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PubMed2006

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

Genetic Predisposition to Disease↗

PubMed2001

Hybrid skeletal muscle fibres: a rare or common phenomenon?

1. The main aim of the present review is to raise awareness of the molecular complexity of single skeletal muscle fibres from "normal" and "transforming" muscles, in recognition of the many types of hybrids that have been observed in vertebrate skeletal muscle. The data used to illustrate various points made in the review were taken from studies on mammalian (mostly rat) and amphibian muscles. 2. The review provides a brief overview of the pattern and extent of molecular heterogeneity in hybrid muscle fibres and of the methodological problems encountered when attempting to identify and characterize such fibres. Particular attention is given to four types of skeletal muscle hybrids: (i) myosin heavy chain (MHC) hybrids; (ii) mismatched MHC-myosin light chains (MLC) hybrids; (iii) mismatched MHC-regulatory protein hybrids; and (iv) hybrids containing mismatched MHC-sarcoplasmic reticulum protein isoforms. 3. Some of the current ideas regarding the functional significance, origin and cognitive value of hybrid fibres are examined critically.

Animals↗

PubMed1990

E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins.

We have previously expressed in transgenic mice a chimeric H-2Kd/Kk protein called C31, which contains the extracellular alpha 1 domain of Kd, whereas the rest of the molecule is of Kk origin. This molecule functions as a restriction element for alloreactive and influenza A-specific cytotoxic T lymphocytes (CTL) but is only weakly expressed at the cell surface of splenocytes. Here, we show that the low cell surface expression is the result of slow intracellular transport and processing of the C31 protein. A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus-specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein. This result implies that the E3/19K protein may act by inhibiting peptide binding or by disrupting the oligomerization of MHC class I molecules required for transport out of the ER. Alternatively, the E3/19K protein may inhibit the function of a positively acting transport molecule necessary for cell surface expression of MHC class I molecules.

Adenovirus E3 Proteins↗

PubMedDate not supplied

Generation of melanoma-specific cytotoxic T lymphocytes for allogeneic immunotherapy.

To exploit alloreactive T-cell responses known as the graft-versus-tumor effect, allogeneic hematopoietic stem cell transplantation is being explored as experimental therapy in selected solid tumors, including metastatic melanoma. However, donor T-cell responses are often delayed and associated with severe graft-versus-host disease. Posttransplant adoptive immunotherapy using tumor-specific cytotoxic T lymphocytes (CTL) of donor origin might provide immediate graft-versus-tumor effects but not graft-versus-host disease. Therefore, the aim of the current study was to define in vitro conditions for the expansion of allogeneic major histocompatibility complex-matched CTLs targeting melanoma-associated antigens (MAA). The CTLs were generated from peripheral blood mononuclear cells (PBMCs) of HLA-A*0201+ healthy donors by repetitive stimulations with HLA-A*0201-restricted MAA-derived peptides. Melanoma reactivity, as determined by lysis of peptide-pulsed T2 cells and HLA-A2+/Ag+ melanoma cells, was detected using in vitro expanded CTL targeting MAA peptides AAGIGILTV(MT(27-35)), IMDQVPFSV(G(209-2M)), and YMDGTMSQV(T(368-376)). In contrast, FLWGPRALV(MAGE3(271)-(279)) and VLPDVFIRCV(GnT-V(nt38-67)) induced peptide-specific recognition of T2 target cells only, whereas ITDQVPFSV(G(209-217)), KTWGQYWQV(G9(154)), MLLAVLYCL(T(1-9)), and tumor lysate could not induce specific CTLs. Specific cytolytic activity was accompanied by interferon-gamma secretion. Peptide-pulsed dendritic cells were required only for the initial stimulation of CTLs and could be substituted by PBMCs during restimulations. The median expansion rate of CTL was five to six times, regardless of whether dendritic cells or PBMCs were used after the initial stimulation. The results delineate the conditions for effective ex vivo expansion of melanoma-specific CTLs from PBMCs of healthy donors to be used as an adjunct in allogeneic cell therapy of metastatic melanoma.

Amino Acid Sequence↗

PubMed2006

Insight into the evolution of avian flight from a new clade of Early Cretaceous ornithurines from China and the morphology of Yixianornis grabaui.

In studies of the evolution of avian flight there has been a singular preoccupation with unravelling its origin. By contrast, the complex changes in morphology that occurred between the earliest form of avian flapping flight and the emergence of the flight capabilities of extant birds remain comparatively little explored. Any such work has been limited by a comparative paucity of fossils illuminating bird evolution near the origin of the clade of extant (i.e. 'modern') birds (Aves). Here we recognize three species from the Early Cretaceous of China as comprising a new lineage of basal ornithurine birds. Ornithurae is a clade that includes, approximately, comparatively close relatives of crown clade Aves (extant birds) and that crown clade. The morphology of the best-preserved specimen from this newly recognized Asian diversity, the holotype specimen of Yixianornis grabaui Zhou and Zhang 2001, complete with finely preserved wing and tail feather impressions, is used to illustrate the new insights offered by recognition of this lineage. Hypotheses of avian morphological evolution and specifically proposed patterns of change in different avian locomotor modules after the origin of flight are impacted by recognition of the new lineage. The complete articulated holotype specimen of Yixianornis grabaui, from the Early Cretaceous Jiufotang Formation of Liaoning Province, in north-eastern China, arguably the best-preserved basal ornithurine specimen yet discovered, provides the earliest evidence consistent with the presence of extant avian tail feather fanning.

Animals↗

PubMed1986

Human and animal serotypes of Bacteroides gingivalis defined by crossed immunoelectrophoresis.

The antigenic complexity of three strains of Bacteroides gingivalis and four strains resembling B. gingivalis isolated from animals was analyzed and compared by crossed immunoelectrophoresis. Thirteen antigens of the human biotype were present in all human strains and six antigens of the animal biotype were present in all animal strains, indicating a marked serological homogeneity within each biotype. Four antigens cross-reacting between the human B. gingivalis and the animal strains were identified. This antigenic relatedness defined the serological homogeneity of the two biotypes within the species and allowed recognition of four species-specific antigens. Two antigens specific to the human strains and two antigens specific to the animal strains were identified, indicating that serotype-specific antigens can distinguish each biotype. It is thus proposed that the oral, black-pigmented asaccharolytic Bacteroides strains of animal origin be classified as catalase-positive variants of B. gingivalis. It is also proposed that two serotypes be recognized within the species B. gingivalis. Serotype 1 includes the catalase-negative human biotype, and serotype 2 includes the catalase-positive animal biotype.

Animals↗

PubMed2003

The Mycobacterium tuberculosis complex-restricted gene cfp32 encodes an expressed protein that is detectable in tuberculosis patients and is positively correlated with pulmonary interleukin-10.

Human tuberculosis (TB) is caused by the bacillus Mycobacterium tuberculosis, a subspecies of the M. tuberculosis complex (MTC) of mycobacteria. Postgenomic dissection of the M. tuberculosis proteome is ongoing and critical to furthering our understanding of factors mediating M. tuberculosis pathobiology. Towards this end, a 32-kDa putative glyoxalase in the culture filtrate (CF) of growing M. tuberculosis (originally annotated as Rv0577 and hereafter designated CFP32) was identified, cloned, and characterized. The cfp32 gene is MTC restricted, and the gene product is expressed ex vivo as determined by the respective Southern and Western blot testing of an assortment of mycobacteria. Moreover, the cfp32 gene sequence is conserved within the MTC, as no polymorphisms were found in the tested cfp32 PCR products upon sequence analysis. Western blotting of M. tuberculosis subcellular fractions localized CFP32 predominantly to the CF and cytosolic compartments. Data to support the in vivo expression of CFP32 were provided by the serum recognition of recombinant CFP32 in 32% of TB patients by enzyme-linked immunosorbent assay (ELISA) as well as the direct detection of CFP32 by ELISA in the induced sputum samples from 56% of pulmonary TB patients. Of greatest interest was the observation that, per sample, sputum CFP32 levels (a potential indicator of increasing bacterial burden) correlated with levels of expression in sputum of interleukin-10 (an immunosuppressive cytokine and a putative contributing factor to disease progression) but not levels of gamma interferon (a key cytokine in the protective immune response in TB), as measured by ELISA. Combined, these data suggest that CFP32 serves a necessary biological function(s) in tubercle bacilli and may contribute to the M. tuberculosis pathogenic mechanism. Overall, CFP32 is an attractive target for drug and vaccine design as well as new diagnostic strategies.

Amino Acid Sequence↗

PubMed2005

Rheumatoid factors: good or bad for you?

BACKGROUND: Rheumatoid factors (RFs) are autoantibodies associated with rheumatoid arthritis. They can be detected in normal individuals, although transiently. This dichotomy has led to questions about the origins and types of RFs. Recently it has been shown that B cells that produce RFs only do so when activated by two signals, one from engagement of the B-cell receptor and the other from recognition of a pathogen-associated molecular pattern through a Toll-like receptor (TLR). These autoantibodies thus link the innate and acquired immune responses. OBJECTIVE: Through a review of the literature, an examination of the current knowledge of RF induction is presented. The focus is on a discussion of a beneficial or detrimental role for RFs in normal individuals and in those with chronic disease. RESULTS: What makes RF 'good' in some cases and 'bad' in others may reflect the type of RF produced. Low-affinity polyreactive IgM RFs are probably beneficial as they aid in the clearance of immune complexes that are more efficiently cleared, and the RF B cell can act as an antigen-presenting cell and stimulate host defense. However, large amounts of high-affinity RFs found in patients with chronic disease may be harmful by participation in a vicious cycle of autoantibody production by stimulation of self lymphocytes, and/or deposition in blood vessels thus causing vasculitis. CONCLUSIONS: Whether RFs are beneficial or detrimental depends on the context in which they are expressed, the type and amount of RF produced, whether the response is perpetuated by TLR ligation and whether other cells are stimulated either directly or indirectly by RF-positive B cells.

Animals↗

PubMed2006

Autoantibodies to intracellular autoantigens and their B-cell epitopes: molecular probes to study the autoimmune response.

A common laboratory finding in systemic autoimmune diseases is the presence of autoantibodies against intracellular autoantigens. Although their pathogenesis is not fully understood, autoantibodies are important tools for establishing diagnosis, classification, and prognosis of autoimmune diseases. Autoantibodies mainly target multicomponent complexes containing both protein antigens and (ribo)-nucleic acid(s), such as the spliceosome or Ro/La RNPs. In this review, we address the main characteristics and the clinical value of the main autoantibody types with respect to their disease association, and we describe the corresponding autoantigens, their biologic function, and their B-cell antigenic determinants (epitopes). The structural characteristics and clinical associations of these epitopes, and their utility as tools to investigate the autoimmune response, are discussed in detail. New insights into the pathogenetic role of epitopes in systemic autoimmunity are also examined. In this regard, using the defined structures of the B-cell antigenic epitopes, complementary epitopes can be designed according to the "molecular recognition" theory. These complementary epitopes can be used as probes to study pathogenetic and immunoregulatory aspects of the anti-idiotypic response. The origin of humoral autoimmunity and the spreading of the epitopes in systemic lupus erythematosus are also discussed. Finally, the ability of post-translational modifications to induce autoreactive immune attack via the generation of neo-epitopes is summarized.

Autoantibodies↗

PubMed2002

Dissecting the molecular origins of specific protein-nucleic acid recognition: hydrostatic pressure and molecular dynamics.

The fundamental processes by which proteins recognize and bind to nucleic acids are critical to understanding cellular function. To explore the factors involved in protein-DNA recognition, we used hydrostatic pressure to perturb the binding of the BamHI endonuclease to cognate DNA, both in experiment and in molecular dynamic simulations. A new technique of high-pressure gel mobility shift analysis was used to test the effects of elevated hydrostatic pressure on the binding of BamHI to its cognate recognition sequence. Upon application of a pressure of 500 bar, the equilibrium dissociation constant of BamHI binding to the cognate site was found to increase nearly 10-fold. A challenge has been to link this type of pure thermodynamic measurement to functional events occurring at the molecular level. Thus, we used molecular dynamic simulations at both ambient and elevated pressures to reveal details of the direct and water-mediated interactions between BamHI and cognate DNA, which allow explanation of the effects of pressure on site-specific protein-DNA binding and complex stability.

Base Sequence↗

PubMed1999

[Two individuals under the same skin--immune mechanisms in pregnancy].

The fetus may be regarded as an allograft in the maternal organism. This paper gives an overview of pregnancy-associated immune mechanisms, based on the literature and studies performed by the authors. During implantation, maternal tissues are invaded by fetal trophoblasts expressing HLA-G, a trophoblast-specific variant of HLA Class I antigens. Recognition of HLA-G stimulates uterine natural killer cells to cytokine production, by which an intrauterine immunosuppression is established. Development, growth and differentiation of placenta is regulated by the cytokines produced. Uterine leukocyte population and expression of cytokine receptors in placental tissues varies throughout gestation, and the complex interplay between trophoblasts and uterine cells, involving a number of cytokines, cytokine receptors, adhesion molecules, enzymes and hormones, changes with gestation. Some cytokines, such as tumour necrosis factor and interleukin-1, may threathen the reproductive process and fetal well-being in high doses. A tight regulation of cytokine activities is probably obtained by the observed upregulation of endogenous cytokine buffer mechanisms in pregnancy. The reproductive success and phenomenons like implantation, placental growth and development, maintenance of pregnancy and delivery, appear to rely on complex, gestational age related interplay between cells of fetal origin and the maternal immune system.

Cytokines↗

PubMed1990

The ABC-primosome. A novel priming system employing dnaA, dnaB, dnaC, and primase on a hairpin containing a dnaA box sequence.

A priming mechanism requiring dnaA, dnaB, and dnaC proteins operates on a single-stranded DNA coated with single-stranded DNA-binding protein. This novel priming, referred to as "ABC-priming," requires a specific hairpin structure whose stem carries a dnaA protein recognition sequence (dnaA box). In conjunction with primase and DNA polymerase III holoenzyme, ABC-priming can efficiently convert single-stranded DNA into the duplex replicative form. dnaA protein specifically recognizes and binds the single-stranded hairpin and permits the loading of dnaB protein to form a prepriming protein complex containing dnaA and dnaB proteins which can be physically isolated. ABC-priming can replace phi X174 type priming on the lagging strand template of pBR322 in vitro, suggesting a possible function of ABC-priming for the lagging strand synthesis and duplex unwinding. Similar to the phi X174 type priming, a mobile nature of ABC-priming was indicated by helicase activity in the presence of ATP of a prepriming protein complex formed at the hairpin. The implications of this novel priming in initiation of replication at the chromosomal origin, oriC, and in its contribution to the replication fork are discussed.

Bacterial Proteins↗

PubMed1986

Antibodies against small nuclear ribonucleoproteins immunoprecipitate complexes containing ts110 Moloney murine sarcoma virus genomic and messenger RNAs.

Small nuclear ribonucleoproteins (snRNPs) are believed to play a role in processing premessenger RNAs. In this study, snRNPs were immunoprecipitated from extracts of cells infected with ts110 Moloney murine sarcoma virus (ts110 MoMuSV). Both the unspliced 4.0 kb and the spliced 3.5-kb ts110 MoMuSV specific RNA species were found in the immunoprecipitates obtained with monoclonal antibody anti-Sm and polyclonal anti-Sm, anti-(U1) RNP and anti-La sera. Although only a portion of the total ts110 RNAs was present in these immunoprecipitates, immune recognition by the anti-snRNPs was specific and not due to contaminating anti-RNA (at least for the anti-Sm sera) or, to anti-viral protein activities. Genomic 8.3-kb RNA and subgenomic 3.0-kb spliced env mRNA from Moloney murine leukemia virus (MoMuLV) infected cells as well as the cellular actin mRNA were also detected in immunoprecipitates obtained with the same antisera. The fact that pre-mRNAs and mature mRNAs of different origin can be recovered from immunoprecipitates formed with anti-snRNP sera establishes their tight association and confirms the role of snRNPs in mRNA processing.

Actins↗

PubMed1995

Genomic structure and expression of the human gene encoding cytochrome b561, an integral protein of the chromaffin granule membrane.

Cytochrome b561 is an electron transfer protein unique to neuroendocrine secretory vesicles. The Southern blot hybridization shows that it is a single copy gene highly conserved throughout phylogeny. The transcription unit spans approximately 11 kilobases, and heterologous transcription sites are located 404 bases 5' to the translation initiation codon. The sequence of the 5'-flanking region is GC-rich and lacks a typical TATA box at the usual position. However, it has a CAAT sequence at -132 and potential recognition sequences for several transcription factors including SP1, GR-PR-MMTV, AP4, gERE, JCV repeat, AP2, and NF-kappa B. Each of the five transmembrane segments are encoded by five consecutive exons. This corroborates the five-transmembrane model proposed for human, mouse, and Xenopus rather than six proposed for bovine. The cytochrome was found to be highly expressed in colon cancer cell lines, T cell lymphomas, and K-562 cell lines. However, in B-cell lymphomas such as Burkitt's and Daudi, the cytochrome b561 expression was completely shut down. The results in this report are the first to demonstrate the structural organization and regulatory sequences of the cytochrome b561 gene encoding an integral membrane protein of neuroendocrine storage vesicles of neurotransmitters and peptide hormones. Unexpected results on cytochrome b561 expression in cells of lymphocytic origin and its complex regulation in tumor cells provide new insights into cytochrome b561 gene regulation.

Animals↗

PubMed2006

Binary tree of SVM: a new fast multiclass training and classification algorithm.

We present a new architecture named Binary Tree of support vector machine (SVM), or BTS, in order to achieve high classification efficiency for multiclass problems. BTS and its enhanced version, c-BTS, decrease the number of binary classifiers to the greatest extent without increasing the complexity of the original problem. In the training phase, BTS has N - 1 binary classifiers in the best situation (N is the number of classes), while it has log4/3 ((N + 3)/4) binary tests on average when making a decision. At the same time the upper bound of convergence complexity is determined. The experiments in this paper indicate that maintaining comparable accuracy, BTS is much faster to be trained than other methods. Especially in classification, due to its Log complexity, it is much faster than directed acyclic graph SVM (DAGSVM) and ECOC in problems that have big class number.

Algorithms↗

PubMed1998

Regulatory implications of protein assemblies at the gamma origin of plasmid R6K - a review.

Recognition of the replication origin (ori) by initiator protein is a recurring theme for the regulated initiation of DNA replication in diverse biological systems. The objective of the work reviewed here is to understand the initiation process focusing specifically on the gamma-ori of the antibiotic-resistance plasmid R6K. The control of gamma-ori copy number is determined by both plasmid-encoded and host-encoded factors. The two central regulatory elements of the plasmid are a multifunctional initiator protein pi, and sequence-related DNA target sites, the inverted half-repeats (IRs) and the direct repeats (DRs). The replication activator and inhibitor activities of pi seem to be at least partially distributed between two naturally occurring pi polypeptides (designated by their molecular weights pi35.0 and pi30.5). Regulatory variants of pi with altered states of oligomerization in nucleoprotein complexes with DRs and IRs have been isolated. The properties of these mutants laid the foundation for our model of pi protein activity which proposes that different protein surfaces are required for the formation of functionally distinct complexes of pi with DRs and IRs. These mutants also suggest that pi polypeptides have a modular structure; the C-terminus contains the DNA-binding domain while the N-terminus controls protein oligomerization. Additionally, pi35.0 binds to a novel DNA sequence in the A+T-rich segment of gamma-ori. This binding site is at or near the site from which synthesis of the leading strand begins.

Base Sequence↗

PubMed1995

Mutation of the Oct-1 POU-specific recognition helix leads to altered DNA binding and influences enhancement of adenovirus DNA replication.

To assess which residues of Oct-1 POU-specific (POUs) are important for DNA recognition and stimulation of adenovirus DNA replication we have mutated 10 residues of the POUs helix-turn-helix motif implicated in DNA contact. Seven of these turned out to have reduced DNA binding affinity. Of these, three alanine substituted proteins were found to have a changed specificity using a binding site selection procedure. Mutation of the first residue in the recognition helix, Gln44, to alanine led to a loss of specificity for the first two bases, TA, of the wild-type recognition site TATGC(A/T)AAT. Instead of the A, a T was selected, suggesting a new contact and a novel specificity. A change in specificity was also observed for the T45A mutant, which could bind to TATAC(A/T)AAT, a site hardly recognized by the wild-type protein. Mutation of residue Arg49 led to a relaxed specificity for three consecutive bases, TGC. This residue, which is critical for high affinity binding, is absent from the structurally homologous lambdoid helix-turn-helix motifs. Employing a reconstituted system all but two mutants could stimulate adenovirus DNA replication upon saturation. Mutation of residues Gln27 and Arg49 impairs the ability of the Oct-1 POU domain protein to enhance replication, with a concomitant loss of DNA contacts. Since the POU domain binds the precursor terminal protein-DNA polymerase complex and guides it to the origin, lack of stimulation may be caused by incorrect targetting of the DNA polymerase due to loss of specificity.

Adenoviridae↗

PubMed2004

Brazilian standardised norms for a set of pictures are comparable with those obtained internationally.

Snodgrass & Vanderwart (1980) standardized a set of 260 pictures in the USA for use in studies of cognitive processes that employ pictured objects as laboratory analogues of object themselves. Since then similar norms for this set were obtained in Britain, Spain, Japan and Iceland and a larger set of 400 pictures (including the original 260: Cycowicz et al., 1997) was studied in France and Brazil. The present article provides a comparison of the norms obtained in Brazil and internationally. The pattern of correlations among the Brazilian and other standardizations were equivalent to that previously observed: despite pictures being judged to be of similar familiarity and visual complexity (high positive correlations), name agreement was less correlated, possibly due to differences in the languages spoken in each country and/or in the sample size used in each study. Results confirm the adequacy of the Brazilian norms.

Brazil↗