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At least 19 recordsLinked to original sources
PubMed1996

Stat1 alpha expression is involved in IFN-gamma induction of the class II transactivator and class II MHC genes.

Class II MHC Ags are critical in the regulation of immune responses by presenting Ag to T lymphocytes, resulting in their activation and differentiation. Class II expression is rare in the normal central nervous system, but elevated expression on glial cells has been observed in several neurologic diseases. We have previously demonstrated that IFN-gamma-induced class II expression in glial cells involves activation of both tyrosine kinase and protein kinase C. IFN-gamma induces tyrosine phosphorylation of the tyrosine kinases Jak1 and Jak2 and of Stat1 alpha. In addition, IFN-gamma enhances expression of Stat1 alpha mRNA and protein. We utilized antisense oligonucleotides against Stat1 alpha to determine directly whether IFN-gamma-induced activation and/or enhancement of Stat1 alpha is involved in class II expression. Antisense oligonucleotides complementary to Stat1 alpha mRNA were introduced in CH235-MG astroglioma cells by transient transfection; such treatment inhibited both constitutive and IFN-gamma-enhanced expression of Stat1 alpha. IFN-gamma-induced class II MHC expression was also inhibited in cells exposed to Stat1 alpha antisense oligonucleotides. The fact that the class II promoter does not contain IFN-gamma-activated sequences for binding Stat1 alpha suggests that Stat1 alpha must activate another protein that is directly involved in class II expression. A likely candidate is the class II MHC transactivator (CIITA). IFN-gamma induction of CIITA mRNA was also inhibited in cells treated with antisense oligonucleotides against Stat1 alpha. These findings demonstrate that Stat1 alpha is involved in IFN-gamma induction of CIITA expression, resulting in class II MHC expression.

Astrocytes↗
PubMed1989

Combined immunodeficiency with defective expression in MHC class II genes.

MHC class II deficiency is an inherited immunodeficiency disease characterized by the presence of a normal number of T and B lymphocytes and profound anomaly of cellular and humoral responses to foreign antigens. All bone-marrow-derived cells (including B lymphocytes, monocytes and activated T lymphocytes) and also enterocytes and endothelial cells do not express all HLA class II (DR, DQ and DP) molecules on their membrane. It is known that the proper recognition of foreign antigens depends on their presentation, together with HLA class II molecules, on the membrane of antigen-presenting cells. MHC class II deficient combined immunodeficiency confirms the important role of MHC gene products in immune-defence mechanisms. Patients suffer from repeated and severe infections that are frequently the cause of death. The defect in HLA class II expression is the consequence of a lack of synthesis of HLA class II alpha and beta chains in patients' cells. Studies performed at DNA and RNA levels showed that there was no gross abnormality of MHC class II genes and that mRNA for all HLA molecules was not detected in patients' cells. These results, together with segregation studies performed in several families, suggested that the defect in HLA class II gene expression involves a transacting regulatory factor. Direct transcription assays showed that the disease is characterized by an absence of HLA class II gene transcription. An analysis of the specific binding of nuclear proteins from patients' cell lines to HLA class II promotor showed that a specific protein, RF-X, which normally binds to a regulatory sequence common to HLA class II promotors, is affected in MHC class II combined immunodeficiency.

Gene Expression Regulation↗
PubMed1999

Mice lacking all conventional MHC class II genes.

MHC class II (MHC-II) molecules play a central role in the selection of the T cell repertoire, in the establishment and regulation of the adaptive immune response, and in autoimmune deviation. We have generated knockout mice lacking all four of the classical murine MHC-II genes (MHCII(Delta/Delta) mice), via a large (80-kilobase) deletion of the entire class II region that was engineered by homologous recombination and Cre recombinase-mediated excision. These mice feature immune system perturbations like those of Aalpha and Abeta knockout animals, notably a dearth of CD4(+) lymphocytes in the thymus and spleen. No new anatomical or physiological abnormalities were observed in MHCII(Delta/Delta) mice. Because these animals are devoid of all classical MHC-II chains, even unpaired chains, they make excellent recipients for MHC-II transgenes from other species, avoiding the problem of interspecies cross-pairing of MHC-II chains. Therefore, they should be invaluable for engineering "humanized" mouse models of human MHC-II-associated autoimmune disorders.

Animals↗
PubMed2000

Common chimpanzees have greater diversity than humans at two of the three highly polymorphic MHC class I genes.

MHC class I polymorphism improves the defense of vertebrate species against viruses and other intracellular pathogens. To see how polymorphism at the same class I genes can evolve in different species we compared the MHC-A, MHC-B, and MHC-C loci of common chimpanzees and humans. Diversity in 23 Patr-A, 32 Patr-B, and 18 Patr-C alleles obtained from study of 48 chimpanzees was compared to diversity in 66 HLA-A, 149 HLA-B, and 41 HLA-C alleles obtained from a study of over 1 million humans. At each locus, alleles group hierarchically into families and then lineages. No alleles or families are shared by the two species, commonality being seen only at the lineage level. The overall nucleotide sequence diversity of MHC class I is estimated to be greater for modern chimpanzees than humans. Considering the numbers of lineages, families, and alleles, Patr-B and Patr-C have greater diversity than the HLA-B and HLA-C, respectively. In contrast, Patr-A has less polymorphism than HLA-A, due to the absence of A2 lineage alleles. The results are consistent with ancestral humans having passed through a narrower population bottleneck than chimpanzees, and with pathogen-mediated selection having favored either preservation of A2 lineage alleles on the human line and/or their extinction on the chimpanzee line.

Alleles↗
PubMed1995

Transcriptional regulation of MHC class II genes.

MHC class II molecules play a fundamental role in the homeostasis of the immune response, functioning as receptors for antigenic peptides to be presented to regulatory T cells. Both quantitative and qualitative alterations in the expression of these molecules on the cell surface dramatically affect the onset of the immune response, and may be the basis of a wide variety of disease states, such as autoimmunity, immunodeficiencies, and cancer. Most regulation of MHC class II molecule expression is under the control of transcription mechanisms which are both cell type and development specific. In the last few years classical genetics together with molecular biology have greatly contributed to the widening of our knowledge on the regulatory mechanisms operating in the control of class II gene expression. This review deals with the latest developments in this fundamental area of immunology.

Animals↗
PubMed2002

Characterization and phylogenetic relationship of prosimian MHC class I genes.

MHC class I cDNA sequences from the most divergent primate group of extant primates compared to human, the suborder Strepsirrhini (prosimians), are described. The sequences are derived from the gray mouse lemur (Microcebus murinus) and the ring-tailed lemur (Lemur catta), which are members of the malagasy Lemuriformes, as well as from the pygmy slow loris (Nycticebus pygmaeus), a prosimian from East Asia. The M. murinus sequences have been analyzed in detail. Analysis of the expression level, G/C content, and synonymous vs. nonsynonymous substitution rates in the peptide-binding region codons suggests that these cDNA clones represent classical class I (class Ia) genes. According to Southern blot analysis, the genome of the gray mouse lemur might contain about 10 class I genes. In gene tree analysis, the strepsirrhine class Ia genes described here cluster significantly separately from the known class I genes of Catarrhini (humans, apes, Old World monkeys) and Platyrrhini (New World monkeys) species, suggesting that the class I loci of Simiiformes arose by gene duplications which occurred after the divergence of prosimians.

Amino Acid Sequence↗
PubMed1997

Trinucleotide repeat polymorphism within exon 5 of the MICA gene (MHC class I chain-related gene A): allele frequency data in the nine population groups Japanese, Northern Han, Hui, Uygur, Kazakhstan, Iranian, Saudi Arabian, Greek and Italian.

We recently identified a trinucleotide repeat polymorphism, (GCT)n, within the transmembrane (TM) segment of the human MHC class I MICA gene (MHC class I chain-related gene A). Five distinct alleles (A4, A5, A5.1, A6, A9) corresponding to 4, 5, 5 with one nucleotide insertion, 6 and 9 repetitions, respectively, have been detected in various HLA-homozygous B cell lines. Here we present allele frequencies for this trimeric short tandem repeat (STR) in 604 unrelated individuals collected from nine human populations (Japanese, Northern Han, Hui, Uygur, Kazakhstan, Iranian, Saudi Arabian, Greek and Italian) determined using the polymerase chain reaction (PCR) combined with fluorescent-based automated fragment detection technology. All alleles were present in each population, but allelic distributions varied from one population to another. No new alleles (such as A7 or A8) were identified. The evolutionary and structural significance of these data as well as the potential application to forensic medicine is discussed.

Alleles↗
PubMed1997

Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency.

BACKGROUND: Major-histocompatibility-complex (MHC) class II deficiency is an autosomal recessive primary immunodeficiency disease in which MHC class II molecules are absent. It is a genetically heterogeneous disease of gene regulation resulting from defects in several transactivating genes that regulate the expression of MHC class II genes. The mutations responsible for MHC class II deficiency are classified according to complementation group (a group in which the phenotype remains uncorrected in pairwise fusions of cells). There are three known complementation groups (A, B, and C). METHODS: To elucidate the genetic defect in patients with MHC class II deficiency that was not classified genetically, we performed direct complementation assays with the three genes known to regulate the expression of MHC class II genes, CIITA, RFX5, and RFXAP, and the relevant mutations were identified in each patient. RESULTS: Mutations in the RFXAP gene were found in three patients from unrelated families, and the resulting defect was classified as belonging to a novel complementation group (D). Transfection with the wild-type RFXAP gene restored the expression of MHC class II molecules in the patients' cells. CONCLUSIONS: Mutations in a novel MHC class II transactivating factor, RFXAP, can cause MHC class II deficiency. These mutations abolish the expression of MHC class II genes and lead to the same clinical picture of immunodeficiency as in patients with mutations in the other two MHC class II regulatory genes.

Cell Line↗
PubMed1991

Tumor-specific immunity can be enhanced by transfection of tumor cells with syngeneic MHC-class-II genes or allogeneic MHC-class-I genes.

Mouse Sal sarcoma cells are lethal in the autologous A/J (KkDd) host. In order to improve the immune response to the Sal tumor, Sal cells have been transfected with syngeneic MHC-class-II or allogeneic MHC-class-I genes. MHC-class-II transfectants are uniformly rejected by the autologous host and immunization with them protects against subsequent Sal challenge. The improved immunity is probably the result of enhanced generation of tumor-specific Th cells. We hypothesize that class-II tumor cells trigger an improved Th-cell response because they directly present Sal tumor antigens in the context of class-II molecules to Th cells, by-passing professional APC. Studies by others have demonstrated that antigen presentation requires an intracellular signal transmitted by the cytoplasmic domain of the APC class-II molecule. Sal cells expressing class-II antigens with truncated cytoplasmic domains are as malignant as wild-type Sal cells. These experiments therefore support the role of tumor-cell class-II molecules as antigen presentation elements, and demonstrate the requirement for intact class-II molecules for tumor protection. Sal cells have also been transfected with allogeneic MHC-class-I genes. Although Kb-transfected cells are not rejected by A/J mice, Db-transfected Sal cells and Kb- plus Db-transfected cells are rejected. The Db transfectants effectively immunize A/J mice against subsequent Sal challenge. These experiments demonstrate that expression of certain allogeneic MHC-class-I genes can lead to tumor-specific immunity, and that such transfectants can protect against challenges of wild-type tumor cells. Transfection of tumor cells with syngeneic MHC-class-II or allogeneic MHC-class-I genes may therefore be a potential strategy for improving tumor-specific immunity in the autologous host.

Animals↗
PubMed1988

The origin of MHC class II gene polymorphism within the genus Mus.

The I region of the major histocompatibility complex (MHC) of the mouse (H-2) contains a tightly-linked cluster of highly polymorphic genes (class II MHC genes) which control immune responsiveness. Speculation on the origin of this polymorphism, which is believed to be essential for the function of the class II proteins in immune responses to disease, has given rise to two hypotheses. The first is that hypermutational mechanisms (gene conversion or segmental exchange) promote the rapid generation of diversity in MHC genes. The alternative is that polymorphism has arisen from the steady accumulation of mutations over long evolutionary periods, and multiple specific alleles have survived speciation (trans-species evolution). We have looked for evidence of 'segmental exchange' and/or 'trans-species evolution' in the class II genes of the genus Mus by molecular genetic analysis of I-A beta alleles. The results indicate that greater than 90% (28 out of 31) of the alleles examined can be organized into two evolutionary groups both on the basis of restriction site polymorphisms and by the presence or absence of a short interspersed nucleotide element (SINE). Using this SINE sequence as an evolutionary tag, we demonstrate that I-A beta alleles in these two evolutionary groups diverged at least three million years ago and have survived the speciation events leading to several modern Mus species. Nucleotide sequence comparisons of eight Mus m. domesticus I-A beta alleles representing all three evolutionary groups indicate that most of the divergence in exon sequences is due to the steady accumulation of mutations that are maintained independently in the different alleles. But segmental exchanges between alleles from different evolutionary groups have also played a role in the diversification of beta 1 exons.

Alleles↗
PubMed2000

Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene.

MHC class II deficiency patients are mutated for transcription factors that regulate the expression of major histocompatibility complex (MHC) class II genes. Four complementation groups (A-D) are defined and the gene defective in group A has been shown to encode the MHC class II transactivator (CIITA). Here, we report the molecular characterization of a new MHC class II deficiency patient, ATU. Cell fusion experiments indicated that ATU belongs to complementation group A. Subsequent mutation analysis revealed that the CIITA mRNA lacked 84 nucleotides. This deletion was the result of the absence of a splice donor site in the CIITA gene of ATU. As a result of this novel homozygous genomic deletion, ATU CIITA failed to transactivate MHC class II genes. Furthermore, this truncated CIITA of ATU did not display a dominant negative effect on CIITA-mediated transactivation of various isotypic MHC class II promoters.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2003

Frequent segmental sequence exchanges and rapid gene duplication characterize the MHC class I genes in lemurs.

Major histocompatibility complex (MHC) class I genes have complicated and profound evolutionary histories. To reconstruct and better understand their histories, partial class I genes (exon 2-intron 2-exon 3) were sequenced in a sampling of prosimians (Strepsirhini, Primates). In total, we detected 117 different sequences from 36 Malagasy prosimians (lemurs) and 1 non-Malagasy prosimian (galago) representing 4 families, 7 genera, and 13 species. Unlike the MHC class II genes ( MHC-DRB), MHC class I genes show a generally genus-specific mode of evolution in lemurs. Additionally, no prosimian class I loci were found to be orthologous to HLA genes, even at highly conserved loci (such as HLA-E, HLA-F). Phylogenetic analysis indicates that nucleotide diversity among loci was very small and the persistence time of the polymorphisms was short, suggesting that the origin of the lemur MHC class I genes detected in this study was relatively recent. The evolutionary mode of these genes is similar to that of classic HLA genes, HLA-A, HLA-B, and HLA-C, in terms of their recent origin and rarity of pseudogenes, and differs from them with respect to the degree of gene duplications. From the viewpoint of MHC genes evolution, some interlocus sequence exchanges were apparently observed in the lemur lineage upon phylogenetic and amino acid motif analyses. This is also in contrast to the evolutionary mode of HLA genes, where intralocus exchanges have certainly occurred but few interlocus exchanges have taken place. Consequently, the gene conversion model for explaining the generation of the MHC diversity among different loci can be thought to play more important roles in the evolution of lemur MHC class I genes than in that of HLA genes.

Animals↗
PubMed1992

Interferon-gamma response region in the promoter of the class II MHC gene, DPA.

The class II MHC gene DPA is inducible by interferon-gamma (IFN-gamma), whereas the DQB gene is not inducible in most cell types. To investigate the DNA region specifically responsible for inducibility or its lack that may be required (in addition to the elements required for constitutive expression of class II genes), hybrid promoters were constructed between the proximal 5' regions of the DPA promoter up to -148 bp, which is IFN-gamma inducible, and of the DQB promoter up to -160 bp, which is not inducible. As a result of these and previous studies [9, 10], the region of the DPA gene required for its IFN-gamma inducibility was localized to 27 bp between -55 and -81, including the Y-box element and its flanking nucleotides.

Base Sequence↗
PubMed2004

Potential regulatory sequences in the untranslated regions of the baboon MHC class Ib gene, Paan-AG, more closely resemble those in the human MHC class Ia genes than those in the class Ib gene, HLA-G.

The baboon major histocompatibility complex (MHC) class Ib gene, Paan-AG, is structurally similar to the human MHC class Ia gene, HLA-A, but exhibits characteristics similar to those of the class Ib gene HLA-G. These include limited polymorphism, alternative splicing of a single message, and restricted tissue distribution, with high expression in the placenta. In order to determine whether regulatory elements controlling expression of Paan-AG resemble those of HLA-A or HLA-G, we cloned the 5' and 3' untranslated regions of Paan-AG. Unexpectedly, sequence comparisons showed that potential regulatory elements in Paan-AG strikingly resembled those in HLA-A and differed in major respects from those in HLA-G. Unlike HLA-G, Paan-AG contained an intact interferon-gamma stimulated response element (ISRE) in the promoter. Studies using luciferase reporter assays showed that the Paan-AG ISRE was functional. The basal activity of the Paan-AG ISRE and its response to interferon-gamma was similar to that of class Ia MHC genes. Further, we identified an ISRE in the 3' untranslated region of Paan-AG that is known to be functional in HLA-A2 but is deleted in HLA-G. These experiments predict that functional studies may demonstrate differences in regulation of expression of Paan-AG and HLA-G genes, which could restrict the use of the baboon as a primate model for studying HLA-G expression and function.

Animals↗
PubMed1996

MHC class I-processed pseudogenes in New World primates provide evidence for rapid turnover of MHC class I genes.

The MHC class I genes of the New World primate, the cotton-top tamarin (Saguinus oedipus), are an exception to the high polymorphism and variability displayed by this multigene family. We report the isolation of the first two processed pseudogenes from the MHC region in primates. These two MHC class I-processed pseudogenes (MHC-PS1 and -PS2) were found in several species of New World primates, suggesting a possible explanation for the cotton-top tamarin's limited MHC class I diversity. The pattern of synonymous and nonsynonymous substitutions in PS1 suggests that the gene that gave rise to this processed pseudogene was once subject to selection for variability in the peptide binding region and might, therefore, have been functional. Additionally, PSI is not closely related to the expressed cotton-top tamarin's MHC class I genes, but does show some similarity to So-N1, a tamarin pseudogene from which no transcript has been found. Thus, PS1 may represent a remnant of a once active MHC class I gene that is no longer functional in the cotton-top tamarin. The MHC class I loci in primates, therefore, appear to be evolving by a continual process of duplication and inactivation. This process seems to be exaggerated in New World primates and may in part be responsible for the cotton-top tamarin's limited MHC class I diversity.

Animals↗
PubMed1990

Syrian hamsters express diverse MHC class I gene products.

MHC class I glycoproteins are highly diverse in most species. The Syrian hamster has long been thought to express monomorphic MHC class I molecules and thus be an exception to this rule. Here we show that Syrian hamsters express diverse MHC class I gene products. The nucleotide sequences of the alpha 1 and alpha-2 domains of classical Syrian hamster MHC class I molecules are highly variable and show evidence of having been under selective pressures at their Ag recognition sites. Interestingly, none of the Syrian hamster class I genes was closely related to their counterparts in the mouse. These observations suggest that Syrian hamsters in the wild may express diverse MHC class I molecules.

Animals↗
PubMed1989

Combined immunodeficiency with abnormal expression of MHC class II genes.

The MHC class II CID represents an example of immunodeficiency in which the defect in expression of membrane glycoproteins leads to abnormal cell to cell interactions and thus to abnormal immune responses. It represents an interesting model which confirms the importance of MHC molecules in all immune responses to foreign antigens. It also underlines the complexity of regulatory mechanism which control the expression of MHC class II genes. To elucidate these mechanisms, it is essential to identify and characterize the genes involved in control of MHC class II expression.

Agammaglobulinemia↗