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M D Cooper

Publications and source records attributed to M D Cooper.

At least 55 records · Page 3Linked to original sources
PubMed1998

Leukocyte transfusion-associated granulocyte responses in a patient with X-linked hyper-IgM syndrome.

X-linked hyper-IgM syndrome (XHIM) is a severe congenital immunodeficiency caused by mutations in CD154 (CD40 ligand, gp39), the T cell ligand for CD40 on B cells. Chronic or cyclic neutropenia is a frequent complicating feature that heightens susceptibility to severe infections. We describe a patient with a variant of XHIM who produced elevated levels of serum IgA as well as IgM and suffered from chronic severe neutropenia. Eight of ten leukocyte transfusions with cells from a maternal aunt, performed because of mucosal infections, resulted in similar episodes of endogenous granulocyte production. Transfection studies with the mutant CD154 protein indicate that the protein is expressed at the cell surface and forms an aberrant trimer that does not interact with CD40. The data suggest that allogeneic cells from the patient's aunt, probably activated T cells bearing functional CD154, may interact with CD40+ recipient cells to produce maturation of myeloid precursors in the bone marrow.

Adolescent↗
PubMed1998

Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region.

IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European HLA-DR3 haplotypes to help localize the IgA-D susceptibility gene(s). With the knowledge that approximately 13% of HLA-DR3 homozygous individuals of North European origin are IgA-D, we examined 43 HLA-DR3 homozygous Sardinians to find that all had normal serum IgA, IgG and IgM levels. A detailed analysis of their MHC haplotypes indicated a common Sardinian HLA-DR3 haplotype TAP1A, TAP2A, HLA-DQB1*0201, -DQA1*0501, -DRB1*0301, LH1-(Z + 2), D3A-(Z + 2), C4B-0, C4A-L, G11-15, Bf-0-4, C2-a, HSP70-7.5, 9N3-(Z + 10), 82I-(Z - 2), TNFalpha-9, 62-(Z - 20), HLA-B18, -Cw5, -A30 which diverges from the common North European HLA-DR3 haplotype telomeric to the HLA-DR region. In parallel studies of five Sardinians with IgA-D, two of the 10 HLA haplotypes (20%) contained HLA-DR3, a frequency similar to that observed in the background population. One of these was the HLA-DR3- B8 North European haplotype, which occurs rarely in Sardinia. Our data favour the hypothesis that a class III region allele, present on the common North European but not on the Sardinian HLA-DR3 haplotype, confers susceptibility to IgA-D.

Disease Susceptibility↗
PubMed1998

Genomic structure of PIR-B, the inhibitory member of the paired immunoglobulin-like receptor genes in mice.

The genes encoding the murine paired immunoglobulin-like receptors PIR-A and PIR-B are members of a novel gene family which encode cell-surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and their non-inhibitory/activatory counterparts. PIR-A and PIR-B have highly homologous extracellular domains but distinct transmembrane and cytoplasmic regions. A charged arginine in the transmembrane region of PIR-A suggests its potential association with other transmembrane proteins to form a signal transducing unit. PIR-B, in contrast, has an uncharged transmembrane region and several ITIMs in its cytoplasmic tail. These characteristics suggest that PIR-A and PIR-B which are coordinately expressed by B cells and myeloid cells, serve counter-regulatory roles in humoral and inflammatory responses. In the present study we have determined the genomic structure of the single copy PIR-B gene. The gene consists of 15 exons and spans approximately 8 kilobases. The first exon contains the 5' untranslated region, the ATG translation start site, and approximately half of the leader peptide sequence. The remainder of the leader peptide sequence is encoded by exon 2. Exons 3-8 encode the six extracellular immunoglobulin-like domains and exons 9 and 10 code for the extracellular membrane proximal and transmembrane regions. The final five exons (exons 11-15) encode for the ITIM-bearing cytoplasmic tail and the 3' untranslated region. The intron/exon boundaries of PIR-B obey the GT-AG rule and are in phase I, with the notable exception of the three boundaries determined for ITIM-containing exons. A microsatellite composed of the trinucleotide repeat AAG in the intron between exons 9 and 10 provides a useful marker for studying population genetics.

Amino Acid Sequence↗
PubMed1998

T-cell and natural killer cell development in thymectomized Xenopus.

The Xenopus early-thymectomy model system is used to investigate the extent to which the thymus controls T-cell development and to probe the evolution of natural killer (NK) cells. Loss of T-cell function following thymectomy, together with the paucity of cells expressing monoclonal antibody-defined T-cell surface markers, and greatly reduced expression of T-cell receptor beta transcripts in spleen, liver and intestine, indicate that T-cell development in minimal in the absence of the thymus. Our findings therefore mitigate against the idea that a substantial extrathymic pathway of T-cell development exists in early vertebrate evolution. Rather, they suggest that in this amphibian representative T cells are predominately thymus dependent. In vitro studies with control and thymectomized Xenopus splenocytes reveal that a non-T/non-B population and also two T-cell subsets all display natural cytotoxicity towards allogeneic thymus lymphoid tumour cells (which are deficient in MHC antigen expression). Since Xenopus thymectomized early in larval development are permanently deficient in T cells, they may provide a useful phylogenetic model for the study of NK cells.

Animals↗
PubMed1998

The enigmatic role of glutamyl aminopeptidase (BP-1/6C3 antigen) in immune system development.

The murine B-lymphocyte differentiation antigen BP-1/6C3, a homodimeric integral membrane protein composed of M, 140,000 subunits, has been identified as glutamyl aminopeptidase (EAP, EC 3.4.11.7). This ecto-enzyme cleaves acidic amino acid residues from the amino terminal of polypeptide substrates such as angiotensin II and cholecystokinin-8. Although BP-1/6C3/EAP is expressed by cells in many tissues, among hematopoietic cell lineages this ecto-enzyme is restricted to immature B-lineage cells where its expression is upregulated by interleukin-7 and viral transformation. BP-1/6C3/EAP thus serves as a valuable marker of progression along the B-cell differentiation pathway, but a corresponding biological role has not yet been established.

Aminopeptidases↗
PubMed1998

Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes.

BACKGROUND: A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members. MATERIALS AND METHODS: We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers. RESULTS: Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA- DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1. CONCLUSION: Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.

Adult↗
PubMed1998

Topical fluorides.

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Acidulated Phosphate Fluoride↗
PubMed1998

MAVIS: an interactive visualization tool for computational chemistry calculations in a distributed networked environment.

This paper describes the software package, MAVIS (Molecular Animation and VI-sualization System), which was developed as a collaborative project between the University of Manchester Department of Chemistry and the Manchester Visualization Centre as a tool for the visualization of chemical systems and their properties and for the generation, submission, monitoring and study of results from calculations in a networked computing environment. MAVIS has been developed using AVS, a general visualization environment, as a suite of modules which can be extended with relative ease. Using the AVS system gives the application the power and flexibility of a general system with no requirement for the programmer to understand many of the complexities involved in modern image rendering systems and allowing them to concentrate upon the features of the functionality and the user interface. It also allows the code to be as portable between platforms as the AVS package itself and so it is available on a wide range of systems.

Chemistry, Organic↗
PubMed1998

A moral dilemma.

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Confidentiality↗
PubMed1997

Ontogeny of the immune system: gamma/delta and alpha/beta T cells migrate from thymus to the periphery in alternating waves.

The embryonic thymus is colonized by the influx of hemopoietic progenitors in waves. To characterize the T cell progeny of the initial colonization waves, we used intravenous adoptive transfer of bone marrow progenitors into congenic embryos. The experiments were performed in birds because intravenous cell infusions can be performed more efficiently in avian than in mammalian embryos. Progenitor cells, which entered the vascularized thymus via interlobular venules in the capsular region and capillaries located at the corticomedullary junction, homed to the outer cortex to begin thymocyte differentiation. The kinetics of differentiation and emigration of the T cell progeny were analyzed for the first three waves of progenitors. Each progenitor wave gave rise to gamma/delta T cells 3 d earlier than alpha/beta T cells. Although the flow of T cell migration from the thymus was uninterrupted, distinct colonization and differentiation kinetics defined three successive waves of gamma/delta and alpha/beta T cells that depart sequentially the thymus en route to the periphery. Each wave of precursors rearranged all three TCR Vgamma gene families, but displayed a variable repertoire. The data indicate a complex pattern of repertoire diversification by the progeny of founder thymocyte progenitors.

Adoptive Transfer↗
PubMed1997

B cells in the bursa of Fabricius express a novel C-type lectin gene.

The avian bursa of Fabricius provides an essential microenvironment for B cell development and Ab repertoire expansion by a gene conversion mechanism. To explore regulatory interactions between B lineage cells and the bursal microenvironment, we sought to identify genes encoding cell surface molecules selectively expressed on bursal B cells. We report in this work the identification of the chB1 gene that encodes a C-type lectin molecule that is a distant relative of the mammalian B cell differentiation Ag, CD72. The chB1 gene is expressed by intrabursal B cells and a B cell line, DT40, that also diversifies its Ig V region genes by gene conversion. Two forms of this type II membrane protein, differing in their cytoplasmic domains, are generated by the differential usage of two translational initiation sites. The longer chB1 isoform, which is the most abundant, contains a consensus immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic domain. Cross-linkage of the chB1 molecules inhibits proliferation of bursal B cells and the DT40 cell line. The chB1 lectin-like molecule may thus modulate intrabursal B cell development.

Amino Acid Sequence↗
PubMed1997

Aberrations of the B-cell receptor B29 (CD79b) gene in chronic lymphocytic leukemia.

Leukemic B cells in chronic lymphocytic leukemia (B-CLL) typically exhibit low or undetectable surface Ig. Because the B29 (CD79b and Ig beta) and mb-1 (CD79a and Ig alpha) gene products are required for surface Ig display in the B-cell receptor complex (BCR), we analyzed the expression of these genes in B-CLL cells. The majority (83%) of the randomly selected B-CLL patient samples analyzed exhibited low or undetectable surface BCR measured by mu heavy chain and B29 expression. Levels of mb-1 mRNA in these B-CLL samples with low surface BCR were similar to those in normal B cells. Among those with decreased surface expression, B29 mRNA was not detected in half of these B-CLL samples. The remaining B-CLL samples with diminished surface BCR contained normal levels of B29 mRNA. Further analysis of cDNA clones from the majority of these latter samples contained point mutations, insertions, or deletions that were largely located in the B29 transmembrane and cytoplasmic domains. These results indicate the occurrence of somatic mutations predicted to affect B29 expression and/or function in the majority of B-CLL and suggest that these aberrations underlie the diminished surface BCR display and loss of BCR signaling characteristic of this leukemia.

Antigens, CD↗
PubMed1997

Catfish thrombocytes express an integrin-like CD41/CD61 complex.

A thrombocyte-specific antigen was identified in two closely related catfish, Ictalurus punctatus and Ictalurus furcatus, by monoclonal antibodies 4-20 and 7-2. The antibodies immunoprecipitate two noncovalently associated glycoprotein chains of Mr 180,000 and Mr 95,000. Under reducing conditions the Mr 180,000 chain is resolved into Mr 150,000 and 32,000 subcomponents. Analysis of N-terminal amino acid sequences indicates homology of the Mr 95,000 chain with the beta3 integrin subunit and homology of the Mr 150,000 chain with the alphaIIb integrin subunit. These antibodies induce catfish thrombocyte aggregation and alteration of cell shape. The data indicate conservation of the megakaryocyte/platelet-restricted CD41/CD61 complex in bony fish.

Amino Acid Sequence↗
PubMed1997

High-resolution genetic map of the human glutamyl aminopeptidase gene (ENPEP).

The murine B-lymphocyte differentiation antigen BP-1/6C3 has been identified as glutamyl aminopeptidase (EAP), the gene symbol for which is ENPEP. Using genomic DNA encoding for human EAP as a probe, we identified the ENPEP gene location on human chromosome 4q25 by polymerase chain reaction analysis of a human/rodent somatic cell hybrid mapping panel and by fluorescence in situ hybridization. Using a radiation hybrid panel, the gene order around ENPEP was determined to be centromere-D4S1236-(570 kb)-ENPEP-(210 kb)-D4S262-(270 kb)-D4S953-(270 kb)-D4S474-(570 kb)-IF. The linkage of ENPEP to complement factor I (IF) confirms the human chromosome band 4q25 localization predicted from the chromosomal location of murine ENPEP. Human ENPEP thus provides an additional marker for the long arm of chromosome 4 that should facilitate studies of this genomic region.

Aminopeptidases↗
PubMed1997

A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells.

An Fcalpha receptor probe of human origin was used to identify novel members of the Ig gene superfamily in mice. Paired Ig-like receptors, named PIR-A and PIR-B, are predicted from sequence analysis of the cDNAs isolated from a mouse splenic library. Both type I transmembrane proteins possess similar ectodomains with six Ig-like loops, but have different transmembrane and cytoplasmic regions. The predicted PIR-A protein has a short cytoplasmic tail and a charged Arg residue in the transmembrane region that, by analogy with the FcalphaR relative, suggests the potential for association with an additional transmembrane protein to form a signal transducing unit. In contrast, the PIR-B protein has an uncharged transmembrane region and a long cytoplasmic tail containing four potential immunoreceptor tyrosine-based inhibitory motifs. These features are shared by the related killer inhibitory receptors. PIR-A proteins appear to be highly variable, in that predicted peptide sequences differ for seven randomly selected PIR-A clones, whereas PIR-B cDNA clones are invariant. Southern blot analysis with PIR-B and PIR-A-specific probes suggests only one PIR-B gene and multiple PIR-A genes. The PIR-A and PIR-B genes are expressed in B lymphocytes and myeloid lineage cells, wherein both are expressed simultaneously. The characteristics of the highly-conserved PIR-A and PIR-B genes and their coordinate cellular expression suggest a potential regulatory role in humoral, inflammatory, and allergic responses.

Amino Acid Sequence↗
PubMed1997

Memory B lymphocytes migrate to bone marrow in humans.

IgM-bearing B lymphocytes with mature phenotype (CD10- CD24(lo) IgD+) are acquired after birth in the bone marrow of humans. These B cells are defined here as relatively large, nondividing lymphocytes, variable proportions of which express cell surface molecules indicative of relatively recent activation. Analysis of V(H)5(2) (heavy chain variable region) gene transcripts indicated point mutations throughout the Ig variable region from the mature IgM+ B population but not from the immature B cells in the bone marrow. The mutations were concentrated in the complementarity determining regions, and amino acid substitutions were favored over silent mutations, findings indicative of antigen selection within germinal centers in peripheral lymphoid tissues. The V(H) sequence analysis also revealed the existence of clonal relatives in individual bone marrow samples. These antigen-experienced lymphocytes did not secrete Ig spontaneously but could be induced to do so in vitro. The data suggest that a subpopulation of memory B lymphocytes generated during antigen responses recirculates to the bone marrow in humans.

Adult↗
PubMed1997

Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography.

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D2 receptor positron emission tomography (PET) radioligand, 18F-fallypride. In vitro dissociation of 18F-fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k(off), of 1.76 x 10(-2) min(-1) while the association rate constant, k(on), was found to be 5.30 x 10(8) M(-1) min(-1). This resulted in a dissociation constant, K(D) of 33 pM for 18F-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on 18F-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18F-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18F-fallypride in the striata was observed (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tracer cleared from other parts of the brain. Striata/cerebellum ratios for 18F-fallypride were approximately 8 at 80 min postinjection, respectively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d-amphetamine (AMPH) pre- and postinjection of the radioligand. There was a decrease of specifically bound 18F-fallypride as well as evidence of an enhanced clearance of specifically bound 18F-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of 18F-fallypride without AMPH was <10(-4) min(-1) but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 x 10(-3) min(-1) and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 x 10(-3) to 4.0 x 10(-3) min(-1). Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of 18F-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18F-fallypride has a maximum response at doses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in binding. These results indicate that AMPH stimulated release of endogenous dopamine reduces the specific binding of 18F-fallypride.

Animals↗