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H O McDevitt

Publications and source records attributed to H O McDevitt.

At least 145 records · Page 8Linked to original sources
PubMed1983

The murine E alpha immune response gene.

We have isolated and sequenced cDNA and genomic clones of the murine E alpha gene, one of the immune response genes of the major histocompatibility complex. Comparison of our data with those recently reported for the human homolog DR alpha shows an identical intron-exon structure, and a good conservation of the protein-coding sequences, including the amino acids potentially involved in organizing the second external protein domain into an immunoglobulin-like fold. Noncoding sequences are less conserved, with the exception of the promoter region. Finally, we show that differential expression of the gene in various cell types appears to be transcriptionally regulated, and that genomic rearrangements do not seem necessary for expression.

Amino Acid Sequence↗
PubMed1983

Regions of allelic hypervariability in the murine A alpha immune response gene.

The murine Ia antigens, a group of cell surface glycoproteins, are involved in the control of the immune response. The structure of one of these class II major histocompatibility complex molecules, A alpha, was recently deduced from sequence analysis of a cDNA clone produced from k haplotype mice. We have now isolated and sequenced A alpha cDNA clones from five other mouse haplotypes: d, b, f, u, and q. Sequence comparison revealed a surprisingly high degree of allelic polymorphism. Interestingly, amino acid substitutions were clustered within the first external domain of this polypeptide chain, particularly at a few highly variable positions. Functional implications of A alpha polymorphism and possible mechanisms for its generation are discussed.

Alleles↗
PubMed1983

Biochemical characterization of an invariant polypeptide associated with Ia antigens in human and mouse.

Ii, a 31,000 mol. wt polypeptide chain associated with murine and human Ia antigens was investigated for its labeling pattern, carbohydrate content and structural polymorphism. Two-dimensional gel electrophoretic analysis of tunicamycin treated cells from mouse and human lymphocytes shows that Ii contains two N-linked carbohydrate chains. Ii is a methionine rich polypeptide. Tryptic and chymotryptic two dimensional peptide maps of Ii chain associated with I-A and I-E subregion products are identical. This absence of polymorphism holds true when Ii chain is isolated from different mouse haplotypes. Human Ii chains from different HLA-DR types appear also invariant by peptide map analysis. By molecular weight, carbohydrate content, charge and tryptic and chymotryptic maps criteria, Ii of mouse and human are strikingly homologous.

Animals↗
PubMed1983

Several mechanisms can account for defective E alpha gene expression in different mouse haplotypes.

The murine Ia antigens, encoded by the I region of the major histocompatibility complex, are cell-surface glyco-proteins (consisting of alpha and beta polypeptides) thought to be involved in the control of immune responsiveness. Mice of haplotypes b, s, q, and f fail to express one of the Ia antigen complexes, the E complex, on the cell surface. We have attempted to determine at the molecular level how such a defect (or defects) might be generated. By using I-region E alpha and A alpha gene probes for analyses of RNA and DNA structure, it was possible to conclude that at least three mechanisms can operate. Mice of haplotypes b and s bear a deletion in the E alpha gene, f haplotype mice synthesize predominantly an E alpha mRNA of aberrant size, and mice of the q haplotype seem to have a defect in RNA processing or a problem with mRNA stability, or both.

Animals↗
PubMed1983

The murine Ia alpha chains, E alpha and A alpha, show a surprising degree of sequence homology.

The I region of the murine major histocompatibility complex codes for a group of glycoproteins, the Ia antigens, thought to be involved in the control of immune responsiveness. Each Ia antigen complex contains a "heavy chain," a "light chain," and the "invariant chain." We describe here the isolation and characterization of genomic and cDNA clones for one of the heavy chains, Ak alpha. The complete nucleotide sequence of the cDNA clone is presented, and the predicted amino acid sequence is compared with that of another alpha chain, Ek alpha. About 50% of the amino acids are identical, a finding somewhat unexpected on the basis of preliminary protein sequence data.

Amino Acid Sequence↗
PubMed1983

Isolation and characterization of a cDNA clone for the murine I-E beta polypeptide chain.

The Ia antigens, encoded within the I region of the major histocompatibility complex, are a group of cell surface glycoproteins that are involved in the control of immune responsiveness. We isolated and determined the sequence of a 1,045-base-pair cDNA clone for one of the murine immune response genes, Ek beta. Comparison of the predicted amino acid sequence of the product of Ek beta with that of Ed beta shows that most of the amino acid differences are clustered in short stretches of peptide sequence in the first external protein domain. This clustering of allelic variation suggests that observed haplotype-specific immune responsiveness to certain antigens may be controlled, at least in part, by differences in configuration defined by these regions of allelic variability in the NH2-terminal domain of the E beta chain.

Amino Acid Sequence↗
PubMed1983

Use of synthetic oligonucleotide probes complementary to genes for human HLA-DR alpha and beta as extension primers for the isolation of 5'-specific genomic clones.

We have synthesized 175-nucleotide-long probes for the DNA of human histocompatibility antigens HLA-DR alpha and beta by extending on poly(A)+ mRNA from B-cell lines with short synthetic deoxyribonucleotide primers complementary to the predicted nucleotide sequence of the NH2 terminus of both polypeptides. The synthesis of the probe for the alpha-chain DNA was a two-step process starting with 11-mers which were extended by dideoxynucleotide chain termination experiments to a 20-mer of predicted sequence. The synthesized 20-mer was then used to generate a 175-nucleotide cDNA probe which was shown to encode the appropriate amino acids for the alpha chain and was used to select a human genomic DNA clone containing the coding sequences for HLA-DR alpha. For the beta polypeptide an 18-mer homologous to the NH2-terminal sequence of a cDNA clone from another B-cell line was used to extend on poly(A)+ mRNA isolated from a B-cell line. Preliminary sequence analysis of a 175-base-long extension product indicates a match of the cDNA sequence to the published sequence of a clone for HLA-DR beta. Information from these extension experiments helps to establish the sensitivity and specificity of the primer extension method.

Amino Acid Sequence↗
PubMed1983

In vivo therapy with monoclonal anti-I-A antibody suppresses immune responses to acetylcholine receptor.

A monoclonal antibody to I-A gene products of the immune response gene complex attenuates both humoral and cellular responses to acetylcholine receptor and appears to suppress clinical manifestations of experimental autoimmune myasthenia gravis. This demonstrates that use of antibodies against immune response gene products that are associated with susceptibility to disease may be feasible for therapy in autoimmune conditions such as myasthenia gravis.

Animals↗
PubMed1983

The genetics of the HLA system.

The availability of cDNA probes for Class I and Class II major histocompatibility complex (MHC) antigens has revealed the existence of more genes in both the Class I and Class II subsets than had been previously detected. The use of restriction endonucleases has demonstrated that restriction enzyme site polymorphisms exist in the flanking sequences for many of the Class I and Class II genes of the MHC. The development of locus specific probes should permit utilization of these restriction site polymorphisms in characterizing particular HLA haplotypes (combinations of HLA A, B, C, DR, DC, and SB) and the availability of allele specific probes, if feasible, would permit direct determination of genotype by DNA hybridization methods. These methods would greatly enhance our understanding of Class I and Class II HLA population genetics, linkage disequilibrium, and association of HLA with susceptibility to autoimmune diseases.

Animals↗
PubMed1982

Identification of a fourth class of proteins linked to the murine major histocompatibility complex.

A series of proteins biochemically and genetically distinct from previously defined murine major histocompatibility complex class I and class II antigens is precipitated by a congeneic anti-H-2d antiserum. Sixteen such proteins have been defined, exhibiting a range of molecular weights (approximately 15,000-30,000) and isoelectric points (pI approximately 4-9). These proteins are not glycosylated, and they are probably not expressed at the cell surface. They are expressed most strongly in normal macrophages and macrophage cell lines and are also found in fibroblasts, B, T, and null cell lines. The genes controlling the expression of these proteins have been tentatively mapped within the H-2 complex, between the K and I-A subregions. Three alleles have been defined: mice of the H-2 haplotypes b and q possess a "null" allele, i.e., do not express any demonstrable protein product. Mice of the d haplotype cane be distinguished by their two-dimensional gel pattern from mice of all other positive H-2 types tested thus far (a, k, f, s, and ja).

Animals↗
PubMed1981

In vivo effects of antibodies to immune response gene products. I. Haplotype-specific suppression of humoral immune responses with a monoclonal anti-I-A.

Immune response (Ir) gene products control immunologic function at several critical sites. We administered in vivo a monoclonal antibody reactive with I-Ak to F1 mice with the genotype H-2k/b. These treated mnice made a markedly reduced antibody response to antigen (H,G)-A--L, under the control of I-Ak, but not to antigen (T,G)-A--L, under the control of I-Ab. This relative specificity was lost if the antigen was given in complete Freund's adjuvant rather than aqueous solution. The monoclonal antibody reduced the antibody titer in an ongoing, secondary response as well. Several potential mechanisms can be postulated for this effect. This haplotypic specificity might ultimately be relevant to human disease.

Animals↗
PubMed1981

Structure of murine Ia antigens. Two dimensional electrophoretic analyses and high pressure liquid chromatography tryptic peptide maps of products of the I-A and I-E subregions and of an associated invariant polypeptide.

We demonstrate that an invariant polypeptide, first described by Jones et al. (21), co-immunoprecipitates with our Ia molecules, that its interaction with Ia polypeptides varies with haplotype, and that it is not a precursor of the Aalpha, Abeta, Ealpha, or Ebeta. polypeptides. We also show that the polypeptides that we have previously characterized are contaminated with very little, if any, invariant protein. Further, we have used our high-pressure liquid chromatography tryptic peptide map technique to formally map the genes encoding Aalpha, Abeta, and Ebeta to the I-A subregion using recombinant and F1 hybrid mice.

Animals↗
PubMed1981

Treatment of NZB/NZW F1 hybrid mice with Mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease.

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.

Animals↗
PubMed1981

Variable synthesis and expression of E alpha and Ae (E beta) Ia polypeptide chains in mice of different H-2 haplotypes.

The genetic and molecular requirements for cell-surface expression of Ia antigens precipitated by anti-I-E subregion sera have been examined. Inbred mice f the d, k, p, and r haplotypes synthesize and express on their lymphocytes the two I-region products normally found in anti-I-E-subregion immunoprecipitates, E alpha and Ae (E beta). Cells from mice of the b and s haplotypes fail to synthesize E alpha chains but do synthesize Ae chains, which remain in the cytoplasm as partially glycosylated precursors. Cells of the f and q haplotypes fail to synthesize either the Ae or E alpha polypeptide chains, as shown by both genetic complementation tests and analyses of total cell proteins by two-dimensional polyacrylamide gel electrophoresis. The patterns of expression of the intact E alpha: Ae complex are consistent with the theory that both the Ae and E alpha polypeptide chains must be present in the cells for either chain to be expressed in normal amounts on the cell surface. The implications of these observations for the genetics of I-region-controlled functions are discussed.

Animals↗