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H O McDevitt

Publications and source records attributed to H O McDevitt.

At least 127 records · Page 7Linked to original sources
PubMed1986

Absence of polymorphism between HLA-B27 genomic exon sequences isolated from normal donors and ankylosing spondylitis patients.

Ninety percent of individuals with ankylosing spondylitis (AS) express HLA-B27. To determine if HLA-B27 coding sequences from normal vs AS individuals show differences that might relate to the etiology of the disease, the gene coding for this allele was cloned from three different partial genomic libraries. These libraries were made with DNA from three different cell lines expressing HLA-B27: MRWC (HLA-B27, 14), obtained from an AS patient; KCA (HLA-B27, w44), obtained from a known normal individual; and MVL (HLA-B27, 27), a homozygous consanguineous cell line of unknown origin. To increase the number of clones coding for the HLA-B locus, partial libraries were made using a complete Eco RI digestion of genomic DNA in the lambda vector 607. The libraries were screened with two probes; one probe hybridizes to all HLA-A, B, C class I genes, and the other to a small subpopulation of class I genes, including the B locus. DNA from clones hybridizing with both probes was transfected into murine L cells. Cell surface expression of HLA-B27 on murine L cells was detected with a polymorphic monoclonal antibody (ME1) specific for HLA-B27, 7, 22. DNA from those clones positive for HLA-B27 by transfection was subcloned into the Xba I site of M13mp18 and the DNA sequence for exons 2 through 4 (encoding domains alpha 1, alpha 2, and alpha 3) was determined by the dideoxy technique by using synthetic oligonucleotide primers or the M13 primer. The resulting sequences show no difference between HLA-B27 alpha 1, alpha 2, alpha 3 domains from a known AS patient and a known normal individual.

Base Sequence↗
PubMed1986

E alpha u and E beta u chain association: where lies the anomaly?

H-2u haplotype mice are unique among all E alpha+ strains because they do not provide in heterozygotes an E alpha chain that interacts with E betak,s,etc. sufficiently well to allow certain E-restricted immune responses. As a first step in understanding this peculiarity, we have sequenced E alpha u and E beta u cDNA and compared the derived amino acid sequences with those of previously analyzed alleles. Although no glaring structural abnormalities were found, we have identified some u-specific residues and suggest which are the most likely to provoke a pairing anomaly.

Alleles↗
PubMed1986

The LMP antigens: a stable MHC-controlled multisubunit protein complex.

In addition to encoding the well-known class I (H-2), II (Ia), and III (complement components C2, C4, and factor B) antigens, the murine MHC controls the expression of a large, intracellular protein complex of unknown function. This complex is composed of a large number of noncovalently linked low molecular weight polypeptide subunits (hence the name, LMP) which are biochemically, serologically, and genetically distinct from class I, II, and III antigens. Only two of these subunits display electrophoretic polymorphism within the standard inbred mouse strains, and both of these polymorphisms map within the H-2 complex, between the H-2K and I-A subregions. The remainder of the LMP complex subunits have not been mapped, and may be encoded elsewhere in the genome. A biochemically similar complex has been detected in human cells, although linkage to HLA remains to be established. In this article we will review the biochemistry, serology, and genetics of the LMP antigens, and will speculate on their biological function.

Alleles↗
PubMed1986

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

I-A beta-chain cDNA clones from mice of the q, k, u, s, and f haplotypes have been isolated and sequenced. Nucleotide sequence comparisons among these five A beta chains show considerable allelic variation in the region encoding the first external (beta 1) domain of the mature A beta protein. The beta 1 domain variability is clustered into three discrete regions, two of which divide the A beta chains into subgroups, suggesting an evolutionary history for the separation of alleles in inbred strains of mice. The amino acid sequences of these five chains are compared to each other and to previously published I-A beta chains. Correlations are made between the primary structural differences and the serologic and immune response characteristics mapping to the I-A subregion.

Amino Acid Sequence↗
PubMed1985

DNA sequence and characterization of human class II major histocompatibility complex beta chains from the DR1 haplotype.

Two HLA class II beta-chain clones from a cell line homozygous for the DR1 haplotype have been characterized and sequenced. They represent a DR beta chain (2918.4) and a DQ beta chain (2918.8). Clone 2918.4 has been used to select mRNA from a lymphoblastoid cell line, and this was injected into Xenopus oocytes with mRNA selected with a DR alpha chain. The translation products were immunoprecipitated with a beta-chain-specific monoclonal antibody and electrophoresed on two-dimensional gels. This revealed positive signals in the positions predicted for beta and alpha chains. Sequence comparisons of 2918.4 with previously published DR beta-chain sequences confirm the presence of two regions of variability in the membrane distal domain. Analysis of the sequence of 2918.8 identified it as a DQ beta chain identical to one previously published from a DR3,w6 cell line. We speculate, therefore, that the DQ beta sequence represents the DQ1 specificity shared by the DR1 and DRw6 haplotypes.

Animals↗
PubMed1985

In vivo prevention of thyroid and pancreatic autoimmunity in the BB rat by antibody to class II major histocompatibility complex gene products.

Evidence is accumulating that the development of insulin-dependent diabetes mellitus involves autoimmune phenomena, both in the human and in the BB rat model. A strong association is observed in both cases with alleles of the class II major histocompatibility complex (MHC). Results of the present study show that autoimmune phenomena, as assessed by the presence of clinical diabetes or histological thyroiditis, are prevented by the injection of monoclonal antibodies to class II gene products in the BB rat. Immunosuppression was specifically obtained with a monoclonal antibody to the murine I-E equivalent, as opposed to the murine I-A equivalent, of the rat major histocompatibility complex. This represents indirect evidence for I-E subregion control of immune responses to islet cell and thyroid antigens in the BB rat model. The frequent occurrence of anaphylactic type deaths in young (1 month old) animals receiving more than six weekly injections of partially purified homologous (rat) monoclonal antibodies to rat class II gene products underscores the potential risks of this type of immunotherapy. The presumed immunologic mechanism (IgE antibody) and its specificity (anti-allotype, anti-idiotype, or anti-impurity) must be clarified to assess the risks and feasibility of this type of therapy.

Anaphylaxis↗
PubMed1985

HLA-B locus polymorphism: studies with a specific hybridization probe.

The large number of class I histocompatibility genes (HLA) and their extensive homology has made it difficult to assign bands on genomic Southern blots to known genes. Therefore, we have tried to obtain nucleic acid probes for class I genes that are locus specific or have restricted locus specificity. Computer sequence-homology analysis was used to compare the nucleic acid sequences of two genomic clones, one coding for the HLA-B7 antigen (JY150) and one containing a class I pseudogene (pHLA12.4). A sequence in the 3' untranslated region with very low homology was identified. This sequence from the HLA-B7 gene was subcloned into M13 phage. This fragment, JY150/C5, hybridized with two genomic bands in DNA from human HLA homozygotes--presumably the HLA-B locus gene and a closely related gene. The probe was used to assess restriction fragment polymorphism at the HLA-B locus in homozygous consanguineous cell lines. This analysis permitted the association of certain polymorphic restriction enzyme fragments with some alleles of this locus. However, many HLA-B alleles have identical restriction fragments produced by a number of restriction endonucleases.

Alleles↗
PubMed1985

Predicted protein sequence of the murine I-E-beta S-polypeptide chain from cDNA and genomic clones.

Ia antigens are polymorphic cell-surface glycoprotein complexes, encoded within the I region of the mouse major histocompatibility complex, that control the ability of the organism to mount effective antigen-specific immune responses. We have isolated and determined the nucleotide sequences of cDNA and genomic clones for the I-E beta s gene and we present the predicted protein sequence for most of the E beta s polypeptide chain. The E beta s polypeptide shows 95% protein homology to the other cloned E beta alleles. Comparison of the protein sequences of five E beta alleles from haplotypes that differ in responder phenotype to pigeon cytochrome c suggests that the structure of one of the E beta hypervariable regions may determine responsiveness to this antigen.

Alleles↗
PubMed1985

Structure and polymorphism of murine and human class II major histocompatibility antigens.

The molecular analysis of the Class II region of the MHC of mice and of humans has to date led to some important conclusions. These regions encode sizeable families of related loci, at least 2 alpha and 6 beta in mice and 6 alpha and 7 beta in man. In addition to the sizeable number of potential molecules that could be expressed by the loci of this region, all the beta chains and both A alpha and DC alpha have extensive amounts of polymorphism. This polymorphism is strikingly similar at Class II loci in mouse and man. The majority of the variability is found in the first domain and consists of discrete regions of variability. These variable regions appear to be important functionally in presenting antigen, as evidenced by the bm12 mutant. The allotypy of these molecules is complex and is presumably generated by a combination of gene conversion and point mutation followed by selection. Final definition of the range of allelic variability and further insights into the mechanism by which it was generated are still to be resolved, as in a complete map of all the Class II loci in both mouse and man. The data available at present pose certain questions that now need to be addressed. The precise functional role of individual regions or residues of the Class II molecules can now be analyzed using the available sequence data and site specific mutagenesis. Fine structural analysis of these molecules is impossible at present using only sequence data, and X-ray crystallography will be required to answer fundamental questions about 3-dimensional structure. Finally, disease-specific sequences may be uncovered on particular haplotypes which permit the production of disease-specific probes. The molecular revelations of the last few years have resolved many questions about the polymorphisms of Class II products, but many new questions need to be resolved before these molecules and their extensive polymorphism can be properly understood.

Animals↗
PubMed1984

Gene conversion between murine class II major histocompatibility complex loci. Functional and molecular evidence from the bm 12 mutant.

The experiments presented in this study define the molecular basis of the bm 12 mutation. Initial characterization of an alloreactive T cell clone, 4.1.4, showed this clone to recognize an allodeterminant present on the E beta b and A beta bm12 chains, but not on the bm 12 parent A beta b chain. To define the extent of sequence shared between the I-E beta product and the mutant I-A beta product, we isolated a cDNA clone of the E beta b gene and determined its nucleotide sequence. Comparison of the nucleotide sequences of E beta b, A beta b, and A beta bm12 shows the the A beta bm12 gene to be identical to the E beta b gene in the region where it differs from its A beta b parent. We predict that the bm 12 mutation arose by gene conversion of this region, which spans 14 nucleotides between amino acid residues 67-71 of the mature A beta chain, from the E beta b locus to the corresponding position at the A beta b locus. Recognition of this region, which spans one of the previously defined E beta allelic "hypervariable" regions, by an alloreactive T cell clone provides the first direct evidence of the functional importance of these hypervariable regions in T cell stimulation. The identification of a gene conversion event involving one of these allelic variable regions implicates conversion as a mechanism that acts on class II beta genes to create sequence diversity in regions of Ia molecules that interact with foreign antigen or a T cell receptor, regions where protein sequence polymorphism would presumably be selected for by the expanded ability it affords the organism to mount effective immune responses against a wider variety of foreign antigens.

Animals↗
PubMed1984

Structure, regulatory polymorphisms, and allelic hypervariability regions in murine I-A alpha.

Class II major histocompatibility complex (MHC) molecules, the Ia antigens, are intimately involved in regulating the intensity and specificity of the cellular and humoral responses to T cell-dependent antigens. One approach to understanding the mechanism of this regulation is to analyze the structure and allelic polymorphism of Ia molecules. In addition there are regulatory polymorphisms in the expression of the I-E alpha and I-E beta class II MHC polypeptide chains. Analysis of the cDNA sequence indicates that I-A and I-E alpha chains are similar with short stretches of homology and other regions of nonhomology. Analysis of Northern blots of mRNA indicates that at least three separate types of regulatory polymorphisms result in failure of expression of I-E alpha. Comparison of allelic sequences of six alleles of the I-A alpha chain shows that almost all of the allelic polymorphism is in the first domain and that within the first domain it is clustered in three allelic hypervariable regions within the first domain of I-A alpha. The structural and functional implications of these findings are discussed.

Alleles↗
PubMed1983

Treatment of (NZB x NZW)F1 disease with anti-I-A monoclonal antibodies.

(NZB x NZW)F1 mice spontaneously develop an autoimmune syndrome characterized by a fatal immune complex glomerulonephritis. Administration of monoclonal antibodies specific for an I region gene product (I-Az) of the H-2 haplotype associated with susceptibility to glomerulonephritis in these animals produced a remission in female mice with established renal disease. The results demonstrated that anti-I-A therapy stabilized the level of proteinuria and increased the 1-yr survival rate from 10% to greater than 90% in treated animals relative to control mice. These findings may ultimately have therapeutic potential for the treatment of systemic lupus erythematosus.

Animals↗