Search PubMed⌕ Search

Biomedical subjects

C S David

Publications and source records attributed to C S David.

At least 271 records · Page 15Linked to original sources
PubMed1981

Genetic control of the immune response to haemoglobin. II. Studies using purified alpha-chain and beta-chain as immunogens.

Mice of independent haplotypes and several recombinant inbred strains were immunized with highly purified preparations of either the alpha-chain or beta-chain subunit of human adult haemoglobin. Cells from the sensitized lymph nodes were challenged in vitro with the appropriate subunit (or in some cases both chains) and cell proliferation assessed by 3H-thymidine incorporation. Mice of the H-2b and H-2d haplotypes were high responders to alpha-chain while mice of the H-2f, H-2j, H-2k, H-2r, H-2s, H-2u, and H-2v haplotype were low responders. the low responsivenesss of B10.A(4R) and B 10.MBR and high responsiveness of B10 indicated that the Ir gene(s) determining responsiveness to the alpha-chain subunit resides in the I-A subregion of the mouse major histocompatibility complex. Mice of the H-2d, H-2f, and H-2s haplotypes were high responders and H-2b, H-2j, H-2a, and H-2u haplotype mice were low responders to beta-chain. H-2k, H-2p, H-2r, and H-2v haplotype mice were intermediate responders to beta-chain. The low responsiveness of B10.S(8R) and B10.TL and the high responsivenes of B10.S(9R) mapped the Ir gene(s) to beta-chain to the I-A subregion. Data collected from challenging high responder cells with both subunit indicated that alpha-chain and beta-chain do not crossreact. These results are discussed in reference to earlier observations suggesting that the low responsiveness of some strains of mice to priming and challenging using the intact haemoglobin molecule might be due to a negative regulatory influence mediated by one of the subunits. In the absence of this influence these mice would respond normally.

Adult↗
PubMed1981

Genetic control of the immune response to haemoglobin. III. Variant A beta (bm12) but not Ae (D2.GD) Ia polypeptides alter immune responsiveness towards the alpha -subunit of human haemoglobin.

Mice bearing the I-A subregion mutation bm12 were immunized and challenged with the alpha -subunit of human adult haemoglobin. Under conditions in which parental B6/Kh mice respond, B6.C-H-2bm12 mice are inhibited nearly 100% in their ability to respond to challenge to the alpha-chain of haemoglobin. D2.GD mice which express a variant Ae (E beta) polypeptide of the I-E subregion can respond as well as B10.D2 mice to both subunits (alpha- and beta-) of haemoglobin. These observations as well as other genetic mapping data confirm the I-A mapping of alpha -chain-specific Ir genes and extend the genetic fine mapping to the A beta gene within the I-A subregion or a combinatorial Ia determinant generated by an interaction of A alpha and A beta. In addition they implicate the Ia.8 specificity in determining immune responsiveness to alpha -chain determinants.

Animals↗
PubMed1981

Genetic control of autoimmunity to acetylcholine receptors: role of Ia molecules.

Evidence that human susceptibility to myasthenia gravis (MG) might be determined genetically is suggested by clinical surveys showing an association of MG with an increased frequency of certain histocompatibility antigens. We have studied the experimental autoimmune model of MG in mice to investigate whether or not major histocompatibility complex (MHC) gene products play a role in determining susceptibility to EAMG. When MHC congenic and recombinant strains of mice were inoculated with Torpedo acetylcholine receptor (AChR) and adjuvants, the magnitude of autoantibody responses to muscle AChR and of the defect of neuromuscular transmission (i.e., reduction in MEPP amplitude) closely paralleled in vitro lymphocyte proliferative responses to torpedo AChR. Reduction in MEPP amplitude correlated strikingly with the degree to which autologous muscle AChR was complexed with antibody. Lymphocyte responses to Torpedo AChR, antibody responses to mouse muscle AChR, and susceptibility to EAMG are controlled by gene(s) at the I-A subregion of the H-2 complex. Backcross studies confirmed that lymphocyte proliferative responses to AChR are controlled by a Mendelian dominant gene linked to H-2, probably at the I-A subregion. Mutation at the I-A subregion in the B6 strain, which resulted in structural alteration of the Ia molecule, converted high responsiveness to low responsiveness. Lymphocyte responses were eliminated by blocking Ia antigens on lymph node cell surfaces with specific anti-I-A alloantisera. Cellular immune responses to AChR are dependent on Lyt 1+23- cells and adherent cells. These data implicate a macrophage-associated Ia molecular in induction of autoimmune responses to AChR, probably in the presentation of AChR to helper (Lyt 1+23-) T-lymphocytes, which thereby help B-lymphocytes to differentiate into anti-AChR antibody forming cells.

Action Potentials↗
PubMed1981

Genetic control of the immune response to myoglobin. V. Analysis of the cross-reactivity of 12 myoglobins with sperm-whale myoglobin antisera of inbred mouse strains in terms of substitutions in the antigenic sites and in the environmental residues of the sites.

The determination of the entire antigenic structure of myoglobin has made it possible to focus attention on the molecular factors controlling and influencing immune recognition. Recently, using antisera raised against sperm-whale myoglobin (Mb) in six different host species and investigating their reactions with Mb from 15 species, we showed that the binding capacity of an antigenic site is influenced by substitutions within site residues as well as within the residues close (within 6.0 å) to the sites. Based on these effects it was possible to correlate, at least in qualitative terms, the expected effects of the substitutions in each Mb and its observed cross-reaction with antisera to sperm-whale Mb. In the present work, these correlations were tested using sperm-whale Mb antibodies raised in four inbred mouse strains and in which the amount of antibodies directed to each antigenic site was determined. The amounts of 125I-labelled antibodies that could be bound maximally be each of 12 Mb variants were determined. Because of genetic control, the response to some antigenic sites was not expressed and therefore permitted us to evaluate with a good degree of confidence the effects of amino acid replacements in various myoglobins upon the reactivity of the sites. The values of cross-reaction expected for each Mb variant from these considerations agreed well with the values found experimentally. The results confirm unambiguously that the major factors affecting the cross-reactions of proteins can be attributed to substitutions within the sites and within environmental residues of the sites.

Animals↗
PubMed1981

Genetics of immune response: a survey.

The mouse has served as an invaluable model for investigations of immune response (Ir) genes. Of most importance has been major histocompatibility complex (MHC) linked Ir genes. The MHC genes have been demonstrated to be the prime factor in determination of the ability to respond to an antigenic stimulus. One of the more intriguing findings has been the capacity of a relatively small number of Ir genes to determine immune reactivity to a diverse collection of antigens. This review will deal with the extent of the antigen diversity and the nature of the antigenic determinants. Data are summarized for over 100 independent antigen systems involving infectious agents (bacteria, viruses, parasites), as well as living but not infectious agents (histoincompatible cells). Finally, the more recent findings utilizing antigenically defined (to varying degrees) proteins are presented. The contributions of each antigen type to the understanding of Ir gene function are discussed. Even though studies on synthetic polypeptides have enabled defining and elucidation of immune response genes, we have not extensively covered this area in this survey. Several excellent reviews of this studies are available.

Amino Acids↗
PubMed1981

Serologic and biochemical analyses of a variant Ae (E beta) ia polypeptide chain in D2.gD (H-2g2).

Recombinant D2.Gd (KdAdBbJbEbCbSbDb) was derived from parental strains B6 (H-2b) and DBA/2 H-2d). Recent peptide studies and 2-D electrophoresis studies from other laboratories have shown that the Aed (E beta) chain of D2.GD is structurally different from the parental-derived chain. An antiserum (D2.GD X A. TFR5)F1 anti-DBA/2 was produced that detects an Ia specificity (Ia.50) in the I-E molecule formed by the parent Aed chain and lacking in the I-E molecule formed by the variant Aed. chain. The variant Ae chain could have derived either from a mutational event or an intracistronic cross-over.

Animals↗
PubMed1981

Detection of hybrid (combinatorial) Ia antigens using parent anti-F1 sera.

Ia specificities 22 and 23 were initially identified by using conventional alloantisera and were mapped to the I-E subregion of k and d haplotypes on the basis of their reactivity with selected recombinants. Recently we found that Ia 22 and 23 are hybrid determinants on the basis of their expression on selected F1 cells, but absence from both parental cells. Initial attempts to detect hybrid Ia antigens by immunizing parents with F1 cells were unsuccessful. By utilizing lipopolysaccharide (LPS)-stimulated F1 spleen lymphoblasts as immunogens, 1 of the parents as recipient and the other parent cells for absorption of antisera, specific anti-Ia.22 and 23 antibodies were produced. The specificity of these parent anti-F1 sera was confirmed by cytotoxic and immunoprecipitation analyses.

Absorption↗
PubMed1981

Biochemical evidence for trans complementation of structural genes in the expression of I-E antigens in F1 hybrids.

Analysis of the tryptic peptides obtained from the Ia.7-positive, "I-E" antigens produced by 4 F1 combinations derived from strain A.TFR5 has provided biochemical confirmation that I-A/I-E gene complementation can occur in the transconfiguration. The data obtained support the concept that structural genes, as opposed to regulatory genes, are the essential elements involved in this complementation and support the assignment of the I-E subregion of strain A.TFR5 as I-Ek. The data support the following assignments of the genes encoding the E beta chains: B10.A(4R) as E beta k, B10.A(5R) as E beta b, and B10.HTT as E beta s. Finally, data are presented demonstrating that the E beta chain derived from the recombinant D2.GD strain partially differs from the E beta d chain derived from a conventional H-2d haplotype strain, B10.D2.

Animals↗
PubMed1981

Genetic control of experimental autoimmune myasthenia gravis in mice. II. Lymphocyte proliferative response to acetylcholine receptor is dependent on Lyt-1+23- cells.

The proliferative response of regional lymph node lymphocytes to Torpedo acetylcholine receptor (TAR) is under H-2 linked Ir gene control. In high responder B6 (H-2b) congenic mice, lymphocytes that proliferate in vitro in response to TAR are dependent on T cells of a subpopulation expressing the phenotype associated with helper functions, Lyt-1+23-.

Acetylcholine↗
PubMed1981

Serologic and biochemical identification of minor histocompatibility (H-4) antigens.

Mouse alloantiserum capable of detecting minor histocompatibility antigens has been produced. Cytotoxic antibody to products of the H-4 locus was produced by reciprocal immunization of minor H loci congenic strains B10 (H-4a) and B10.129(21M) (H-4b), with mitogen-stimulated lymphocytes and epidermal cells. Absorption studies suggested antibodies to more than 1 specificity. The antibodies cross-react with products of other minor H loci. Alloantiserum to the H-4 gene product precipitates a glycoprotein with a m.w. of approximately 45,000 from radiolabeled Con A-stimulated lymph node cells.

Absorption↗
PubMed1980

Regulation of granulomatous inflammation in murine schistosomiasis. In vitro characterization of T lymphocyte subsets involved in the production and suppression of migration inhibition factor.

Host granulomatous inflammation in murine schistosomiasis mansoni is a T cell-mediated immune response, which, at the chronic stage of the disease, undergoes T suppressor lymphocyte-dependent modulation. In the present study this phenomenon was further analyzed in vitro. Spleen cells of mice undergoing modulation (20 wk of infection) when mixed with spleen cells of animals exhibiting vigorous granulomatous responses (8 wk of infection) abrogated in vitro migration inhibition factor (MIF) production by the latter. Characterization of the delayed-type hypersensitivity T lymphocytes involved in lymphokine production showed that they belonged to the Lyt-1+ subset and did not express I region-encoded antigens. In contrast, T lymphocytes involved in the suppression of MIF activity belonged to the Lyt-2+ subpopulation of cells, which expressed I-J- and I-C-subregion determinants. These results suggest that the modulation of the granulomatous hypersensitivity response in mice is the result of T-T cell interaction with subsequent regulation of inflammatory lymphokine production.

Animals↗
PubMed1980

The murine H-2.7 specificity is an antigenic determinant of C4d, a fragment of the fourth component of the complement system.

The S region of H-2 controls a polymorphism of the gamma-chain of C4 (gamma 1, gamma 2, and gamma 3) as shown by differences in their isoelectric points. The G region of H-2 was defined by the presence of an alloantigen (H-2.7) on erythrocytes and serum. We found that antisera to H-2.7 immunoprecipitated C4 and no other protein from mouse EDTA-plasma. Furthermore, all H-2.7-positive strains bear C4-gamma 1, and conversely, H-2.7-negative mice bear C4-gamma 2 or gamma 3 (with one exception; see below). The H-2.7 specificity resides on C4d, a 45,000-mol wt fragment generated from the cleavage of the alpha'-chain of C4b by serum control proteins. Because the C4d fragment bears the labile binding site of C4 for cell membranes, it is likely that the erythrocyte alloantigen is acquired from serum as a result of the activation of C4. On the basis of these findings, the existence of a separate G locus is unlikely. Our results also show that C4-gamma 1 and C4-gamma 2 differ from each other at least in their alpha- and gamma-chains, and may represent complex allotypes. No trans effects were observed in F1 hybrids between H-2.7-positive and -negative mice. Mice that bear the k allele in the S region are exceptional in two respects: they are C4-deficient and their C4 molecules bear gamma 2 chains and the H-2.7 alloantigen. Perhaps the low levels of C4 are a consequence of the genetic event leading to this unusual alpha-gamma-chain combination.

Animals↗
PubMed1980

Serological and biochemical identification of hybrid Ia antigens.

Ia specificities 22 and 23 were found to be determinants on hybrid Ia molecules by serological and biochemical studies. Lipopolysaccharide-stimulated splenic lymphocytes from (B10 X B10.D2)F1 expressed Ia.22 although both the parents were negative. Similarly [D2.GD X B10.A(5R)]F1 cells expressed Ia.23, whereas D2.GD and B10.A(5R) lacked it. Ia.22 can be generated by gene complementation of Ak-Ek, Ab-Ed, Ab-Ek, As-Ed, and As-Ek, whereas Ia.23 can be generated by Ad-Ed, Ad-Ek, and Ad-Ep. Other possible complementing combinations are under study. The role of Ia.22 and 23 in mixed lymphocyte reactions and immune responses are discussed.

Electrophoresis, Polyacrylamide Gel↗