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N Otting

Publications and source records attributed to N Otting.

At least 37 records · Page 2Linked to original sources
PubMed1995

Identification of an Mhc-DPB1 allele involved in susceptibility to experimental autoimmune encephalomyelitis in rhesus macaques.

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disorder that in rodents is known to be influenced by genetic background, specifically the Mhc class II region. Immunization of a group of outbred rhesus macaques with bovine high homogenate results in induction of the disease in approximately 65% of the animals. No clear association between the Mamu-DR or -DQ subregion of the rhesus macaque MHC (MhcMamu) and susceptibility or resistance to the disease has been documented. In this communication we describe a CD4+ Th cell line, isolated from an animal diagnosed with EAE, which proliferated in response to purified bovine myelin basic protein (MBP), a major constituent of the myelin sheath surrounding nerve cells. More specifically it only recognized a peptide including residues 61-82 of the molecule. Analysis of the T cell receptor (Tcr) usage of this MBP reactive T cell line showed functional transcripts for only two members of the V alpha 1 and one of each of the V beta 3 and V beta 6 families. The antigen-specific proliferative response was inhibited by a mAb reactive with MHC-DP molecules. Molecular analysis of the Mamu-DP region, in concert with allogeneic antigen presentation studies, demonstrated that the Mamu-DPB1*01 gene product functions as the restriction element for MBP peptide presentation. Retrospective analyses showed that this particular allele is frequently found in the group of EAE susceptible animals but is absent in the resistant animals (P < 0.01). As a consequence, the Mamu-DPB1*01 allele may represent one of the risk factors involved in determining susceptibility to EAE in an outbred population of rhesus macaques.

Alleles↗
PubMed1994

Major histocompatibility complex class I-associated vaccine protection from simian immunodeficiency virus-infected peripheral blood cells.

To evaluate the effectiveness of vaccine protection from infected cells from another individual of the same species, vaccinated rhesus macaques (Macaca mulatta) were challenged with peripheral blood mononuclear cells from another animal diagnosed with acquired immune deficiency syndrome (AIDS). Half of the simian immunodeficiency virus (SIV)-vaccinated animals challenged were protected, whereas unprotected vaccinates progressed as rapidly to AIDS. Protection was unrelated to either total antibody titers to human cells, used in the production of the vaccine, to HLA antibodies or to virus neutralizing activity. However, analysis of the serotype of each animal revealed that all animals protected against cell-associated virus challenge were those which were SIV vaccinated and which shared a particular major histocompatibility complex (MHC) class I allele (Mamu-A26) with the donor of the infected cells. Cytotoxic T lymphocytes (CTL) specific for SIV envelope protein were detected in three of four protected animals vs. one of four unprotected animals, suggesting a possible role of MHC class I-restricted CTL in protection from infected blood cells. These findings have possible implications for the design of vaccines for intracellular pathogens such as human immunodeficiency virus (HIV).

Amino Acid Sequence↗
PubMed1994

Expansion and contraction of rhesus macaque DRB regions by duplication and deletion.

Previous sequence analysis of the rhesus macaque MHC (MhcMamu) class II DRB region has allowed the detection of at least 34 alleles belonging to different lineages. In this communication, 36 new Mamu-DRB alleles are reported. The gene content of the DRB region has been determined for several homozygous animals of consanguineous origin. As in other primates, the number of DRB genes present per haplotype is not constant, varying from two to six genes in rhesus macaques. Six major groups of DRB haplotypes have been defined in our rhesus macaque colony. Two haplotype groups were found to carry, as well as other Mamu-DRB genes, two genes that cluster into distinct HLA-DRB1 lineages. In one of these two groups, a haplotype harbors another two sets of DRB alleles that belong to the Mhc-DRB6 and -DRB*W6 lineages, respectively. Such a haplotype was probably generated by duplication, and our data suggest that after this particular expansion of the DR region, one of the duplicated Mamu-DRB6 alleles was the target of an Alu insertion. Although certain transspecies allelic lineages are evolutionarily stable, and have been conserved for at least 36 million years, the rhesus macaque class II haplotypes differ significantly from those found in humans, chimpanzees, and gorillas. Mhc-DRB regions are therefore comparatively unstable over longer evolutionary time spans, with regard to both the number of genes and the gene content, and must have been subjected to expansion and contraction.

Alleles↗
PubMed1994

Gel electrophoretic analysis of rhesus macaque major histocompatibility complex class II DR molecules.

Rhesus macaque MHC class II DR molecules were isolated from radiolabeled B-cell line extracts by immunoprecipitation with the mAbs 7.3.19.1 and B8.11.2 and subsequently analyzed by 2D-gel electrophoresis. The B-cell lines used for this study were obtained from monkeys that are homozygous for the Mamu-DR region as defined by serologic techniques. Some of these animals have been selectively bred and originate from consanguineous matings. These analyses show that monkeys with the same allotyping may express different types of DR molecules. As in humans, the number of DR molecules expressed per haplotype is not constant and varies from 1 to 3, depending on the serologically defined Mamu-DR specificity, whereas it has been shown that the number of Mamu-DRB genes present per haplotype varies from 2 to 6. Therefore the present study also demonstrates that some of the rhesus macaque DR regions contain one or more pseudogenes.

Animals↗
PubMed1993

Characterization of the rhesus macaque (Macaca mulatta) equivalent of HLA-F.

Nucleotide sequence analysis of rhesus macaque major histocompatibility complex class I cDNAs allowed the identification of the orthologue of HLA-F, designated Mamu-F. Comparison of Mamu-F with earlier published human and chimpanzee orthologues demonstrated that these sequences share a high degree of similarity, both at the nucleotide and amino acid level, whereas a New World monkey (cotton-top tamarin) equivalent is more distantly related. Exon 7, encoding one of the cytoplasmatic domains, is absent for all primate Mhc-F cDNA sequences analyzed so far. In contrast to the human, chimpanzee, and rhesus macaque equivalents, the cotton-top tamarin Saoe-F gene seems to have accumulated far more nonsynonymous than synonymous differences.

Amino Acid Sequence↗
PubMed1993

Mhc-DRB and -DQA1 nucleotide sequences of three lowland gorillas. Implications for the evolution of primate Mhc class II haplotypes.

Mhc-DRB and -DQA1 second-exon and -DRB 3'-untranslated-region nucleotide sequences of three lowland gorillas with no known family relationship with each other and of two HLA homozygous typing cell lines were determined and compared with published primate Mhc-DRB and -DQA1 sequences. Eleven distinct MhcGogo-DRB second-exon sequences were found, which represent the gorilla counterparts of the HLA-DRB1*03, -DRB1*10, -DRB3, -DRB5, and -DRB6 allelic lineages. One Gogo-DRB second-exon sequence does not have an obvious human counterpart and is tentatively designated Gogo-DRBY*01. The gorilla equivalents of the HLA-DRB2 and -DRB8 loci were identified as judged on Mhc-DRB 3'-untranslated-region sequences. In addition, four different Gogo-DQA1 alleles belonging to three different allelic lineages were detected. The Mhc-DRB-DQA1 haplotypes of these gorillas were deduced based on the obtained Mhc-DRB and -DQA1 sequences and the two published Mhc-DRB haplotypes of the lowland gorilla Sylvia. All deduced Gogo-DRB-DQA1 haplotypes show gene constellations different from known HLA-DRB-DQA1 haplotypes, while some of the Gogo-DRB haplotypes presented here contain more DRB genes than the HLA-DRB haplotypes. Based on phylogenetic trees, bootstrap analyses, and the gorilla, chimpanzee, and human Mhc-DRB haplotypes described, we propose that at least two Mhc-DRB loci, here tentatively designated Mhc-DRBI and -DRBII, existed on an ancient primate Mhc-DRB haplotype. The Mhc-DRB1*01, -DRB1*02 (-DRB1*15 and -DRB1*16), -DRB1*03 (-DRB1*03, -DRB1*08, -DRB1*11, -DRB1*12, -DRB1*13, and DRB1*14), and -DRB1*10 allelic lineages and -DRB3 and -DRBY loci probably evolved from the hypothetical primate Mhc-DRBI locus, whereas the present primate Mhc-DRB2, -DRB4, and -DRB6 loci originate from the ancient Mhc-DRBII locus of this core primate Mhc-DRB haplotype.

Amino Acid Sequence↗
PubMed1993

The biologic importance of conserved major histocompatibility complex class II motifs in primates.

Phylogenetic comparisons of polymorphic second-exon sequences of MHC class II DRB genes showed that equivalents of the HLA-DRB1*03 alleles are present in various nonhuman primate species such as chimpanzees, gorillas, and rhesus macaques. These alleles must root from ancestral structure(s) that were once present in a progenitor species that lived about 35 million years ago. Due to accumulation of genetic variation, however, sequences that cluster into a lineage are generally unique to a species. To investigate the biologic importance of such conservation and variation, the peptide-binding capacity of various Mhc-DRB1*03 lineage members was studied. Primate Mhc-DRB1*03 lineage members successfully binding the p3-13 peptide of the 65-kD heat-shock protein of Mycobacterium tuberculosis/leprae share a motif that maps to the floor of the peptide-binding site. Apart from that, some rhesus macaque MHC class-II-positive cells were able to present the p3-13 peptide to HLA-DR17-restricted T cells whereas cells obtained from great ape species failed to do so. Therefore, these studies open ways to understand which MHC polymorphisms have been maintained in evolution and which MHC residues are essential for peptide binding and T-cell recognition.

Amino Acid Sequence↗
PubMed1993

Major histocompatibility complex class II DQ diversity in rhesus macaques.

By the use of restriction fragment length polymorphism analysis 10 Taq I fragments could be identified for the MhcMamu-DQA1 region. A strong correlation exists between the occurrence of Mamu-DQA1/Taq I fragments and Mamu-DQA1 allelic sequence variation. Most restriction fragments correspond with a unique Mamu-DQA1 allele, with one exception being the Taq I 4.5 kb fragment that is associated with two Mamu-DQA1 alleles. The RFLP technique allowed the identification of 15 Mamu-DQB1/Taq I restriction fragments, whereas sequence analysis has permitted the characterization of at least 20 different Mamu-DQB1 alleles. In this communication two unpublished Mamu-DQB1 sequences are described. For Mamu-DQB1, on only four occasions was it possible to demonstrate a correlation between a certain fragment and an allelic sequence. These analyses, performed on material from truly homozygous animals, allowed us to define which combinations of Mamu-DQA1 and -DQB1 molecules form heterodimers at the cell surface. In addition, these studies are helpful in typing non-human primate species that are used in biomedical research.

Alleles↗
PubMed1993

Major histocompatibility complex class II polymorphisms in humans and chimpanzees.

Allelic variation at the MhcPatr-DR and -DQ loci was studied by molecular biological techniques and compared to available HLA data. With regard to the number of allelic lineages, the chimpanzee shows a condensation of its major histocompatibility complex (MHC) class II repertoire as compared to humans. This does not have an impact on the overall degree of MHC class II polymorphism in the chimpanzee since a few lineages that are oligomorphic in humans display an extensive degree of polymorphism in the chimpanzee.

Alleles↗
PubMed1992

Mhc-DQB repertoire variation in hominoid and Old World primate species.

Comparison of 87 distinct Mhc-DQB sequences, obtained from 13 primate species, demonstrates that five out of eight trans-species Mhc-DQB allele lineages are at least 30 million years old and predate divergence of hominoid and Old World primate species. One lineage may be much older because its members are not only traced back in higher primates, but also are present in a New World primate species. Comparing Mhc-DQB repertoire variation in distinct species, allows one to pinpoint when certain polymorphisms were lost or gained in primate evolution. Heterogeneity observed among members of trans-species Mhc-DQB allele lineages can be explained in major part by point mutations, whereas intraexonic crossing-over is a potent mechanism in generating new allele lineages. The stability of Mhc-DQB polymorphisms is influenced by selective forces because distinct allele lineages appear to have accumulated nucleotide substitutions and amino acid replacements at different rates.

Alleles↗
PubMed1992

Resistance to collagen-induced arthritis in a nonhuman primate species maps to the major histocompatibility complex class I region.

Type II collagen-induced arthritis (CIA) is an experimentally inducible autoimmune disorder that is, just like several forms of human arthritis, influenced by a genetic background. Immunization of young rhesus monkeys (Macaca mulatta) with type II collagen (CII) induced CIA in about 70% of the animals. One major histocompatibility complex (MHC) class I allele was present only in young animals resistant to CIA and absent in arthritic animals. This strong association suggests that the MHC class I allele itself, or a closely linked gene, determines resistance to CIA. The mechanism controlling the resistance to CIA becomes less efficient in aged animals since older rhesus monkeys, which were positive for the resistance marker, developed a mild form of arthritis. At the cellular level it is demonstrated that resistance to CIA is reflected by a low responsiveness of T cells to CII. This association between a specified MHC class I allele and resistance to an autoimmune disease points at the importance of the MHC class I region in the regulation of the immune response to an autoantigen.

Alleles↗
PubMed1992

Evolutionary relationships among the primate Mhc-DQA1 and DQA2 alleles.

The variation of the Mhc-DQA1 and DQA2 loci of ten different primate species (hominoids and Old World monkeys) was studied in order to obtain an insight in the processes that generate polymorphism of major histocompatibility complex (Mhc) class II genes and to establish the evolutionary relationships of their alleles. To that end nucleotide sequences of 36 Mhc class II DQA1 and seven DQA2 second exons were determined and phylogenetic trees that illustrate their evolutionary relationships were constructed. We demonstrate the existence of four primate Mhc-DQA1 allele lineages, two of which probably existed before the separation of the ancestors of the hominoids and Old World monkeys (approximately 22-28 million years ago). Mhc-DQA2 sequences were found only in the hominoid species and showed little diversity. We found no evidence for a major contribution of recombinational events to the generation of allelic diversity of the primate Mhc-DQA1 locus. Instead, our data suggest that the primate Mhc-DQA1 and DQA2 loci are relatively stable entities that mutated primarily as a result of point mutations.

Alleles↗
PubMed1992

T-cell receptor gamma/delta: comparison of gene configurations and function between humans and chimpanzees.

The human and chimpanzee T-cell receptor gamma-delta (TCR gamma delta) bearing cells represent a minor subset (3-8%) of T lymphocytes. In the periphery, the TCR gamma delta population has a restricted combinatorial repertoire. The TCRD-V1 and -V2 gene products are expressed in a mutually exclusive fashion, whereas, the TCRD-V2 and the TCRG-V9 encoded proteins show, in general, a coordinated expression. Restriction fragment length polymorphism analysis showed conservation of the restriction sites that identify the TCRG-V9 and TCRD-V2 rearrangements. The human TCRG-V9 locus has two alleles, TCRG-V9A1 and TCRG-V9A2 differing at codon position 31. The chimpanzee TCRG-V9 gene product differs from the products of the human TCRG-V9A1 and TCRG-V9A2 allele by two and three amino acid replacements, respectively. The human and the chimpanzee TCRG-V9-TCRD-V2 lymphocytes show a similar specific proliferative and cytolytic response to human Daudi Burkitt's lymphoma cells. Therefore, the amino acid replacements found in the chimpanzee TCRG-V9 gene product do not change the superantigen specificity across this species barrier.

Alleles↗
PubMed1992

Mhc-DRB diversity of the chimpanzee (Pan troglodytes).

Fifty-four chimpanzee Patr-DRB and five human HLA-DRB second exons were cloned and sequenced from thirty-five chimpanzees and four human B-cell lines and compared with known Mhc-DRB sequences of these two species. Equivalents of the HLA-DRB1*02, -DRB1*03, -DRB1*07 allelic lineages and the HLA-DRB3, -DRB4, -DRB5, -DRB6, and -DRB7 loci were all found in the chimpanzee. In addition, two chimpanzee Patr-DRB lineages (Patr-DRBX and -DRBY) were found for which no human counterparts have been described. None of the Patr-DRB sequences is identical to known HLA-DRB sequences. The Patr-DRB1*0702 and HLA-DRB1*0701 alleles are the most similar sequences in a comparison between the two species and differ by only two nucleotides out of 246 sequenced. Equivalents of the HLA-DRB1*01, -DRB1*04, and -DRB1*09 alleles were not found in our sample of chimpanzees. A per locus comparison of the number of Patr-DRB alleles with the HLA-DRB alleles shows that the Patr-DRB3, -DRB4, -DRB5, and -DRB6 locus are, thus far, more polymorphic than their human homologs. The polymorphism of the Patr-DRB1 locus seems to be less extensive than that reported for the HLA-DRB1 locus. Nevertheless, the Patr-DRB1 locus seems to be the most polymorphic of the Patr-DRB loci. Phylogenetic analyses indicate that the HLA-DRB1*09 allele may have originated from a recombination between a Mhc-DRB5 allele and the DRB1 allele of a Mhc-DR7 haplotype. Although recombination seems to increase the diversity of the Patr-DRB alleles, its contribution to the generation of Patr-DRB variation is probably low. Hence, most Patr-DRB diversity presumably accumulated via recurrent point mutations. Finally, two distinct Patr-DRB haplotypes are deduced, one of which (the chimpanzee equivalent of the HLA-DR7 haplotype) is probably older than 6-8 million years.

Amino Acid Sequence↗
PubMed1992

Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys.

Sequence analysis of rhesus monkey (Macaca mulatta) polymorphic second exon of major histocompatibility complex class II DRB subregion genes demonstrates the existence of at least 34 alleles. Some of these rhesus monkey alleles are very similar (or nearly identical) to HLA-DRB alleles. These data demonstrate that members of the lineages for Mhc-DRB1*03, -DRB1*04, -DRB1*10, and the loci of Mhc-DRB3, -DRB4, -DRB5, and -DRB6 predate speciation of man and rhesus monkey and were already present 25 million years ago. Calculation of evolutionary rates suggests that the various allele lineages have differential stabilities. Furthermore, the data indicate that distinct species may not have inherited or lost transspecies Mhc-DRB lineages in evolution, because several allele lineages in rhesus monkeys appear to be absent in humans and vice versa.

Alleles↗
PubMed1991

RFLP analysis of the rhesus monkey MHC class II DR subregion.

Restriction fragment length polymorphism (RFLP) analysis was performed on a panel of 39 serologically typed DR homozygous monkeys. DNA was digested with the restriction enzyme TaqI and hybridizations were carried out with a human leukocyte antigen (HLA)-DR beta 3'UT-specific probe. In addition a panel of 18 monkeys was analyzed comprising experimental autoimmune encephalomyelitis (EAE) susceptible and nonsusceptible animals. The number of DRB/TaqI fragments detected for the various DR specificities varied from two to six, suggesting that the number of DRB genes per haplotype is not constant. RFLP typing allows that most serologically defined DR specificities can be subdivided. This knowledge was applied to define the DR specificities of the animals used for EAE experiments.

Animals↗