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Biomedical subjects

J Trowsdale

Publications and source records attributed to J Trowsdale.

At least 19 recordsLinked to original sources
PubMed2006

Consistent patterns of expression of HLA class I free heavy chains in healthy individuals and raised expression in spondyloarthropathy patients point to physiological and pathological roles.

OBJECTIVES: Major histocompatibility complex class I (MHC-I) proteins exist at the cell surface in antigen presenting forms and as beta2m-independent free heavy chains (FHCs). FHCs have been implicated in spondyloarthritis, but little is known about their expression in healthy individuals. We studied FHC expression on various human cell types, comparing spondyloarthropathy patients with healthy and rheumatoid arthritis (RA) patient controls. METHODS: MHC-I expression was analysed by flow cytometry. FHC levels were normalized for overall MHC-I to generate a relative expression level. Relative FHC levels were analysed for peripheral blood and trophoblast samples from healthy volunteers, RA and spondyloarthropathy patients. Macrophages and dendritic cells were cultured in vitro to analyse changes following activation. Peripheral blood leucocytes from patients with ankylosing spondylitis (AS) and RA were treated with inflammatory stimuli and subsequent alterations in their relative FHC levels were analysed. RESULTS: We found consistent patterns of differential relative FHC expression across lymphocyte subpopulations and particularly high expression on extravillous trophoblast. FHCs were present at higher levels in a reactive arthritis (ReA) population than in healthy controls and RA patients; differences not merely due to the presence of Human Leucocyte Antigen (HLA) B27. Treatment of leucocytes from arthritic patients with bacterial lipopolysaccharide resulted in significant up-regulation of FHC compared with an HLA B27+ control population. CONCLUSIONS: Our findings define normal levels and tissue expression of FHCs, and support the hypothesis that disregulation of heavy chain expression may play a pathogenic role in spondyloarthropathy.

Adult↗
PubMed2006

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility.

Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell subsets and produce either activation or inhibitory signals upon binding with the appropriate human leucocyte antigen (HLA) ligand on target cells. Recent genetic association studies have implicated KIR genotype in the development of several inflammatory conditions. Ulcerative colitis (UC) is an inflammatory disorder of the colonic mucosa that results from an inappropriate activation of the immune system driven by host bacterial flora. We developed a polymerase chain reaction-sequence specific primer (SSP)-based assay to genotype 194 UC patients and 216 control individuals for 14 KIR genes, the HLA-Cw ligand epitopes of the KIR2D receptors and a polymorphism of the lectin-like-activating receptor NKG2D. Initial analysis found the phenotype frequency of KIR2DL2 and -2DS2 to be significantly increased in the UC cohort (P=0.030 and 0.038, respectively). Logistic regression analysis revealed a protective effect conferred by KIR2DL3 in the presence of its ligand HLA-Cw group 1 (P=0.019). These results suggest that KIR genotype and HLA ligand interaction may contribute to the genetic susceptibility of UC.

Base Sequence↗
PubMed2006

The LRC haplotype project: a resource for killer immunoglobulin-like receptor-linked association studies.

There is increasing evidence for epistatic interactions between gene products (e.g. KIR) encoded within the Leukocyte Receptor Complex (LRC) with those (e.g. HLA) of the Major Histocompatibility Complex (MHC), resulting in susceptibility to disease. Identification of such associations at the DNA level requires comprehensive knowledge of the genetic variation and haplotype structure of the underlying loci. The LRC haplotype project aims to provide this knowledge by sequencing common LRC haplotypes.

Chromosome Mapping↗
PubMed2004

The LILR family: modulators of innate and adaptive immune pathways in health and disease.

Leukocyte immunoglobulin (Ig)-like receptors [LILRs, also known as Ig-like transcripts (ILTs)] are a family of inhibitory and stimulatory receptors encoded within the leukocyte receptor complex and are expressed by immune cell types of both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I. The immunomodulatory role of LILR receptors indicates that they may exert an influence on signaling pathways of both innate and adaptive immune systems. LILR activity can also influence the antigen-presenting properties of macrophages and dendritic cells and may thus play a role in T-cell tolerance. The wide-ranging effects of LILR signaling on immune cell activity imply that these receptors are likely to play an important role in a range of clinical situations including pregnancy, transplantation, and arthritis (including the human leukocyte antigen B27-associated spondyloarthropathies). In this review, we summarize current knowledge on the nature and function of LILRs, focusing on their regulation of immune cell activity and their potential role in disease.

Animals↗
PubMed2003

Cluster of TRIM genes in the human MHC class I region sharing the B30.2 domain.

The major histocompatibility complex (MHC), a region of high gene density, contains a large number of genes relevant to the immune response, belonging to different multigenic families. We studied the genomic organization and polymorphism of a set of genes in the MHC class I region containing the tripartite motif (TRIM), consisting of a RING domain, B-box and coiled coil region, and a B30.2-like domain. A cluster of seven genes at 6p21.33 and two related family members telomeric of the cluster were characterized. All MHC-encoded TRIM-B30.2 genes showed moderate levels of polymorphism, affecting predominantly the RING and B-box domains. In terms of structure, the genes varied by the loss of partial and, in some cases, complete domains. They were strongly conserved in exons 2, 3 and 4, which form the coiled-coil region. The last exon, encoding the B30.2-like domain, is shared with the otherwise unrelated butyrophilin-like (BTN) genes, located 4.3 Mb telomeric of the TRIM-B30.2 cluster. The data are consistent with multiple, ancient duplications giving rise to a set of related genes.

Amino Acid Motifs↗
PubMed2002

Human atherosclerotic plaques express DC-SIGN, a novel protein found on dendritic cells and macrophages.

The association of autoimmune phenomena with atherosclerosis suggests that plaques may contain specialized antigen-presenting cells, dendritic cells (DCs). DC-SIGN is a C-type lectin expressed by DCs. This study assessed whether human atherosclerotic plaques expressed DC-SIGN and several other macrophage/DC markers. Plaques from human coronary and carotid arteries and aorta contained DC-SIGN-immunoreactive cells. Double-labelling showed co-expression of DC-SIGN and macrophage/DC lineage markers CD14, CD68, HLA-DR, and S100. There was no immunoreactivity for the DC activation markers CD83 or CMRF-44. Since DC-SIGN mediates adhesion to T-lymphocytes and endocytosis, its expression in atherosclerotic plaques may have functional implications. Activated DCs migrate quickly from areas of inflammation to regional lymph nodes, possibly explaining the paucity of activated DCs in atherosclerotic plaques. In conclusion, this study has shown that DC-SIGN is expressed in atherosclerosis.

Aorta, Abdominal↗
PubMed2001

In vivo and in vitro modulation of HLA-DM and HLA-DO is induced by B lymphocyte activation.

Ag presentation via HLA class II molecules in B lymphocytes depends on the coordinated action of HLA-DM, the catalyst of class II-peptide loading, and HLA-DO, a pH-dependent modulator of DM, the expression of which is almost completely restricted to B lymphocytes. The relative expression levels of both class II modulators are critical for the composition of the HLA class II peptide repertoire. The data in this work demonstrate that DO and DM expression are both dependent on the cellular activation status in primary human B lymphocytes. In vivo low-density activated primary human B lymphocytes show a prominent reduction in DO and DM expression when compared with high-density resting primary B lymphocytes. In vitro, reduction of DO and DM expression can be induced by B lymphocyte activation via the B cell receptor or by use of the phorbol ester, PMA. Specific inhibition of protein kinase C resulted in a significant reduction of HLA-DO and is potentially due to protein degradation in lysosomal compartments as the phenomenon is reversed by chloroquine. Thus, the expression of the dedicated HLA class II chaperone DM and its pH-dependent modulator DO is regulated and tightly controlled by the activation status of the B lymphocyte.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2001

Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.

We studied recognition of the disease-associated HLA-B27 allele by immunomodulatory receptors encoded within the leukocyte receptor complex. HLA class I are ligands for members of the killer Ig receptor (KIR) and Ig-like transcript (ILT)/LIR/LILR families (the new LILR nomenclature is described at www. gene.ucl.ac.uk/nomenclature/genefamily/lilr.html). Members of these families bound HLA-B27 in both classical and beta(2) microglobulin-independent forms. Classical complexes bound ILT2, ILT4, and LIR6 transfectants but not ILT1, ILT3, or ILT5. A free H chain form of HLA-B27 bound ILT4 and LIR6. Both forms of HLA-B27 bound KIR3DL1 transfectants. HLA-B27 free H chain bound CD14(+) cells in PBL from healthy controls, consistent with ILT4 expression on monocytes. Alternative recognition of different forms of HLA-B27 by KIR or ILT could influence their immunomodulatory function and may imply a role in inflammatory disease.

Antigens, CD↗
PubMed2001

Peptide binding characteristics of the non-classical class Ib MHC molecule HLA-E assessed by a recombinant random peptide approach.

BACKGROUND: Increasing evidence suggests that the effect of HLA-E on Natural Killer (NK) cell activity can be affected by the nature of the peptides bound to this non-classical, MHC class Ib molecule. However, its reduced cell surface expression, and until recently, the lack of specific monoclonal antibodies hinder studying the peptide-binding specificity HLA-E. RESULTS: An in vitro refolding system was used to assess binding of recombinant HLA-E to either specific peptides or a nonamer random peptide library. Peptides eluted from HLA-E molecules refolded around the nonamer library were then used to determine a binding motif for HLA-E. Hydrophobic and non-charged amino acids were found to predominate along the peptide motif, with a leucine anchor at P9, but surprisingly there was no methionine preference at P2, as suggested by previous studies. CONCLUSIONS: Compared to the results obtained with rat classical class Ia MHC molecules, RT1-A1c and RT1-Au, HLA-E appears to refold around a random peptide library to reduced but detectable levels, suggesting that this molecule's specificity is tight but probably not as exquisite as has been previously suggested. This, and a previous report that it can associate with synthetic peptides carrying a viral sequence, suggests that HLA-E, similar to its mouse counterpart (Qa-1b), could possibly bind peptides different from MHC class I leader peptides and present them to T lymphocytes.

Amino Acid Motifs↗
PubMed2001

Role of the ABC transporter Mdl1 in peptide export from mitochondria.

ATP-binding cassette (ABC) adenosine triphosphatases actively transport a wide variety of compounds across biological membranes. Here, the ABC protein Mdl1 was identified as an intracellular peptide transporter localized in the inner membrane of yeast mitochondria. Mdl1 was required for mitochondrial export of peptides with molecular masses of approximately 2100 to 600 daltons generated by proteolysis of inner-membrane proteins by the m-AAA protease in the mitochondrial matrix. Proteolysis by the i-AAA protease in the intermembrane space led to the release of similar-sized peptides independent of Mdl1. Thus, two pathways of peptide efflux from mitochondria exist that may allow communication between mitochondria and their cellular environment.

ATP-Binding Cassette Transporters↗
PubMed2001

DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans.

DC-SIGN, a C-type lectin expressed on the surface of dendritic cells (DCs), efficiently binds and transmits HIVs and simian immunodeficiency viruses to susceptible cells in trans. A DC-SIGN homologue, termed DC-SIGNR, has recently been described. Herein we show that DC-SIGNR, like DC-SIGN, can bind to multiple strains of HIV-1, HIV-2, and simian immunodeficiency virus and transmit these viruses to both T cell lines and human peripheral blood mononuclear cells. Binding of virus to DC-SIGNR was dependent on carbohydrate recognition. Immunostaining with a DC-SIGNR-specific antiserum showed that DC-SIGNR was expressed on sinusoidal endothelial cells in the liver and on endothelial cells in lymph node sinuses and placental villi. The presence of this efficient virus attachment factor on multiple endothelial cell types indicates that DC-SIGNR could play a role in the vertical transmission of primate lentiviruses, in the enabling of HIV to traverse the capillary endothelium in some organs, and in the presentation of virus to CD4-positive cells in multiple locations including lymph nodes.

Amino Acid Sequence↗
PubMed2001

The cluster of BTN genes in the extended major histocompatibility complex.

We sequenced the 170-kb cluster of BTN genes in the extended major histocompatibility complex region, 4 Mb telomeric of human leukocyte antigen class I genes, at 6p22.1. The cluster consists of seven genes belonging to the expanding B7/butyrophilin-like group, a subset of the immunoglobulin gene superfamily. The main complex is composed of six genes, from two subfamilies, BTN2 and BTN3, arranged in pairs. This alternating pattern must have evolved by duplications of an original block of two genes, one from each subfamily. The sequences from the two subfamilies share approximately 50% amino acid identity. By analysis of repeat elements within each block, these duplications may be dated to approximately 100 million years ago, at about the time of the branching of the Rodentia and Primate lineages. The single BTN1A1 (butyrophilin) gene was positioned approximately 25 kb centromeric to the cluster. Each gene covers approximately 12 kb and consists of seven (BTN2 subfamily) or nine (BTN3 subfamily) coding exons. The predicted leader sequence, immunoglobulin-like IgV (variable)/IgC (constant) ectodomains, and the predicted transmembrane domain are encoded on separate exons and are separated from a B30.2 domain by a variable number of very short exons, 21 and 27 nucleotides in length. BTN transcripts were detected in all tissues examined. Alternative splicing, involving particularly the carboxyl-terminal B30.2 domain, was a notable feature. Most transcripts of BTN2 subfamily genes contained this domain, whereas BTN3 genes did not. Using immunofluorescence, we showed surface expression of BTN-green fluorescent protein fusions in mammalian cell transfectants.

Alternative Splicing↗
PubMed2001

Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV.

Mechanisms of transplacental transmission of human immunodeficiency virus (HIV) are poorly understood. DC-SIGN is a C-type lectin able to bind HIV gp120 with high affinity, mediating HIV adsorption to the surface of dendritic cells for up to several days. Via this mechanism, DC-SIGN significantly enhances the infection of CD4(+) co-receptor (CCR5 or CXCR4)(+) T lymphocytes in trans. In this study, DC-SIGN-specific serum was developed to investigate the cell type responsible for the high level of DC-SIGN RNA expression previously observed in the placenta. DC-SIGN expression was shown on CD68(+) HLA-II(+) CD14(low) S100(+/-) CD83(-) CD86(-) cmrf-44(-) villous cells consistent with Hofbauer cells and also on CD68(+) HLA-II(+) CD14(high) S100(-) CD83(-) CD86(-) cmrf-44(-) decidual macrophages. The DC-SIGN(+) Hofbauer cells co-express CD4 and the chemokine receptors, CCR5 and CXCR4, observations which may account for the ability of these cells to become infected with HIV. These fetal DC-SIGN(+) cells are separated by only a layer of trophoblast from both DC-SIGN(+) maternal cells and maternal blood, potential sources of HIV in infected mothers. Previous studies have suggested that this trophoblast layer is frequently breached during pregnancy. It is therefore proposed that DC-SIGN may facilitate the transplacental transmission of HIV.

Antibody Specificity↗