Biomedical subjects

M Godfrey

Publications and source records attributed to M Godfrey.

At least 73 records · Page 4Linked to original sources

PubMed1988

Type II achondrogenesis-hypochondrogenesis: identification of abnormal type II collagen.

We have extended the study of a mild case of type II achondrogenesis-hypochondrogenesis to include biochemical analyses of cartilage, bone, and the collagens produced by dermal fibroblasts. Type I collagen extracted from bone and types I and III collagen produced by dermal fibroblasts were normal, as was the hexosamine ratio of cartilage proteoglycans. Hyaline cartilage, however, contained approximately equal amounts of types I and II collagen and decreased amounts of type XI collagen. Unlike the normal SDS-PAGE mobility. Two-dimensional SDS-PAGE revealed extensive overmodification of all type II cyanogen bromide peptides in a pattern consistent with heterozygosity for an abnormal pro alpha 1(II) chain which impaired the assembly and/or folding of type II collagen. This interpretation implies that dominant mutations of the COL2A1 gene may cause type II achondrogenesis-hypochondrogenesis. More generally, emerging data implicating defects of type II collagen in the type II achondrogenesis-hypochondrogenesis-spondyloepiphyseal dysplasia congenita spectrum and in the Kniest-Stickler syndrome spectrum suggest that diverse mutations of this gene may be associated with widely differing phenotypic outcome.

Amino Acids↗

PubMed1987

Structure and expression of the human and mouse T4 genes.

The T4 molecule may serve as a T-cell receptor recognizing molecules on the surface of specific target cells and also serves as the receptor for the human immunodeficiency virus. To define the mechanisms of interaction of T4 with the surface of antigen-presenting cells as well as with human immunodeficiency virus, we have further analyzed the sequence, structure, and expression of the human and mouse T4 genes. T4 consists of an extracellular segment comprised of a leader sequence followed by four tandem variable-joining (VJ)-like domains, a transmembrane domain, and a cytoplasmic segment. The structural domains of the T4 protein deduced from amino acid sequence are precisely reflected in the intron-exon organization of the gene. Analysis of the expression of the T4 gene indicates that T4 RNA is expressed not only in T lymphocytes, but in B cells, macrophages, and granulocytes. T4 is also expressed in a developmentally regulated manner in specific regions of the brain. It is, therefore, possible that T4 plays a more general role in mediating cell recognition events that are not restricted to the cellular immune response.

Amino Acid Sequence↗

PubMed1986

The T4 glycoprotein is a cell-surface receptor for the AIDS virus.

Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells.

Acquired Immunodeficiency Syndrome↗

PubMed1985

Neuropathy and anti-myelin-associated glycoprotein IgM M proteins: T cell regulation of M protein secretion in vitro.

In patients with plasma cell dyscrasia, individual clones of antibody-producing cells proliferate abnormally and secrete monoclonal antibodies or M proteins in excess. The cause of the monoclonal proliferation of lymphocytes and M protein secretion is unknown and it is not known whether the M protein-secreting B cells are autonomous or capable of responding to regulatory T cells. We carried out experiments using lymphocytes from a patient with neuropathy and plasma cell dyscrasia whose IgM M protein bound to the myelin-associated glycoprotein (MAG) to determine whether secretion of the M protein in vitro was responsive to T cell help or suppression. M protein secretion was measured by an enzyme-linked immunosorbent assay system for measuring anti-MAG IgM, and the number of M protein-secreting lymphocytes was enumerated by a reverse hemolytic plaque assay specific for the M protein idiotype. The patient's B cells were maximally stimulated by pokeweed mitogen-activated autologous OKT4+ T-helper cells and the helper effect was inhibited by OKT8+ suppressor/cytotoxic T cells. Low levels of M protein secretion in the absence of T cells were also observed and there was partial stimulation of M protein secretion by T cells in the absence of pokeweed mitogen.

Autoantibodies↗

PubMed1985

The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family.

The surface glycoproteins T4 and T8 define different functional subsets of T lymphocytes and may act as recognition molecules mediating appropriate interactions between the T cell and its target. Previously we employed gene transfer and subtractive hybridization to isolate a T8 cDNA; now we have isolated and sequenced a cDNA clone encoding the T4 molecule. The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. The overall structure of T4 consists of an N-terminal variable (V)-like domain, a joining (J)-like region, a third extracellular domain, a membrane-spanning region homologous to class II MHC beta-chains, and a highly charged cytoplasmic domain. Comparison of the protein sequences deduced from the T4 and T8 cDNAs reveals structural similarities consistent with their postulated role as recognition molecules, as well as differences suggesting that the two proteins recognize different structures on the target cell.

Amino Acid Sequence↗

PubMed1982

The effect of carcinogens on the accumulation of tyrosine aminotransferase by foetal rat hepatocytes in culture.

The hepatocarcinogen 3'-methyl-4-dimethyl-aminoazobenzene (MDAB) suppresses the accumulation of tyrosine aminotransferase in cultured foetal hepatocytes. Experiments involving liver derived from foetuses of various ages reveals that a response is only obtained with rats older than 16-day gestation. It has been proposed that the lack of an effect in less mature hepatocytes is due to their inability to activate the carcinogen. Chemically synthesized analogues of MDAB which are considered likely to be activated forms of the procarcinogen are shown to be effective in the less mature cells. This supports the proposal that these cells may be unresponsive because they are unable to activate MDAB. Tests with other carcinogens reveal that the hepatocarcinogen dimethylbenzanthracene is also effective in 19-day gestation hepatocytes. However, the non-hepatocarcinogens azaserine and benz(a)pyrene are ineffective. Treatment with MDAB is shown not to alter the level of steroid receptor and reduce its translocation into the nucleus, suggesting that this is not the mechanism by which TAT is suppressed. The effect of the tumour promoter phorbol-myristate acetate (PMA) administered together with MDAB was shown not to modify the response to the carcinogen alone.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1981

HLA-D-DR relationships: PLT studies of HLA-D specificities associated with DR1, DR2, and DR4.

The primed lymphocyte test (PLT) detects gene products of the HLA-D-DR region which activate the secondary (memory) response of MLC stimulated T cells. In the present study attempts were made to determine whether different HLA-D alleles associated with the same DR, such as DR1, 2, and 4 can be discriminated by PLT typing. PLTs were generated by using, as responders and primary MLC stimulators, HLA-D different HTCs which shared all DR groups (major DR, supertypic MT and second locus MB) or only the MT or MB groups. As secondary stimulators, lymphocytes from an HLA-D selected panel of 72 individuals were used. PLTs raised in DR identical responder-primary stimulator combinations were able to discriminate between the different HLA-D antigens associated with the same DR. In contrast, when priming was performed in combinations differing for the major DR group, the restimulation response was highly associated with the DR specificity of the primary stimulator, regardless of whether or not this was compatible with the responding HTC for the MT or MB groups. This data indicate that the specificity of primed lymphocytes largely depends on the combinations used for priming and that the memory response can be activated by both HLA-D and DR antigens. The dissociation of HLA-D from DR by PLT typing might provide a useful tool for further analysis of this HLA region.

Epitopes↗

PubMed1981

New HLA-D alleles associated with DR1 and DR2.

The present study describes two new HLA-D specificities : LD 13, associated with DR1, and LD14 associated with DR2. LD13 is defined by an HTC who is the bc offspring of an a: A25, B18, DR7, Dw7/b: A33, B14, DR1, Dx father, and of a c: A24, B14, Dr1, Dx/d: A26, B41, DR5, Dw5 mother. This HTC was included both as a responder and as a stimulator in our cross-reference studies of 8W HTCs. While failing to cluster with any other 8W HTC, it typed 2 of 64 panel members carrying a "blank" HLA-D, linked to DR1. To exclude the possibility that HTC-LD13 might be a split of Dwl, the entire family was tested with the Family Set of 8W HTCs. No typing responses to any 8W Dw1 HTCs were observed. Furthermore, checkerboard experiments between HTC-LD13 and 8WDw1 HTCs showed strong reciprocal stimulation. The LD13 specificity was only found in Ashkenazi Jews and may be in linkage disequilibrium with HLA-B14. LD14 is defined by three, SD different, HTCs deriving from the same family of Sicilian descent. The family was included in the 8th Workshop and each HTC was shown to have inherited DR2, MT1 from both parents. When tested as stimulators, on our HLA-D reference panel, these cells were clustered in a distinct group, LD14, associated with DR2. None of the 8W HTCs appeared to belong to this cluster. The antigen frequency of LD14 is 0.03.

Alleles↗

PubMed1981