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PubMed1991

Failure to detect MHC class II associations of the human immune response induced by repeated malaria infections to the Plasmodium falciparum antigen Pf155/RESA.

Available evidence suggests that human T and B cell responses to a major Plasmodium falciparum malaria antigen (Pf155/RESA) in individuals primed by repeated infections are genetically regulated. In the present study we have attempted to establish whether these regulations reflect genetic restrictions imposed on the immune response by class II molecules of the donor's MHC system. T cell activation (proliferation and IFN-gamma release in vitro) and antibody activity (ELISA) were assayed with synthetic peptides corresponding to major Pf155/RESA epitopes. To associate T cell and antibody responses with the donors' MHC class II genotypes, leukocytes from 145 donors living in holo- or hyperendemic regions of Africa (Liberia, Gambia, Madagascar) were used for genomic HLA class II typing of their DRB-DQA and DQB genes by means of restriction fragment length analysis (RFLP). No associations between T cell responses and HLA-DR or -DQ alleles or DRB-DQA-DQB haplotypes were seen among the West Africans even when the donors were divided into high, medium or low responders. This was also true for a small group of HLA class II identical Malagasy donors including three pairs of twins. However, while the T cell responses between the twin pairs varied, those within the pairs were similar. Very similar findings were made with antibodies binding to Pf155/RESA peptides. Our data imply that the impact of MHC class II gene products on specific immune responses to Pf155/RESA epitopes is weak and hard to demonstrate in outbred human populations naturally primed by infection. This may be due to genetic regulations by other, non-HLA class II coded factors superimposed on possible HLA class II restrictions.

Adult↗

PubMed2006

Molecular study of Mhc-DRB in wild chacma baboons reveals high variability and evidence for trans-species inheritance.

The MHC class II genes of many primate species were investigated extensively in recent years. However, while Mhc-DRB genes were studied in Old World monkeys such as rhesus macaques, the Mhc-DRB of baboons was only studied in a limited way. Because of their close anatomical and physiological relationship to humans, baboons are often used as models for reproduction and transplantation research. Baboons are also studied as a model species in behavioural ecology. Thus, identification of MHC genes would provide a foundation for studies of Mhc, biology and behaviour. Here, we describe the use of PCR, cloning, denaturing gradient gel electrophoresis (DGGE) and sequencing to identify Mhc-DRB sequences in wild chacma baboons (Papio ursinus). We amplified the highly variable second exon of baboon Mhc-DRB sequences using generic DRB primers. To validate and optimize the DGGE protocol, four DNA samples were initially studied using cloning and sequencing. Clones were screened using a novel RFLP approach to increase the number of clones identified for each individual. Results from cloning and sequencing were used to optimise DGGE conditions for Mhc-DRB genotyping of the remaining study subjects. Using these techniques, we identified 16 Paur-DRB sequences from 30 chacma baboons. On the basis of phylogenetic tree analyses, representatives of the Mhc-DRB1 and Mhc-DRB5 loci, and 13 different DRB lineages were identified. Evidence for trans-species inheritance of some Mhc-DRB sequences comes from high identity between the new Paur-DRB sequences and sequences from Papio cynocephalus, Macaca mulatta and possibly Galago moholi.

Amino Acid Sequence↗

PubMed2004

Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent.

Presentation and CD4(+) T cell responses to Ag in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, IFN-gamma-inducible lysosomal thiol reductase (GILT) functions to catalyze thiol bond reduction, thus unfolding native protein Ag and facilitating further processing via cellular proteases. In contrast with professional APCs such as B cells, class II-positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II Ag presentation, GILT was not regulated by CIITA. Rather, studies revealed STAT1 plays a direct role in IFN-gamma-inducible GILT expression. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas.

Antigen Presentation↗

PubMed1999

A defect in the nuclear translocation of CIITA causes a form of type II bare lymphocyte syndrome.

The severe immunodeficiency type II bare lymphocyte syndrome (BLS) lacks class II MHC gene transcription. One defect from a complementation group A type II BLS patient is a 24 aa deletion in the MHC class II transactivator (CIITA). We show here that the molecular defect present in this protein is a failure of CIITA to undergo nuclear translocation. This defect was mapped to a position-dependent, novel nuclear localization sequence that cannot be functionally replaced by a classical NLS. Fusion of this 5 aa motif to an unrelated protein leads to nuclear translocation. Furthermore, this motif is not critical for transactivation function. This is a description of a genetic disease resulting from a novel defect in the subcellular localization of a transcriptional coactivator.

Amino Acid Sequence↗

PubMedDate not supplied

A perspective on narcolepsy.

Neurochemical analyses were performed on brains obtained at post mortem from 3 patients with narcolepsy. The salient findings were an increase in noradrenergic and serotonergic neuronal activity, a decrease in dopaminergic neuronal activity, and, in 2 of the 3 brains, a decrease in the number of alpha-1-noradrenergic receptors in the frontal cortex and amygdala. A pathophysiological model for narcolepsy is developed on the basis of these findings. The neurobiology of narcolepsy is compared with that of depression. The role of MHC--class II gene products in the genesis of narcolepsy is discussed. Some treatment implications follow.

Brain Chemistry↗

PubMed1990

Allele specific oligonucleotide probes for mouse I-A region and gene: I-A beta.

MHC Class II gene expression is being intensively studied in vitro. In vivo class II gene expression that occurs during G.V.H.R. and allograft reaction has not been studied as well as the gene expression in vitro because such studies require unambiguous detection of graft or host specific MHC class II genes. Although this is possible by using allele specific oligonucleotide probes for individual class II genes, such probes for class II genes in mice have not been described before. We compared the nucleotide sequences of I-A beta genes from various haplotypes and selected a region of minimal homology in the 2nd exon of this gene. We synthesized two oligonucleotide probes corresponding to a 20 nucleotide stretch in the hypervariable region of the I-A beta 1 genes of H-2k and H-2d haplotype mice. These probes specifically detect I-A beta mRNA from mice of appropriate haplotypes. These allele-specific probes should help study the in vivo expression of graft or host specific I-A genes in G.V.H.R. or allograft reaction.

Animals↗

PubMed1988

MHC-chromosome dosage effects: evidence for increased expression of Ia glycoprotein and alteration of B cell subpopulations in neonatal aneuploid chickens.

Quantitative variation in the expression of MHC-encoded class II (Ia) glycoproteins has been associated with stages of lymphocyte development and a number of disease conditions. We have used an avian MHC dosage model to study the regulation of Ia expression and the effects of quantitative variation in membrane Ia on B-cell development. Lymphocyte membrane expression of Ia glycoprotein molecules and the frequency of small-versus-large lymphocytes were examined in trisomic line chickens containing either two (disomic), three (trisomic), or four (tetrasomic) copies of the microchromosome encoding the MHC. This was accomplished by quantitative laser flow cytometry analysis of bursa-resident B lymphocytes from neonatal trisomic line chickens. The aneuploids (trisomics and tetrasomics) expressed more cell surface Ia than did normal disomic birds. Furthermore, the aneuploids exhibited a greater frequency of small B lymphocytes as compared to disomic chickens. Dual parameter analysis of Ia quantity and cell size was undertaken to study B lymphocyte subpopulations in these birds. It was observed that the aneuploids had altered frequencies of two distinct subpopulations of cells: (1) an increased percentage of small cells which express high levels of Ia antigen and (2) a decreased percentage of large cells which express medium levels of Ia antigen. These findings support the view that MHC class II genes are regulated and expressed in a dosage-dependent manner. Therefore, increases in the number of MHC copies per cell result in the increased expression of Ia glycoprotein on bursa-resident B cells. The stepwise increase in membrane Ia on trisomic and tetrasomic B cells is correlated, and perhaps casually linked, with progressive degrees of alteration of developing B cell subpopulations in the bursa of aneuploid chicks. These events may ultimately alter the humoral immunity of the aneuploid animals.

Aneuploidy↗

PubMed1988

An enhancer factor defect in a mutant Burkitt lymphoma cell line.

RJ 2.2.5 is an immunoselected mutant of the Burkitt lymphoma line Raji. It fails to display MHC class II antigens at the cell surface due to a transcriptional defect. We have identified the function of a regulatory factor that is defective in RJ 2.2.5 cells; this factor is absolutely required for the activity of an MHC class II gene enhancer.

DNA-Binding Proteins↗

PubMed1991

The nucleotide sequence and evolution of ovine MHC class II B genes: DQB and DRB.

The nucleotide sequences of one Ovar-DQB gene, excluding exon 1 and parts of the introns, and one Ovar-DRB pseudogene are presented. The structure of the Ovar-DQB gene is typical of a major histocompatibility complex (MHC) class II B gene and demonstrates considerable sequence similarity with that of humans including such characteristics as the less common polyadenylation signal, ATTAAA. The ovine sequence has a typical 5' acceptor splice signal for exon 5, thus potentially encoding a full length cytoplasmic tail. The Ovar-DRB gene identified in this study was found to be a pseudogene, lacking a defined exon 2 and containing premature termination codons in both exons 3 and 4. The 3' donor splice site of exon 3 is also atypical. A purine-pyrimidine microsatellite repeat, (dC.dA)15, in the 3' region of the pseudogene may be a hotspot for recombination within the ovine DR subregion.

Amino Acid Sequence↗

PubMed2004

Persistence of MHC DR nonexpression on swine cells by introduction of a mutated MHC class II transactivator gene: a comparison with the effect induced by antisense RNA.

CIITA (class II transactivator) is a coactivator essential for transcription of MHC class II genes. In this study, a construct with a mutated CIITA gene with N-terminal domains depleted was constructed. This mutated CIITA (mCIITA) was able to repress DR and DQ expression in 45.0-60.0% of the mCIITA-transfected clones of swine endothelial cell line PIEC and in B cell line L23, as well as in human cell lines HeLa and Raji. Similarly, 30.0-46.7% of swine cell clones containing the human CIITA antisense RNA also failed to express DR molecules. However, the persistence of the DR repression on the cell lines is quite different. Transfection with mCIITA was persistent for at least 120 days, while with the CIITA antisense RNA, persistence existed for only 35-45 days. To explore the underlying mechanism, Raji cells were transfected with pUHD10-3-mCIITA, a mCIITA-containing, doxycycline-dependent plasmid. The intensity of DR repression is correlated quite well with the efficiencies of the mCIITA expression within the cells in a doxycycline dose-dependent manner. This implicates a competition between the mCIITA and its endogenous full-length counterpart. In addition, we were able to show that purified human CD4 T cells did not respond to the mCIITA-transfected PIECs in xenogeneic mixed lymphocyte endothelial reaction (MLER). The stimulating indices (SI) were only 1.0-1.5, compared with 15.2-18.2 for those transfected with empty vector or an initiation codon-depleted mCIITA that is dysfunctional for protein translation. The results we obtained, especially those for persistent suppression of class II genes, show promise for the possible development of mCIITA-transgenic swine for organ/tissue xenotransplantation.

Animals↗

PubMed1989

Positive and negative selection of the T cell repertoire in MHC class II transgenic mice.

Nowhere has the power of transgenic mouse technology been more evident than in the field of immunology. It has become possible to ordain the specificities expressed by an animal's B and T cells, to stipulate where and when these cells encounter antigen, and to influence how they respond to it by controlling the appearance of cell-surface or soluble regulatory molecules. This new ability to manipulate the immune system from within' has tremendous potential for answering some previously intractable questions about the shaping of the T cell repertoire. Amongst these are where and when the various repertoire selection events take place. We and others have recently addressed these two questions by creating and characterizing transgenic mice with altered patterns of major histocompatibility complex (MHC) class II gene expression. Results from these studies are the focus of this review.

Animals↗

PubMed2002

Extensive Mhc-DQB variation in humans and non-human primate species.

Non-human primates are often used in biomedical research, and the application of these animals as a model in immune-related diseases necessitates the characterisation of their MHC system. In particular, the MHC class II regions of the chimpanzee (Pan troglodytes), the rhesus macaque (Macaca mulatta)and the common marmoset (Callithrix jacchus) have been subject of molecular biological studies in recent years. In this study the emphasis was on MHC class II genes of another macaque species, Macaca fascicularis(crab eating macaque or cynomolgous monkey). The exon 2 of the Mhc-DQB gene (Mafa-DQB) was sequenced in each of a random panel of 60 non-pedigreed cynomolgous monkeys. This resulted in the detection of 23 Mafa-DQB1alleles that had not previously been published. In addition, unreported alleles were found in chimpanzees, rhesus macaques, orang-utans (Pongo pygmaeus) and stump-tailed macaques (Macaca arctoides), of which a few individuals were included in this study. Phylogenetic analyses confirm the trans-species model of evolution of the MHC-DQBlineages, in which a group of major alleles is passed on in the phylogeny, and has led to the sharing of allelic lineages by different species of non-human primates. The sharing of alleles is observed only for closely related macaque species. Furthermore, this manuscript provides an overview of all published, and whenever necessary corrected, non-human primate Mhc-DQB exon 2 alleles.

Alleles↗

PubMed1999

Analysis of genetic polymorphisms in the major histocompatibility complex of Japanese quail.

The restriction fragment length polymorphisms (RFLP) of the Japanese quail MHC were assayed in seven lines using PvuII-digested DNA and a chicken Class II probe. The lines of Japanese quail surveyed included a randombred control population (R1) and sublines of R1 divergently selected for 4-wk body weight (HW and LW lines) or plasma yolk precursor as measured by total plasma phosphorus (TPP) (HP and LP lines). In addition, two sublines (HW-HP and HW-LP) of the HW line were included in the analysis. Males of both sublines were selected for increased 4-wk body weight whereas the females were selected for increased (HW-HP) or decreased (HW-LP) TPP. The number of birds surveyed per line ranged from 13 to 16. The chicken probe used produced discernible bands or fragments using Southern blot analysis. There were 16 different RFLP patterns as well as 7 different heterozygote patterns detected in the various Japanese quail lines. The band or fragment number of each pattern varied from 7 to 15. A total of 28 different bands or fragments were seen in the RFLP patterns and only 2 bands or fragments were common to all 16 patterns. The distribution of the RFLP patterns differed greatly among the Japanese quail lines. The R1 line differed in frequency of the patterns from all of the selected lines. The divergently selected lines (HW vs LW; HP vs LP; and HW-HP vs HW-LP) also differed in the frequency of the various RFLP patterns. In the comparison of the HW and LW lines, there were no RFLP patterns in common between the two lines. The results of the present study indicated that the Japanese quail MHC Class II genes were highly polymorphic.

Animals↗

PubMed1996

Evidence for the in vivo role of class II transactivator in basal and IFN-gamma induced class II expression in mouse tissue.

The class II transactivator (CIITA) is a protein that induces the transcription of MHC class II genes. We studied the expression of CIITA in vivo, comparing steady state levels of CIITA and class II mRNA in various mouse tissues. Many tissues in normal mice contained mRNA for CIITA, correlating with class II mRNA. The basal expression of CIITA and class II mRNA in mice with disrupted IFN-gamma genes (GKO mice) was similar to that in wild-type mice. Injection of rIFN-gamma strongly induced CIITA and class II mRNA: CIITA mRNA increased at 2 hr and declined to baseline by 48 hr, whereas class II mRNA increased at 24 hr and returned to baseline at 7 days. Proinflammatory stimuli that induce IFN-gamma production (allogeneic cells and LPS) induce CIITA and class II expression in wild-type mice, but not in GKO mice. CIITA induction by IFN-gamma was partially sensitive to cycloheximide, suggesting that another protein is required for CIITA induction. The data suggest that CIITA is a major regulator of basal and induced class II expression in vivo.

Animals↗

PubMed1991

Interferon-beta specifically inhibits interferon-gamma-induced class II major histocompatibility complex gene transcription in a human astrocytoma cell line.

We established cultures of human astrocytes and astrocytoma cells from surgical specimens, to study regulation of class II major histocompatibility (MHC) complex antigen expression by interferons. Using these cultures we previously showed that expression of the class II MHC determinant HLA-DR could be induced by interferon-gamma and this induction was inhibited by interferon-beta. In this report, we extend these observations by showing that the inhibitory effect of interferon-beta on interferon-gamma induction of the class II MHC gene HLA-DR alpha was exerted at the transcriptional level, as documented by nuclear run-on experiments and confirmed with blot hybridization analysis. Astrocyte expression of intercellular adhesion molecule-1 (ICAM-1) was induced efficiently by interferon-gamma, but not by interferon-beta, and induction of ICAM-1 expression by interferon-gamma could not be impaired by interferon-beta, suggesting that the suppressive effect on induction of HLA-DR was relatively gene-specific. Furthermore, interferon-beta did not antagonize interferon-gamma induction of HLA-DR expression in human monocytes, suggesting that the inhibition observed in astrocytes was relatively tissue-specific.

Astrocytes↗

PubMed1999

Assessment of the role of determinant selection in genetic control of the immune response to insulin in H-2b mice.

The immune response to insulin is regulated by MHC class II genes. Immune response (Ir) gene-linked low responsiveness to protein Ags can be mediated by the low affinity of potential antigenic determinants for MHC molecules (determinant selection) or by the influence of MHC on the functional T cell repertoire. Strong evidence exists that determinant selection plays a key role in epitope immunodominance and Ir gene-linked unresponsiveness. However, the actual measurement of relative MHC-binding affinities of all potential peptides derived from well-characterized model Ags under Ir gene regulation has been very limited. We chose to take advantage of the simplicity of the structure of insulin to study the mechanism of Ir gene control in H-2b mice, which respond to beef insulin (BINS) but not pork insulin (PINS). Peptides from these proteins, including the immunodominant A(1-14) determinant, were observed to have similar affinities for purified IAb in binding experiments. Functional and biochemical experiments suggested that PINS and BINS are processed with similar efficiency. The T cell response to synthetic pork A(1-14) was considerably weaker than the response to the BINS peptide. We conclude that the poor immunogenicity of PINS in H-2b mice is a consequence of the T cell repertoire rather than differences in processing and presentation.

Amino Acid Sequence↗

PubMed1996

The major histocompatibility complex class II Ea promoter requires TFIID binding to an initiator sequence.

The major histocompatibility complex (MHC) class II Ea promoter is dependent on the presence of conserved upstream X and Y boxes and of initiator (Inr) sequences. In vitro transcription analysis of the Inr region with linker-scanning mutants pinpoints a functionally essential element that shows homology to the terminal deoxynucleotidyltransferase (TdT) Inr; contrary to the TdT Inr and other Inrs identified so far, the key sequence, between positions +5 and +12, is located within a transcribed area. Swapping the TdT sequence into the corresponding Ea position leads to a fivefold increase in transcription rate, without altering start site selection. Inr-binding proteins LBP-1/CP2 and TIP--a TdT Inr-binding protein unrelated to YY1--recognize the Ea Inr; they interact with overlapping yet distinct sequences around the Cap site, but their binding does not coincide with Ea Inr activity. A good correlation is, rather, found with binding of immunopurified holo-TFIID to this element. TFIID interacts both with Ea TATA-like and Inr sequences, but only the latter is functionally relevant. Unlike TBP, TFIID binds in the absence of TFIIA, indicating a stabilizing role for TBP-associated factors in Ea promoter recognition. Sequence comparison with other mouse and human MHC class II promoters suggests a common mechanism of start site(s) selection for the MHC class II gene family.

Animals↗

PubMed1988

Major histocompatibility complex gene product expression on pancreatic beta cells in acutely diabetic BB rats.

Type I diabetes mellitus was induced in young, diabetes-prone BB rats by the passive transfer of concanavalin A-activated T lymphocytes from the spleens of acutely diabetic BB rats. The pancreas of the recipients was examined 1-2 days after the onset of glycosuria by immunocytochemistry by means of monoclonal antibodies for determining whether 1) Class I and/or II major histocompatibility gene complex (MHC) products were expressed on beta cells and 2) the mononuclear cell infiltrates were represented by T cells. Marked expression of Class I MHC gene products was evident on beta cells. In contrast, Class II MHC gene products were not identified on normal-appearing beta cells. Dendritic cells dispersed throughout the acinar and interstitial pancreas were markedly increased in number. The mononuclear cell infiltrate contained few cells (1-15%) recognized by a pan-T cell marker. Although it is possible that this passive transfer model might differ considerably from the spontaneously occurring diabetic state in the rat, this study suggests that 1) Class I, rather than Class II, MHC gene expression may be pivotal to beta-cell injury in diabetic rats, and 2) non-T cells may constitute an effector cell population central to beta-cell necrosis in Type I diabetes mellitus.

Animals↗