Biomedical subjects

Max D Cooper

Publications and source records attributed to Max D Cooper.

17 recordsLinked to original sources

PubMed2003

Identification and characterization of a TAP-family gene in the lamprey.

An expressed sequence tag obtained from a sea lamprey ( Petromyzon marinus) cDNA library was used to obtain a full-length coding sequence showing significant similarity to ABCB transporter proteins. The sequence is closely related to the mammalian ABCB9 protein and the TAP1 and TAP2 proteins that transport peptides for loading onto nascent Mhc class I molecules. The Pema-ABCB9 gene has an exon-intron organization similar to that of the mammalian TAP genes, with the exception of exon 2, which in the lamprey is split into two by a 949-bp long intron. The gene probably occurs in a single copy in the haploid lamprey genome. The ABCB9 genes appear to be evolving four-to-ten times slower than the TAP1 and TAP2 genes. Six putative transmembrane helices and the nucleotide-binding domain of the lamprey ABCB9 protein show high sequence similarity with the TAP1 and TAP2 molecules. The lamprey protein also contains sequence stretches that resemble the putative peptide interacting parts of the TAP1 and TAP2 molecules, but are peppered with ABCB9-specific residues.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Macrophage migration inhibitory factor (MIF) of jawed and jawless fishes: implications for its evolutionary origin.

The macrophage migration inhibitory factor (MIF) is a cytokine produced by T lymphocytes and macrophages in response to inflammatory stimuli. We sequenced MIF cDNA clones of two jawless fishes, the sea lamprey (Petromyzon marinus) and the North Atlantic hagfish (Myxine glutinosa), as well as of the jawed (cichlid) fish Paralabidochromis chilotes. The fish MIF-encoding genes have the same exon-intron organization as the mammalian MIF genes and are present in one copy per haploid genome. Secondary and tertiary structure predictions suggest that the fish MIF proteins have a topology characteristic of the entire MIF-family of proteins. Phylogenetic analysis separates the known nematode members of the family into two groups, one having a sister group relationship with the mammalian D-dopachrome tautomerase (DDT) proteins and the other being related to vertebrate MIFs. It also reveals a high degree of convergent evolution among the members of the family. Finally, it suggests that the divergence of MIF and DDT occurred before the emergence of nematodes in metazoan evolution.

Amino Acid Sequence↗

PubMed2003

Contribution of Vh gene replacement to the primary B cell repertoire.

V(H) replacement has been proposed as one way to modify unwanted antibody specificities, but analysis of this mechanism has been limited without a dynamic cellular model. We describe a human cell line that spontaneously undergoes serial V(H) gene replacement mediated by cryptic recombination signal sequences (cRSS) located near the 3' end of V(H) genes. Recombination-activating gene products, RAG-1 and RAG-2, bind and cleave the cRSS to generate DNA deletion circles during the V(H) replacement process. A V(H) replacement contribution to normal repertoire development is revealed by the identification of V(H) replacement "footprints" in IgH sequences and double-stranded DNA breaks at V(H) cRSS sites in immature B cells. Surprisingly, the residual 3' sequences of replaced V(H) genes contribute charged amino acids to the CDR3 region, a hallmark of autoreactive antibodies.

B-Lymphocytes↗

PubMed2003

Molecular mechanism of serial VH gene replacement.

The molecular mechanism of serial VH replacement was analyzed using a human B cell line, EU12, that undergoes continuous spontaneous differentiation from pro-B to pre-B and then to B cell stage. In earlier studies, we found that this cell line undergoes intraclonal V(D)J diversification. Analysis of the IgH gene sequences in EU12 cells predicted the occurrence of serial VH replacement involving the cryptic recombination signal sequences (cRSS) embedded within framework 3 regions and concurrent extension of the CDR3 region. Detection of double-stranded DNA breaks at the cRSS site and different VH replacement excision circles confirm the ongoing nature of this diversification process in the EU12 cells. In vitro binding and cleavage assays using recombinant RAG-1 and RAG-2 proteins further validated the cRSS participation in this RAG-mediated recombination process. Serial VH replacements may represent an additional mechanism for diversification of the primary B cell repertoire.

Immunoglobulin Heavy Chains↗

PubMed2002

Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes.

To shed light on the origin of adaptive immunity, a cDNA library was prepared from purified lymphocyte-like cells of a jawless vertebrate, the sea lamprey (Petromyzon marinus). Randomly selected cDNA clones were sequenced, and their homologies to proteins in the databases were determined. Of the sequences homologous to proteins involved in immune responses, five were selected for further characterization. Their encoding genes corresponded to loci that in jawed vertebrates are essential for activities of lymphocytes. These activities include regulation of T and B cell stimulation and proliferation (CD45); stabilization of molecular complexes involved in lymphocyte activation, adhesion, migration, and differentiation (CD9/CD81); adaptor functions in signaling leading to the activation of B lymphocytes (BCAP) and T lymphocytes (CAST); and amino acid transport associated with cell activation (CD98). The presence of these genes in the lamprey genome and their expression in lymphocyte-like cells support the notion that these cells perform many of the functions of gnathostome lymphocytes. It reopens the question of the stage jawless fishes reached in the evolution of their immune system.

Amino Acid Sequence↗

PubMed2002

Isolation and characterization of lymphocyte-like cells from a lamprey.

Lymphocyte-like cells in the intestine of the sea lamprey, Petromyzon marinus, were isolated by flow cytometry under light-scatter conditions used for the purification of mouse intestinal lymphocytes. The purified lamprey cells were morphologically indistinguishable from mammalian lymphocytes. A cDNA library was prepared from the lamprey lymphocyte-like cells, and more than 8,000 randomly selected clones were sequenced. Homology searches comparing these ESTs with sequences deposited in the databases led to the identification of numerous genes homologous to those predominantly or characteristically expressed in mammalian lymphocytes, which included genes controlling lymphopoiesis, intracellular signaling, proliferation, migration, and involvement of lymphocytes in innate immune responses. Genes closely related to those that in gnathostomes control antigen processing and transport of antigenic peptides could be ascertained, although no sequences with significant similarity to MHC, T cell receptor, or Ig genes were found. The data suggest that the evolution of lymphocytes in the lamprey has reached a stage poised for the emergence of adaptive immunity.

ATP-Binding Cassette Transporters↗

PubMed2002

V(D)J recombinatorial repertoire diversification during intraclonal pro-B to B-cell differentiation.

The initial B-cell repertoire is generated by combinatorial immunoglobulin V(D)J gene segment rearrangements that occur in a preferential sequence. Because cellular proliferation occurs during the course of these rearrangement events, it has been proposed that intraclonal diversification occurs during this phase of B-cell development. An opportunity to examine this hypothesis directly was provided by the identification of a human acute lymphoblastic leukemic cell line that undergoes spontaneous differentiation from pro-B cell to the pre-B and B-cell stages with concomitant changes in the gene expression profile that normally occur during B-cell differentiation. After confirming the clonality of the progressively differentiating cells, an analysis of immunoglobulin genes and transcripts indicated that pro-B cell members marked by the same DJ rearrangement generated daughter B cells with multiple V(H) and V(L) gene segment rearrangements. These findings validate the principle of intraclonal V(D)J diversification during B-cell generation and define a manipulable model of human B-cell differentiation.

Antibody Diversity↗

PubMed2002

TCL1 participates in early embryonic development and is overexpressed in human seminomas.

Overexpression of the TCL1 oncogene has been shown to play a causative role in T cell leukemias of humans and mice. The characterization of Tcl1-deficient mice in these studies indicates an important developmental role for Tcl1 in early embryogenesis. In wild-type embryos, Tcl1 is abundant in the first three mitotic cycles, during which it shuttles between nuclei and the embryo cortical regions in a cell-cycle-dependent fashion. The absence of this protein in early embryogenesis results in reduced fertility of female mice. The present studies elucidate the mechanism responsible for the reduced female fertility through analysis of the oogenesis stages and early embryo development in Tcl1-deficient mice. Even though Tcl1(-/-) females display normal oogenesis and rates of oocyte maturation/ovulation and fertilization, the lack of maternally derived Tcl1 impairs the embryo's ability to undergo normal cleavage and develop to the morula stage, especially under in vitro culture conditions. Beyond this crisis point, differentiative traits of zygotic genome activation and embryo compaction can take place normally. In contrast with this unanticipated role in early embryogenesis, we observed an overexpression of TCL1 in human seminomas. This finding suggests that TCL1 dysregulation could contribute to the development of this germinal cell cancer as well as lymphoid malignancies.

Animals↗

PubMed2002

Reversible disruption of thymic function by steroid treatment.

The effect of steroid treatment on the thymic output of T cells was examined in an avian model. Recent thymic emigrants in chickens transiently express the chicken T cell Ag 1 thymocyte marker, and thymic function can be monitored indirectly by measuring the levels of TCR gene rearrangement excision circles in peripheral T cells. Both parameters were used to show that intensive steroid treatment induces thymic involution and a profound reduction in the supply of naive T cells to the periphery. Conversely, resident T cells in the peripheral lymphocyte pool were relatively spared. Thymopoiesis immediately recovered following cessation of steroid treatment, concurrent with restoration of the thymic output of newly formed T cells. Repopulation of the peripheral T cell pool recapitulated the ontogenetic pattern of gamma delta T cell replenishment before alpha beta T cell reseeding, thereby indicating the complete recovery of thymic function after a course of steroid treatment.

Animals↗

PubMed2002

Differential surrogate light chain expression governs B-cell differentiation.

Surrogate light chain expression during B lineage differentiation was examined by using indicator fluorochrome-filled liposomes in an enhanced immunofluorescence assay. Pro-B cells bearing surrogate light chain components were found in mice, but not in humans. A limited subpopulation of relatively large pre-B cells in both species expressed pre-B cell receptors. These cells had reduced expression of the recombinase activating genes, RAG-1 and RAG-2. Their receptor-negative pre-B cell progeny were relatively small, expressed RAG-1 and RAG-2, and exhibited selective down-regulation of VpreB and lambda5 expression. Comparative analysis of the 2 pre-B cell subpopulations indicated that loss of the pre-B cell receptors from surrogate light chain gene silencing was linked with exit from the cell cycle and light chain gene rearrangement to achieve B-cell differentiation.

Animals↗

PubMed2002

The transient expression of pre-B cell receptors governs B cell development.

Only a subpopulation of relatively large pre-B cells express pre-B cell receptors (preBCR) that can be seen with very sensitive immunofluorescence methods. Inefficient assembly of the multicomponent preBCR coupled with their ligand-induced endocytosis may account for the remarkably low in vivo levels of preBCR expression. Signaling initiated via the preBCR promotes cellular proliferation and RAG-1 and RAG-2 downregulation to interrupt the immunoglobulin V(D)J gene rearrangement process. Silencing of the surrogate light chain genes, VpreB and lambda5, then terminates preBCR expression to permit cell cycle exit, recombinase gene upregulation, and VJ(L) rearrangement by small pre-B cells destined to become B cells.

Animals↗

PubMed2002

Pathogenic significance of IgA receptor interactions in IgA nephropathy.

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently progresses to renal failure. The pathogenesis of this disease involves the deposition of undergalactosylated IgA1 complexes in the glomerular mesangium. How the IgA1 complexes are generated and why they are deposited in the mesangium remains unclear. We propose a model wherein two types of IgA receptors participate in sequential steps to promote the development of IgAN, with FcalphaRI (CD89) being initially involved in the formation of circulating IgA-containing complexes and, subsequently, transferrin receptor (CD71) in mediating mesangial deposition of IgA1 complexes.

Animals↗

PubMed2002

Exploring lymphocyte differentiation pathways.

Highlights in a 4-decade exploration of lymphocyte differentiation begin with comparative studies in birds and mammals leading to recognition of the separate T- and B-cell differentiation pathways and their cooperative interaction. The global effects of aborting IgM B-cell development with anti-mu antibodies indicated that B cells can undergo immunoglobulin isotype switching. A search for the mammalian bursa equivalent that began with an extended excursion through the gut-associated lymphoepithelial tissues ultimately led to the hematopoietic tissue origin of mammalian B cells. The identification of the precursors of B cells in hematopoietic tissues provided an expanded view of the life history of B cells. A recurring theme in this essay is the interplay between understanding normal lymphocyte differentiation and the defects that underlie immunodeficiency diseases and lymphoid malignancies.

Allergy and Immunology↗

PubMed2002

Fc receptor homologs: newest members of a remarkably diverse Fc receptor gene family.

Newfound relatives of the classical Fc receptors (FcR) have been provisionally named the Fc receptor homologs (FcRH). The recent identification of eight human and six mouse FcRH genes substantially increases the size and functional potential of the FcR family. The extended family of FcR and FcRH genes spans approximately 15 Mb of the human chromosome 1q21-23 region, whereas in mice this family is split between chromosomes 1 and 3. The FcRH genes encode molecules with variable combinations of five subtypes of immunoglobulin (Ig) domains. The presence of a conserved sequence motif in one Ig domain subtype implies Ig Fc binding capability for many FcRH family members that are preferentially expressed by B lineage cells. In addition, most FcRH family members have consensus tyrosine-based activating and inhibitory motifs in their cytoplasmic domains, while the others lack features typical of transmembrane receptors. The FcRH family members, like the classical FcRs, come in multiple isoforms and allelic variations. The unique individual and polymorphic properties of the FcR/FcRH members indicate a remarkably diverse Fc receptor gene family with immunoregulatory function.

Amino Acid Sequence↗

PubMed2002

Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells.

The recent identification of five human Fc receptor (FcR) homologs, hFcRH1-5, has extended the known FcR family and identified an unanticipated richness of the chromosome 1q region in genes encoding potential Ig-binding proteins. In a database search for additional relatives of this family we identified expressed sequence tag representatives of a new FcR-related molecule (hFcRX) and its mouse ortholog (mFcRX). The FcRX cDNAs were cloned from human lymph node and mouse spleen cDNA libraries. hFcRX is located centromeric of FcgammaRII and FcgammaRIII at 1q23, and its mouse ortholog resides in a syntenic region of chromosome 1. The genes encode proteins with 67% interspecies identity that lack both N-linked glycosylation sites and transmembrane regions. Two of the four FcRX domains are Ig-like, and share characteristics similar to FcgammaRI domains 2 and 3, having 28% overall extracellular identity with hFcgammaRI and 27% identity with mFcgammaRI respectively. FcRX transcripts are found primarily in secondary lymphoid tissues, where they are expressed by B lineage cells. FcRX thus may function as a secreted or intracellular protein in normal and neoplastic B cells.

Amino Acid Sequence↗

PubMed2002

Mast cell regulation via paired immunoglobulin-like receptor PIR-B.

Activating (PIR-A) and inhibitory (PIR-B) isoforms of the paired immunoglobulin (Ig)-like receptor family have been evaluated for their modulating potential in mast cell responses to IgE antibody and mast/stem cell growth factor (SCF). Mast cells produce PIR-A and PIR-B, but PIR-B was found to be predominantly expressed on the cell surface, where it was constitutively tyrosine phosphorylated and associated with SHP-1 tyrosine phosphatase. Efficient coligation of PIR-B with FcepsilonRI inhibited IgE-induced mast cell activation and serotonin release. PIR-B and c-kit (or mast/SCF receptor) coligation also inhibited SCF-induced mast cell responses. The PIR-B inhibitory activity was unimpaired in SHP-1-deficient mast cells, perhaps because of non-SHP-1-binding tyrosine-based inhibitory motif in the cytoplasmic tail of PIR-B. This analysis suggests that PIR-B may serve to control mast cell activity.

Animals↗

PubMedDate not supplied

Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice.

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.

Aminopeptidases↗