance of multiple independently segregating genes.

Animals↗
PubMed1995

Glycosyltransferase mutants: key to new insights in glycobiology.

Glycosyltransferases (Glyc-T's) catalyze the synthesis of the carbohydrate portions of glycoproteins, glycolipids, and proteoglycans. Most Glyc-T's transfer one sugar in one linkage and are encoded by a unique gene. Thus, synthesis of a branched carbohydrate may require expression of at least 30 Glyc-T genes. Mutations that alter Glyc-T activity therefore provide an approach to identifying functions for carbohydrates. These fall into two general categories: 1) intramolecular functions pertaining to the physical and biochemical properties of a glycoconjugate; and 2) intermolecular functions that involve recognition of sugar (or sugars) by another molecule, such as the selectins that bind to specific sugar sequences at the cell surface. In this review, the origin, nature, and uses of Glyc-T mutants that have been used to study both types of carbohydrate function will be summarized. Many Glyc-T genes are now cloned, so transgenic and gene disruption techniques are the latest strategies for identifying new functions for carbohydrates. It is already apparent that the consequences of altering the spectrum of carbohydrates expressed by a cell or an organism range from "none" to "death." A key challenge for the future is to identify molecular bases for the complex phenotypes created by glycosylation engineering. Equally important will be to understand factors that regulate Glyc-T genes, a new class of genes whose study may reveal novel mechanisms of biological regulation.

Animals↗
PubMed1987

Complexes of DNA hairpins and a single-stranded oligonucleotide detected by affinity chromatography and mung bean nuclease cleavage.

The emergence of a simple translation device consisting of an assembler strand (primordial mRNA) and RNA hairpins (primordial tRNA) is presumed to be an important step leading to the origin of life. The assumption of a non-enzymatic interaction of primordial tRNA and mRNA is experimentally approached. DNA hairpins containing five or more adenosine residues in the loop are able to bind to complementary oligonucleotides covalently bound to cellulose. The exact number of base pairs formed between the hairpins and the assembler strand is determined by two methods applied to DNA hairpin/assembler complexes. The melting temperature of a complex is measured and the cleavage pattern by nuclease from mung bean is determined. The loop of the smallest hairpin able to bind consists of five adenosine residues and only three base pairs are formed. This supports the idea of a primordial recognition similar to the contemporary codon-anticodon interaction.

Biological Evolution↗
PubMed1997

The HLA system, antigen processing and presentation.

Human leukocyte antigens (HLA) restrict immune responses by binding antigenic peptides and presenting them in the context of self to T lymphocytes. In transplantation, a vigorous T cell response, termed alloreactivity, is caused by recognition of non-self HLA. The major histocompatibility complex (MHC) encodes two major classes of HLA molecules, designated I and II. In general, HLA class I molecules present peptides derived by proteolysis of intracellular proteins (the endogenous pathway), while HLA class II molecules present peptides sampled from the extracellular body fluids (the exogenous pathway). The dichotomy between class I and class II antigens is reflected in the T cells in that the CD8 cell surface glycoprotein is expressed by cytotoxic T lymphocytes and recognizes HLA class I, while CD4 is expressed on helper T cells and recognizes HLA class II. Although the two classes of HLA molecules are thought to have originated from a common ancestral gene, they have evolved specific structures and intracellular trafficking compartments that account for their functions. The class I proteins bind short peptides of eight to nine amino acids that are tightly anchored at their ends. The class II proteins bind longer peptides that are more heterogeneous in size (12 to 28 amino acids) and have ragged ends. The class I peptides are generated by proteasomes and other mechanisms in the cytosol and translocated from the cytosol into the endoplasmic reticulum (ER). In the ER, functional HLA class I complexes are formed and then transported to the cell surface for presentation. HLA class II molecules are assembled without antigenic peptide. An "invariant chain" promotes the assembly of the class II molecule and protects its groove from binding peptides in the ER. In an endosomal compartment, antigens that have entered the cell via pinocytosis or via receptor-mediated internalization are processed, the invariant chain is degraded, and antigenic peptides bind to the HLA class II molecule. This mature complex is transported to the cell surface for presentation. Alloreactivity is the special case of antigen presentation responsible for transplant rejection.

Antigen Presentation↗
PubMed1992

Induction of lymphokine-activated killer cells of equine origin: specificity for equine target cells.

The in vitro stimulation of peripheral blood mononuclear cells (PBMC) with interleukin 2 (IL-2) results in the development of potent cytotoxic effector cells, referred to as lymphokine-activated killer (LAK) cells. LAK cells are capable of lysing a wide variety of autologous, allogeneic and xenogeneic tumor cells. The exact mechanism of target cell recognition by LAK cells remains unknown. LAK cell activity has been reported for a variety of domesticated species except the horse. We report here that IL-2-stimulated equine PBMC, which fail to lyse either human or murine tumor cell lines, exhibit potent cytolytic activity against an equine tumor cell line, EqT8888. Cytolytic activity against the EqT8888 cells required 3 days of incubation with IL-2, was mediated primarily by T-cells, and was not restricted by major histocompatibility complex antigens. Though LAK activity could only be demonstrated using equine-derived target cells, xenogeneic targets could be lysed in a lectin-mediated cytotoxicity assay. The xenogeneic targets also failed to block LAK cell-killing of the EqT8888 cells in a cold-target competition assay. These results indicate that LAK cells in the horse appear to utilize a species-specific recognition mechanism during target cell lysis.

Animals↗
PubMed1999

A rhoptry-protein-associated mechanism of clonal phenotypic variation in rodent malaria.

The recognition and invasion of host cells are mediated by components of the apical complex of the ookinete, sporozoite and merozoite stages of Plasmodium parasites. The paired rhoptries (organelles involved in host-cell recognition) in the apical complex contain many proteins of as-yet unknown function. In the rodent malaria agent P. yoelii yoelii, a multigene family codes for merozoite rhoptry proteins of relative molecular mass 235,000 (p235 proteins); these proteins are thought to determine the subset of erythrocytes that the parasites invade. Further support for this idea came from the identification of a region in p235 with weak but significant homology to reticulocyte-binding protein-2 of P. vivax and the demonstration that at least one p235 member binds to the erythrocyte surface membrane. Here, using single, micromanipulated P.y.yoelii parasites, we describe a new mechanism of gene expression by which the merozoites originating from a single schizont each express a distinct member of this multigene family. We propose that this new type of clonal phenotypic variation provides the parasite with a survival strategy in the mammalian host; this strategy contributes to the observed chronicity of malarial infections. This phenomenon is genetically and functionally distinct from classical antigenic variation, which is mediated by the var multigene family of P. falciparum.

Animals↗
PubMed1992

Total synthesis of horse heart cytochrome C.

A strategy based on complexation-assisted condensation of large synthetic protein fragments and mitochondria-mediated stereospecific heme insertion has been utilized to assemble a functional molecule corresponding to native horse heart holocytochrome c. This original approach offers the unique opportunity of selective modifications both in the C-terminal and in the N-terminal regions of the apoprotein and may represent an useful alternative to site-directed mutagenesis, particularly when D-amino acids, chemically and/or isotopically modified or other unnatural amino acids have to be introduced in this important molecule. The present result is an example of how solid phase peptide synthesis of large protein fragments in conjunction with the availability of a specific recognition process may extend the potentiality of the chemical approach to the synthesis of an entire protein.

Amino Acid Sequence↗
PubMed1996

Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha.

JC virus is activated to replicate in glial cells of many AIDS patients with neurological disorders. In human glial cells, the human immunodeficiency virus 1 (HIV-1) Tat protein activates the major late promoter of JC virus through a Tat-responsive DNA element, termed upTAR, which is a recognition site for cellular Pur alpha, a sequence-specific single-stranded DNA binding protein implicated in cell cycle control of DNA replication and transcription. Tat interacts with two leucine-rich repeats in Pur alpha to form a complex that can be immunoprecipitated from cell extracts. Tat enhances the ability of purified glutathione S-transferase-Pur alpha (GST-Pur alpha) to bind the upTAR element. Tat acts synergistically with Pur alpha, in a cell-cycle-dependent manner, to activate transcription at an upTAR element placed upstream of a heterologous promoter. Since Pur alpha is ubiquitously expressed in human cells and since PUR elements are located near many promoters and origins of replication, the Tat-Pur alpha interaction may be implicated in effects of HIV-1 throughout the full range of HIV-1-infected cells.

Amino Acid Sequence↗
PubMed1998

Mechanistic studies on the DNA linking activity of Epstein-Barr nuclear antigen 1.

The DNA replication, plasmid segregation and transactivation functions of Epstein-Barr nuclear antigen 1 (EBNA1) require the binding of EBNA1 to specific DNA recognition sites in the two non-contiguous functional elements of the Epstein-Barr virus latent origin of replication, oriP . EBNA1 molecules bound to these elements interact with each other resulting in the formation of looped individual DNA molecules and multiply linked DNA molecules. We have developed a glycerol gradient sedimentation assay suitable for quantitative analysis of the DNA linking activity of EBNA1 and used it to investigate the contribution of EBNA1 residues to the linking interaction and the mechanism of the interaction. Using overlapping internal deletion mutants, we found that two regions of EBNA1 can cause DNA linking, amino acids 40-100 and 327-377, but that the stabilities of the linked complexes formed by the two regions differ dramatically; only complexes formed through the latter region are stable to glycerol gradient sedimentation analysis. Mechanistic studies using EBNA1 in combination with GAL4-EBNA1 fusion proteins showed that linking interactions mediated by residues 327-377 are homotypic. Our results also suggest that only the DNA-bound form of EBNA1 participates in the protein-protein interactions seen in DNA linking.

Binding Sites↗
PubMed1995

Sustained T-cell reactivity to Mycobacterium tuberculosis specific antigens in 'split-anergic' leprosy.

Split anergy represented by delayed-type hypersensitivity skin reaction to tuberculin, but not to leprosin, is known to occur in a distinct proportion of leprosy patients. The mechanism was originally attributed to Mycobacterium leprae-specific suppression of T cells toward common mycobacterial antigens. This study ascertained an alternative explanation, attributing the phenomenon to selective responsiveness to M. tuberculosis-specific epitopes. Indeed, the results of blood T-cell proliferative responses in 11 split-anergic patients showed normal responsiveness to the M. tuberculosis-specific 38 kDa lipoprotein and peptide 71-91 of the 16 kDa antigen but diminished responsiveness to 2 common mycobacterial antigens, represented by the 65 kDa heat shock protein and the fibronectin-binding Ag85 complex, as compared with leprosin responsive patients and healthy contacts. These findings support the hypothesis that split anergy is due to selective recognition of M. tuberculosis-specific epitopes and deletion of T cells reacting to shared mycobacterial antigens.

Adolescent↗
PubMed1993

On the interaction of polypeptides with bile salts or bilirubin-IX alpha.

Aqueous solutions formed by polypeptides, simple models of proteins, and bile salts (sodium cholate and deoxycholate, NaC and NaDC, respectively) or bilirubin-IX alpha (BR) have been studied by CD measurements. They could mimic more complicated biliary systems, thus supplying a possible interpretation of the behavior of some amino acid residues in the biliary proteins. The aggregation of NaDC and NaC in water can be monitored by CD measurements. Bile salts, in submicellar and micellar form, stabilize poly(L-Lys) (PLL) in alpha-helical conformation. The alpha-helix content increases with increasing bile salt concentration and ionic strength. NaDC seems to be a slightly better stabilizing agent of the alpha-helix conformation than NaC. Models characterized by hydrogen bonds between bile salts and PLL are proposed, also resorting to previous data available on the systems formed by NaDC and poly(L-Leu-L-Leu-L-Lys) (PLLL) or poly(L-Leu-L-Leu-L-Asp) (PLLA). Binding of BR to PLL, poly(D-Lys), poly(L-Glu), PLLL, and PLLA in water has been investigated by CD spectra in order to clarify the nature of the association complexes and the mechanism of the BR enantioselective complexation. Potential energy calculations provide binding models capable of explaining the enantioselective ability of the PLL and PLLL alpha-helices toward the left- and right-handed enantiomer of BR, respectively. BR is bound to -NH2 groups of PLL and PLLL lying on a right- and left-handed spiral, respectively. These results, together with those formerly obtained for some bile salts-BR systems, indicate that the selectivity originates from a binding that involves large regions of the BR molecule and gives rise, very probably, to moderate conformational changes from the "ridge tile" structure observed in the crystals. In some cases van der Waals forces can play a crucial role in the chiral recognition of bilirubin. Moreover, possible interaction models of BR with human serum albumin are proposed on the basis of a recent x-ray crystal structure of the protein.

Amino Acid Sequence↗
PubMed1991

Sequence of general transcription factor TFIIB and relationships to other initiation factors.

Transcription factor TFIIB is a ubiquitous factor required for transcription initiation by RNA polymerase II. Previous studies have suggested that TFIIB serves as a bridge between the "TATA"-binding factor (TFIID) and RNA polymerase II during preinitiation complex assembly and, more recently, that TFIIB can be a target of acidic activators. We have purified TFIIB to homogeneity, shown that activity resides in a 33-kDa polypeptide, and obtained cDNAs encoding functional TFIIB. TFIIB contains a region with amino acid sequence similarity to a highly conserved region of prokaryotic sigma factors. This is consistent with analogous functions for these factors in promoter recognition by RNA polymerases and with similar findings for TFIID, TFIIE, and TFIIF/RAP30. Like TFIID, TFIIB contains both a large imperfect repeat that could contribute an element of symmetry to the folded protein and clusters of basic residues that could interact with acidic activator domains. These findings argue for a common origin of TFIIB, TFIID, and other general transcription factors and for the evolutionary segregation of complementary functions.

Amino Acid Sequence↗
PubMedDate not supplied

Postictal psychosis after partial complex seizures: a multiple case study.

Bouts of unusually frequent partial complex seizures originating in the temporal lobe, that sometimes became secondarily generalized, induced psychotic episodes in 9 patients. In 7, the increase in seizures occurred at a time when antiepileptic drugs (AEDs) were being reduced during intensive EEG monitoring with a view to surgical treatment of intractable epilepsy. According to DSM-III-R criteria, the postictal psychosis resembled an organic delusional syndrome which was paranoid in 7 and schizophreniform in 1 and an organic mood syndrome in 1. A high incidence of ictal fear, of bilateral independent epileptogenic discharge, and of small foreign tissue lesion were unexpected findings and appeared to represent risk factors, especially in patients otherwise handicapped by an epileptic personality disorder. Recognition of postictal psychosis in this setting and in others is important both prognostically and therapeutically. Postictal psychosis does not constitute a contraindication to surgical treatment of epilepsy.

Adult↗
PubMed1996

Tetrapolar fungal mating types: sexes by the thousands.

In order to achieve genetic rearrangement in a sexual cycle, eukaryotes go through the processes of meiosis and mating. Different mating types assure that mating is only possible between two genetically diverse individuals. Basidiomycetous fungi display thousands of different mating types that are determined by two genetically unlinked loci. One locus is multiallelic and contains genes for homeodomain transcription factors which are able to form heterodimers. The activation of target genes is dependent on heterodimers formed from the monomeric transcription factor proteins originating from different alleles of this genetic locus. The interactions between the two monomeric transcription factors and the activation of target genes by the heterodimeric proteins make this regulatory system both complex and interesting. The second locus contains a pheromone receptor system: the pheromone receptor is similar to the G protein-linked serpentine receptors in Saccharomyces cerevisiae that activate the pheromone response via a phosphorylation signal transduction cascade in S. cerevisiae. This pheromone perception is a trigger of sexual development and not, as with yeast, itself under control of mating type genes. Rather it directly senses diversity at the mating type loci. Whereas heterobasidiomycetes display a bi-allelic structure for this locus with recognition between one receptor and the opposite pheromone, homobasidiomycetes contain multiple specificities for pheromone receptors and pheromones.

Basidiomycota↗
PubMed1991

Expression of class I major histocompatibility complex antigens in Epstein-Barr virus-carrying lymphoblastoid cell lines and Burkitt lymphoma cells.

Epstein-Barr virus (EBV) carrying lymphoblastoid cell lines (LCLs) and EBV-positive Burkitt lymphoma (BL) cells were compared for their expression of class I antigens of the major histocompatibility complex. Five common BL lines, LCLs, pokeweed mitogen-stimulated blasts and resting B-cells from healthy donors, and eight pairs of BL cells and LCLs, each pair originating from one patient, were tested. Quantitative analysis was performed using a radioimmunoassay; qualitative aspects were studied by one- and two-dimensional gel electrophoresis. In general, LCLs expressed significantly higher amounts of class I antigens than BL cells, the latter showing class I densities similar to or lower than peripheral resting B-cells. From analysis of the expression of class I-specific RNA, there is some evidence that class I antigen expression is regulated on the transcriptional level. In two BL cells studied, class I expression could be enhanced by gamma-interferon, whereas the corresponding LCLs seemed to be refractory to this treatment. One- and two-dimensional gel electrophoresis showed that in some BL lines, in addition to the generally lower class I expression, distinct class I specificities were down-regulated. None of these alterations in class I expression was EBV specific; however, they may well play a role in the recognition of BL cells and LCLs by cellular immune mechanisms. Thus, down-regulation of class I antigens may contribute to the resistance of BL cells to cytotoxic T-lymphocytes, whereas their enhanced expression may improve the recognition of EBV-infected LCLs.

Blotting, Northern↗
PubMed1996

A concerted tryptophanyl-adenylate-dependent conformational change in Bacillus subtilis tryptophanyl-tRNA synthetase revealed by the fluorescence of Trp92.

A semi-conserved tryptophan residue of Bacillus subtilis tryptophanyl-tRNA synthetase (TrpRS) was previously asserted to be an essential residue and directly involved in tRNATrp binding and recognition. The crystal structure of the Bacillus stearothermophilus TrpRS tryptophanyl-5'-adenylate complex (Trp-AMP) shows that the corresponding Trp91 is buried and in the dimer interface, contrary to the expectations of the earlier assertation. Here we examine the role of this semi-conserved tryptophan residue using fluorescence spectroscopy. B. subtilis TrpRS has a single tryptophan residue, Trp92. 4-Fluorotryptophan (4FW) is used as a non-fluorescent substrate analog, allowing characterization of Trp92 fluorescence in the 4-fluorotryptophanyl-5'-adenylate (4FW-AMP) TrpRS complex. Complexation causes the Trp92 fluorescence to become quenched by 70%. Titrations, forming this complex under irreversible conditions, show that this quenching is essentially complete after half of the sites are filled. This indicates that a substrate-dependent mechanism exists for the inter-subunit communication of conformational changes. Trp92 fluorescence is not efficiently quenched by small solutes in either the apo- or complexed form. From this we conclude that this tryptophan residue is not solvent exposed and that binding of the Trp92 to tRNATrp is unlikely. Time-resolved fluorescence indicates conformational heterogeneity of B. subtilis Trp92 with the fluorescence decay being best described by three discrete exponential decay times. The decay-associated spectra (DAS) of the apo- and complexed-TrpRS show large variations of the concentration of individual fluorescence decay components. Based on recent correlations of these data with changes in the local secondary structure of the backbone containing the fluorescent tryptophan residue, we conclude that changes observed in Trp92 time-resolved fluorescence originate primarily from large perturbations of its local secondary structure. The quenching of Trp92 in the 4FW-AMP complex is best explained by the crystal structure conformation, in which the tryptophan residue is found in an alpha-helix. The amino acid residue cysteine is observed clearly within the quenching radius (3.6 angstroms) of the conserved tryptophan residue. These tryptophan and cysteine residues are neighbors, one helical turn apart. If this local alpha-helix was disrupted in the apo-TrpRS, this disruption would concomitantly relieve the putative cysteine quenching by separating the two residues. Hence we propose a substrate-dependent local helix-coil transition to explain both the observed time-resolved and steady-state fluorescence of Trp92. A mechanism can be further inferred for the inter-subunit communication involving the substrate ligand Asp132 and a small alpha-helix bridging the substrate tryptophan residue and the conserved tryptophan residue of the opposite subunit. This putative mechanism is also consistent with the observed pH dependence of TrpRS crystal growth and substrate binding. We observe that the mechanism of TrpRS has a dynamic component, and contend that conformational dynamics of aminoacyl-tRNA synthetases must be considered as part of the molecular basis for the recognition of cognate tRNA.

Adenosine Monophosphate↗
PubMed1985

Clonal analysis of cytotoxic T-lymphocyte response to autologous human metastatic melanoma.

Peripheral blood lymphocytes (PBL) from a melanoma (Me) patient, previously shown to be unable to react against the autologous tumor (Me 28) after mixed lymphocyte-tumor culture (MLTC), were cultured in vitro with the autologous tumor in MLTC and/or with IL-2-containing supernatants. T-cell clones were then obtained by limiting dilution and by micromanipulation. Eleven clones, selected for autologous tumor (Auto-Tu) cytotoxicity, were tested for specificity on a panel of 17 cell cultures of normal and neoplastic origin, revealing a complex spectrum of lytic activities. Three groups of clones could be identified depending on the patterns of cytotoxicity. One clone (B11.12) lysed Me28 and expressed a borderline reactivity against one allogeneic Me. A second group of clones (A4, A4.18, H10, E12, C9) lysed the Auto-Tu and allogeneic Me. The last group of clones (A4.2, A4.3, A4.4, A7, B7) expressed a broader pattern of reactivity with significant cytotoxicity against targets of different histologic origin. Furthermore, the second and third groups of clones lysed K562 while B11.12 did not. The Auto-Tu-restricted reactivity of clone B11.12, confirmed by a further test on 13 allogeneic Me and on autologous IL-2 cultured lymphocytes, suggests the recognition of antigenic structures preferentially expressed on Me28. Blocking studies, performed with monoclonal antibodies (MAb), revealed that an anti-HLA class I MAb (w6/32), but not two anti-DR MAbs (L243, DI.12), could inhibit the cytotoxic activity of clones B11.12 on Me28. A significant blocking effect by w6/32 on Me28 was achieved also with clones A4.4 and H10 but not with clones A4.2, A4.3 and A7. The phenotype of all clones was T3+, T4-, T8+, HNK-I-, suggesting that the anti-tumor effectors were of the T-cell lineage. Taken together, these data indicate that it is possible to isolate anti-tumor CTL-clones after MLTC from a PBL population of a metastatic melanoma patient. Furthermore, we present evidence suggesting a role of class-I antigens in the interaction of some cloned effectors with the autologous tumor target.

Antibodies, Monoclonal↗
PubMed2002

The medial pain system: neural representations of the motivational aspect of pain.

In this article, we propose that the pathways mediating the motivational aspect of pain originate in laminae VII and VIII of the spinal cord, and in the deep layers of the spinal trigeminal complex, and projections from these areas reach three central structures where pain motivation is represented, the ventrolateral quadrant of the periaqueductal gray, posterior hypothalamic nucleus, and intralaminar thalamic nuclei. A final representation of the motivational aspect of pain is located within the anterior cingulate cortex, and this representation receives inputs from the intralaminar nuclei. Outputs from these representations reach premotor structures located in the medulla, striatum, and cingulate premotor cortex. We discuss pathways and structures that provide inputs to these representations, including those involved in producing involuntary (innate) and instrumental responses which occur in response to the recognition of stimuli associated with footshock and other nociceptive stimuli.

Animals↗