Assignment of the giant panda MHC class II gene cluster to chromosome 9q by fluorescence in situ hybridization.
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Animals↗
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Results for “Genes, MHC Class II”
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Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice.
We developed a new mouse model of human anti-glomerular basement membrane (GBM) disease to better characterize the genetic determinants of cell-mediated injury. While all major histocompatibility complex (MHC) haplotypes (H-2a, k, s, b, and d) immunized with alpha3 NC1 domains of type IV collagen produce anti-alpha3(IV) NC1 antibodies that cross-react with human Goodpasture [anti-GBM/anti-alpha3(IV) NC1] autoantibodies, only a few strains developed nephritis and lung hemorrhage associated with Goodpasture syndrome. Crescentic glomerulonephritis and lung hemorrhage were MHC-restricted in haplotypes H-2s, b, and d (A beta/A alpha region in H-2s) and associated with the emergence of an IL-12/Th1-like T cell phenotype. Lymphocytes or anti-alpha3(IV) NC1 antibodies from nephritogenic strains transfer disease to syngeneic recipients. However, passive transfer of isogenic alpha3(IV) NC1 antibodies into -/- T cell receptor-deficient mice failed to produce nephritis. Finally, nephritis and its associated IL-12/Th1-like T cell response attenuate in disease-susceptible mice tolerized orally to alpha3(IV) collagen before immunization. Our findings suggest collectively, as a hypothesis, that anti-GBM antibodies in mice only facilitate disease in MHC haplotypes capable of generating nephritogenic lymphocytes with special T cell repertoires.
Adoptive Transfer↗
Complementation cloning of mammalian transcriptional regulators: the example of MHC class II gene regulators.
Cloning by complementation of mutant cell lines is a powerful way in which to identify and isolate important regulatory genes on the basis of functional assays. The recent cloning of two essential regulators of major histocompatibility complex (MHC) class II gene expression has not only advanced our understanding of the complex mechanisms controlling these genes, but also helps to illustrate the feasibility of this approach for the study of mammalian gene regulation.
Animals↗
The structure of human MHC class II genes.
The class II molecules of the human major histocompatibility complex bind intracellularly processed peptides and present them to T-helper cells. They therefore have a critical role in the initiation of the immune response. A salient feature of the class II molecules is their polymorphism. It has been shown that some autoimmune diseases are associated with certain class II alleles. This article reviews the basic structural features of class II molecules, and the genes encoding them as well as mechanisms governing the development of their extraordinary polymorphism.
Autoimmune Diseases↗
Retrovirus-mediated transfer and expression of swine MHC class II genes in CD34+ monkey stem cells.
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Animals↗
Class II MHC genes: a model gene regulatory system with great biologic consequences.
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Antigens, Differentiation, B-Lymphocyte↗
MHC class II genes in HCV viral clearance of hepatitis C infected Hispanic patients.
The frequency of class II human leukocyte antigen (HLA) alleles in 112 infected patients of Hispanic ancestry with serology positive for hepatitis C virus (HCV) was investigated. Our studies failed to demonstrate significant association between class II HLA alleles and the outcome of HCV infection: chronic viremia versus spontaneous viral clearance. Our results suggest that the genes responsible for the outcome are unknown, so far, and those HLA associations reported in several ethnic groups may represent genetic markers in nonrandom association with the responsible genes involved in determining viral clearance or chronic viremia following HCV infection.
Adult↗
Hetero- and homozygosity of MHC class II gene products in systemic lupus erythematosus. The Members of the Deutsche Multizentrische SLE-Studie.
An analysis of HLA class II antigens in 356 white patients with systemic lupus erythematosus (SLE) showed that all HLA-DR and -DQ homozygous and heterozygous combinations appear with frequencies expected from the observed gene frequencies. HLA-DR2 and HLA-DR3 gene frequencies were both increased in SLE, as were the odds ratios of all DR2 and DR3 hetero- and homozygous combinations. HLA-DR2/C4AQ0 heterozygotes were also not increased over expected values. Therefore, gene complementation at MHC loci does not contribute to susceptibility to SLE, but rather one or two MHC allele(s) in linkage with HLA-DR2 and HLA-DR3.
Alleles↗
[The role of MHC class II genes in the etiopathogenesis of rheumatoid arthritis].
Rheumatoid arthritis (RA) is associated with HLA-DR4 and DR1 antigens. HLA-DRB1 gene sequences analysis demonstrated that only a limited set of alleles is positively associated with RA. Third hypervariable region sequences (70-74, 86) Q(R)R(K)RAA, G(V) are found in up to 95% of erosive RA. The presence of disease-associated allels may predict severe outcome of the disease. Therefore, their presence may allow us to start aggressive therapy in early stage of the disease.
Arthritis, Rheumatoid↗
Tissue-specific, inducible and functional expression of the E alpha d MHC class II gene in transgenic mice.
We have introduced the class II E alpha d gene into (C57BL/6 X SJL) F2 mice which do not express their endogenous E alpha gene. The mRNA expression of the E alpha d gene shows the same tissue distribution as the endogenous class II genes except in the case of one mouse, which carried 19 copies of the E alpha d gene. In this mouse expression of E alpha d mRNA was seen in all tissues tested. Expression of the transgene was induced by gamma-interferon in isolated macrophages from the transgenic mice. In addition, fluorescence activated cell sorter (FACS) analysis, mixed lymphocyte response and antigen-presentation experiments showed that the product of the transferred gene is expressed on the cell surface and functions as a major histocompatibility complex restriction element. Transmission of the gene occurred only with female transgenic mice, all males were infertile or did not transmit the gene, suggesting an effect of the transferred DNA sequence on male reproductive function.
Animals↗
MHC class II genes of a marsupial, the red-necked wallaby (Macropus rufogriseus): identification of new gene families.
In placental mammals, the class II region of the major histocompatibility complex (Mhc) consists of several gene families which show orthologous relationships in the different species. As these families are not orthologous with the Mhc class II beta-chain-encoding gene families of birds, the different mammalian families must have diverged after the separation of birds and mammals approximately 250 Mya but before the radiation of placental mammals (60-80 Mya). To obtain further information about the origin of the class II genes in mammals, we studied the beta-chain-encoding genes of the wallaby as a representative of marsupials, which split from placental mammals approximately 125 Mya. Three beta-chain-encoding genes were isolated from a red-necked wallaby (Macropus rufogriseus) cDNA library by using a chimpanzee DRB probe, and their nucleotide sequences were determined. The genes are not orthologous to any of the genes in mammals studied thus far but belong to two new families which we designated Maru-DAB and Maru-DBB. One of the three sequences (DAB2) seems to be derived from a transcribed pseudogene; it lacks the codons specifying the first 51 amino acid residues of the beta 2 domain. The fact that the DAB and DBB families have thus far not been found in placental mammals and that none of the DOB, DPB, DQB, or DRB genes seems to be expressed in the one representative marsupial species can be interpreted as suggesting that class II gene families of eutherian and metatherian mammals evolved from different ancestral genes.
Amino Acid Sequence↗
The enhancer in an MHC class II gene, in vitro and in mouso.
The E alpha class II gene of the major histocompatibility complex is expressed in a variety of immunocompetent cells. Part of the control of tissue-specific expression is mediated by a block of sequences found far upstream of the transcriptional startsite; this stretch is necessary for expression in the B lymphocytes of transgenic mice, but largely dispensable elsewhere. We review the evidence for the role of this region in E alpha transcription in transgenic animals, as well as data from transfections into tissue-culture cells, which indicate that this region has non-specific enhancer activity. We discuss possible models to explain how a non-specific enhancer can participate in cell-specific control.
Animals↗
Inheritance of MHC class II genes in IDDM studied in population-based affected and control families.
The transmission of HLA-DR and DQ was compared between 46 families with at least one child affected by insulin dependent diabetes mellitis (IDDM) and 43 healthy control families. In the patient families, there was an increased transmission of DR4 (p < 0.025) and DQB1*0302 (p < 0.01) from both parents to the index patient. There was an increased transmission of DQB1*0302 (p < 0.03) from the mothers only. The non-inherited maternal haplotypes showed a significantly decreased frequency (p < 0.01) of positively associated haplotypes (DR4-DQA1* 0301-DQB1*0302, DR3-DQA1*0501-DQB1*0201) compared to all parental haplotypes in the control families. In the control families neither transmission rates nor frequencies of non-inherited haplotypes differed from those expected in the control families. In conclusion, the observed reduction of IDDM-positively associated haplotypes in patient non-inherited maternal haplotypes, but not in non-inherited paternal haplotypes, suggests that tolerance during fetal life to maternal non-inherited HLA molecules may be important to diabetes development.
Adolescent↗
An isotype-specific activator of major histocompatibility complex (MHC) class II genes that is independent of class II transactivator.
Patients with one type of major histocompatibility complex class II combined immunodeficiency have mutations in a gene termed class II transactivator (CIITA), which coordinately controls the transcription of the three major human class II genes, HLA-DR, -DQ, and -DP. However, the experimentally derived B-lymphoblastoid cell line, clone 13, expresses high levels of HLADQ in the absence of HLA-DR and HLA-DP, despite its mapping by complementation analysis to this group. It was possible that one of the clone 13 CIITA alleles bore a mutation that allowed HLA-DQ, but not HLA-DR or -DP transcription. Alternatively, another factor, distinct from CIITA, might control HLA-DQ expression. We report here that ectopic expression of CIITA cDNAs derived by reverse transcriptase polymerase chain reaction from clone 13 do not restore expression of HLA-DQ in another CIITA-deficient cell line, RJ2.2.5. In addition, no CIITA protein is detectable in clone 13 nuclear extracts. In contrast, somatic cell fusion between clone 13 and RJ2.2.5 restored expression of the HLA-DQ haplotype encoded by the RJ2.2.5 DQB gene. Taken together, these data demonstrate the existence of an HLA-DQ isotype-specific trans-acting factor, which functions independently of CIITA.
Blotting, Western↗
Inheritance of MHC class II genes in Lithuanian families with type 1 diabetes.
Type 1 diabetes mellitus (DM) is caused by genetic and environmental factors. Twice as many fathers as mothers of children with type 1 DM have the disease. The reason for the differences remains unclear. We looked at the transmission rates of diabetes-related alleles from parents to children with diabetes. All children with newly diagnosed type 1 DM from August 1, 1996 to August 1, 2000, aged 0 to 15 years, in Lithuania were invited to participate. Blood samples for full genetic analysis were available from 125 families. HLA DQA1, DQB1, and DRB1 typing was done on DNA extracted from peripheral blood, by polymerase chain reaction amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide probe 3'-end labeling with (32)P-dCTP, and hybridization, followed by stringency washes, autoradiography, and allele calling. Frequency of diabetes risk-related alleles DQB1*0302, DQA1*0201, DR4, and DR3 was less prevalent among Lithuanian than among Swedish children with type 1 DM. Transmission rates of DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501 haplotypes from parents were higher than expected: chi(2) (TDT) 30.56, p < 0.0001, and chi(2) (TDT) 11.26, p = 0.0008, respectively. DQB1*0302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently only from mothers. Any of these alleles had similar frequencies among female and male offspring. We conclude that, besides DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501, there are other inherited alleles that determine risk for type 1 DM among children in Lithuania. Fathers might transfer other alleles of disease susceptibility in higher frequency or mothers might provide a protective environment during pregnancy, which results in higher risk to offspring of fathers than mothers to develop diabetes.
Adolescent↗
The DY genes of the cattle MHC: expression and comparative analysis of an unusual class II MHC gene pair.
The major histocompatibility complex of cattle (BoLA) contains the class II genes DYA and DIB which are transcribed with a dendritic cell restricted distribution. As part of the process to determine whether these genes have any functional significance, we demonstrate that they form a closely linked pair characteristic of other expressed class II MHC molecules. Accepted nomenclature convention suggests that BoLA-DIB should therefore be renamed BoLA-DYB. Analysis of the first full-length DYA and DYB transcripts revealed open reading frames with potential to translate 253 and 259 amino acid proteins, respectively. Comparative sequence analysis between the DY polypeptides and classical cattle, human and mouse class II MHC alpha and beta polypeptide chains revealed 16 unique amino acid residues at positions predicted to form and line the putative peptide-binding region. Expression of tagged constructs demonstrates for the first time that the DY genes of cattle are capable of translating distinctive class II MHC alpha and beta polypeptide chains.
Amino Acid Sequence↗
Characterization of astrocyte nuclear proteins involved in IFN-gamma- and TNF-alpha-mediated class II MHC gene expression.
IFN-gamma is a potent inducer of class II MHC Ags on different cell types, including the astrocyte. TNF-alpha alone has no effect on class II MHC expression, but enhances IFN-gamma-induced class II expression. IFN-gamma acts by inducing transcription of the class II gene, and TNF-alpha enhances the rate of IFN-gamma-induced transcription. We have previously described two factors, IFN-gamma-enhanced factor X (IFNEX) and TNF-alpha induced complex X (TIC-X), whose expression is induced by IFN-gamma and IFN-gamma/TNF-alpha, respectively, which interacted with the X box of the DRA promoter. In this study, we show that IFNEX and TIC-X bind to the X2 core, with contacts extending into the 3' end of X1 and into the spacer region of the DRA promoter. We also show a functional correlation between binding activity and transcriptional activity of the DRA promoter. These results strongly suggest that both IFNEX and TIC-X play important roles in the regulation of class II MHC gene expression in the astrocyte.
Animals↗
The expression of MHC class II genes in macrophages is cell cycle dependent.
Using different drugs, we stopped the cell cycle of bone marrow-derived macrophages at different points. After IFN-gamma stimulation, macrophages arrested at the G(1) phase of the cell cycle did not increase cell surface expression of the MHC class II IA. This inhibition is specific, because, under the same conditions, IFN-gamma induces the expression of Fcgamma receptors and the inducible NO synthase mRNA. Treatments that inhibit macrophage proliferation by blocking the cell cycle at the G(1) phase, such as adenosine, forskolin, or LPS, blocked the IFN-gamma induction of IA. Under IFN-gamma treatment, the steady-state levels of IAalpha and IAss mRNA did not increase in cells arrested at the G(1) phase and the half-life of the MHC mRNA was not modified. These data suggest that the cell cycle modulation of IFN-gamma-induced MHC II gene expression occurs at the transcriptional level. The expression of the class II transactivator mRNA induced by IFN-gamma was also blocked when macrophages were arrested at the G(1) phase of the cell cycle, suggesting that the lack of IFN-gamma response occurs at the early steps of MHC class II expression. Finally, macrophages arrested at the G(1) phase showed increased basal levels of cell surface IA due to an increase of the translational efficiency. These data show that the expression of MHC class II genes is regulated by the cell cycle.
Animals↗