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PubMed1996

Genetic evidence for a new type of major histocompatibility complex class II combined immunodeficiency characterized by a dyscoordinate regulation of HLA-D alpha and beta chains.

Major histocompatibility complex (MHC) class II combined immunodeficiency (CID), also known as type II bare lymphocyte syndrome, is an autosomal recessive genetic disorder characterized by the complete lack of expression of MHC class II antigens. The defect results from a coordinated lack of transcription of all class II genes. Cell fusion studies using many patient- and experimentally derived class II-negative cell lines have identified four distinct genetic complementation groups. In this report, we present genetic evidence that cell lines derived from two newly described MHC class II-deficient patients, KER and KEN, represent a fifth complementation group. In addition, the KER and KEN cell lines display a unique pattern of dyscoordinate regulation of their MHC class II genes, which is reflected in a new phenotype of in vivo promoter occupancy as revealed by in vivo genomic footprinting. These data point to a new defect that can result in the MHC class II-deficient phenotype.

Cell Fusion↗

PubMed1990

Two DNA-binding proteins discriminate between the promoters of different members of the major histocompatibility complex class II multigene family.

The regulation of major histocompatibility complex (MHC) class II gene expression is a key feature of the control of normal and abnormal immune responses. In humans, class II alpha - and beta-chain genes are organized in a multigene family with three distinct subregions, HLA-DR, -DQ, and -DP. The regulation of these genes is generally coordinated, and their promoters contain highly conserved motifs, in particular the X and Y boxes. We have identified five distinct proteins that bind to specific DNA sequences within the first 145 base pairs of the HLA-DR promoter, a segment known to be functionally essential for class II gene regulation. Among these, RF-X is of special interest, since mutants affected in the regulation of MHC class II gene expression have a specific defect in RF-X binding. Unexpectedly, RF-X displays a characteristic gradient of binding affinities for the X boxes of three alpha-chain genes (DRA greater than DPA much greater than DQA). The same observation was made with recombinant RF-X. We also describe a novel factor, NF-S, which bound to the spacer region between the X and Y boxes of class II promoters. NF-S exhibited a reverse gradient of affinity compared with RF-X (DQA greater than DPA much greater than DRA). As expected, RF-X bound well to the mouse IE alpha promoter, while NF-S bound well to IA alpha. The drastic differences in the binding of RF-X and NF-S to different MHC class II promoters contrasts with the coordinate regulation of HLA-DR, -DQ, and -DP genes.

Animals↗

PubMed2004

MHC class I and class II genes in Mexican patients with Chagas disease.

Chagas' disease contributes significantly to cardiovascular morbidity and mortality in several Latin-American countries. Previous studies have reported the effect of the human leukocyte antigen (HLA) molecules in the immune response regulation of Trypanosoma cruzi infection, and the association of HLA antigens with heart damage. We studied the major histocompatibility complex (MHC) class I (HLA-A and HLA-B), and class II (HLA-DR) genes in a sample of 66 serologically positive individuals with and without cardiomyopathy, and in 127 healthy controls. The total group of seropositive individuals revealed increased frequencies of HLA-B39 (pc=4.3x10(-5), odds ratio [OR]=3.35) and DR4 (pc=1.8x10(-5), OR=2.91) when compared to healthy controls. Increased frequencies of HLA-A68 and HLA-B39 were found in asymptomatic individuals when compared to patients with cardiomyopathy (pc=0.014, OR=4.99 and pc=0.001, OR=4.46, respectively). Also, patients with cardiomyopathy exhibited increased frequency of HLA-B35 when compared to healthy controls (pc=0.048, OR=2.56). The HLA-DR16 frequency was increased in patients with cardiomyopathy compared with asymptomatic individuals (pc=0.05, OR=No determined) and healthy controls (pc=0.02, OR=5.0). The results suggest that MHC alleles might be associated with the development of chronic infection and with heart damage in Chagas' disease. HLA-DR4 and HLA-B39 could be associated directly with the infection by T. cruzi, whereas, HLA-DR16 could be marker of susceptibility to heart damage and HLA-A68 might confer protection to develop cardiomyopathy.

Animals↗

PubMed2003

Phosphorylation of class II transactivator regulates its interaction ability and transactivation function.

The MHC class II transactivator (CIITA) plays a central role in adaptive immune responses by controlling the expression of MHC class II genes. CIITA binds DNA-binding proteins and co-activator proteins to form an enhanceosome complex necessary for MHC class II gene expression. Here we demonstrate that CIITA interactions depend upon the phosphorylation status of CIITA. Hyper-phosphorylated CIITA interacts with co-activator p300, RFX5 and CIITA itself, which in turn results in induction of MHC class II promoter activity. Moreover, the C-terminal region of CIITA containing leucine-rich repeats (LRR) is a regulatory domain for CIITA self-association and LRR binding to CIITA is negatively regulated by phosphorylation. cAMP-dependent protein kinase (PKA) phosphorylates CIITA, and serine residues residing in a region between the proline/serine/threonine-rich domain and the GTP-binding domain are phosphorylated by PKA in vitro. The maximum transactivation potential of CIITA requires PKA phosphorylation as demonstrated by reduced transactivation activities of the mutant bearing substitutions of serine residues at the PKA site.

Amino Acid Sequence↗

PubMed2002

Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome.

Bare lymphocyte syndrome (BLS) is an autosomal recessive severe-combined immunodeficiency that can result from mutations in four different transcription factors that regulate the expression of major histocompatibility complex (MHC) class II genes. We have identified here the defective gene that is responsible for the phenotype of the putative fifth BLS complementation group. The mutation was found in the regulatory factor that binds X-box 5 (RFX5) and was mapped to one of the arginines in a DNA-binding surface of this protein. Its wild-type counterpart restored binding of the RFX complex to DNA, transcription of all MHC class II genes and the appearance of these determinants on the surface of BLS cells.

Amino Acid Motifs↗

PubMed1994

Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3.

Cosmid walking of about 250 kb from MHC class III gene CYP21 to class II was conducted. The gene for receptor of advanced glycosylation end products of proteins (RAGE, a member of immunoglobulin superfamily molecules), the PBX2 homeobox gene designated HOX12, and the human counterpart of the mouse mammary tumor gene int-3 were found. The contiguous RAGE and HOX12 genes were completely sequenced, and the human int-3 counterpart was partially sequenced and assigned to a Notch homolog. This human Notch homolog, designated NOTCH3, showed both the intracellular portion present in the mouse int-3 sequence and the extracellular portion absent in the int-3. It thus corresponds to the intact form of a Notch-type transmembrane protein. About 20 kb of dense Alu clustering was found just centromeric to the NOTCH3.

Amino Acid Sequence↗

PubMed1996

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele.

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.

Alleles↗

PubMed1999

Differential expression of alternative H2-M isoforms in B cells, dendritic cells and macrophages by proinflammatory cytokines.

Major histocompatibility (MHC) class II heterodimers bind peptides generated by degradation of endocytosed antigens and display them on the surface of antigen presenting cells (APCs) for recognition by CD4+ T cells. Efficient loading of MHC class II molecules with peptides is catalyzed by the MHC class II-like molecule H2-M. The coordinate regulation of MHC class II and H2-M expression is a prerequisite for efficient MHC class II/peptide assembly in APCs determining both the generation of the T cell repertoire in the thymus and cellular immune responses in the periphery. Here we show that expression of H2-M and MHC class II genes is coordinately and cell type-specific regulated in splenic B cells, splenic dendritic cells (DCs) and peritoneal macrophages (Mphi) in response to proinflammatory and immunoregulatory cytokines, including GM-CSF, IFN-gamma, TGF-beta2, IL-4, IL-10 and viral IL-10. In addition, ratio-RT-PCR expression analysis of the duplicated H2-Mbeta-chain loci demonstrates for the first time that Mbl and Mb2 genes are differentially expressed in individual APC types. Mb2 is preferentially expressed in IL-4, GM-CSF, IL-10, vIL-10 and IFN-gamma stimulated splenic B cells, whereas splenic DCs express both Mb genes at almost equal levels. In contrast, peritoneal Mphi express predominantly Mb2 but stimulation with IFN-gamma induces a switch towards Mb1 expression. These data suggest a common mechanism that regulates coordinate expression of H2-M and MHC class II genes in professional APCs. Differential expression of Mb1 and Mb2, and by consequence alternative H2-M isoforms (Malphabeta1 or Malphabeta2), may influence the nature of the peptide repertoire presented by different APC types.

Animals↗

PubMed1990

The MHC class II deficiency syndrome: heterogeneity at the level of the response to 5-azadeoxycytidine.

The involvement of DNA methylation in aberrant MHC class II gene expression in EBV-transformed B-cell lines from 2 patients (THF and DGN) with the MHC class II deficiency syndrome (bare lymphocyte syndrome) was investigated. Incubation of the cells in the presence of various concentrations of 5-azadeoxycytidine resulted in the induction of expression of HLA DR genes in the DGN cell line, whereas, in the THF cell line, no effect of 5-azadeoxycytidine treatment on the expression of the HLA DR genes could be detected. Subsequent Southern blot analysis using methylation-sensitive restriction enzymes (ApyI, EcoRII and HhaI) and 5-azadeoxcycytidine-treated and untreated genomic DNA, indicated that the lack of HLA DR-A expression in the DGN cell line is not caused by hypermethylation of the 5' region of the HLA DR-A gene. These results indicate that 5-azadeoxycytidine treatment of the DGN cell line leads to activation of a methylation-sensitive factor that is involved in the regulation of transcription of the DR-A gene. In cell line THF, however, demethylation does not restore the activity of this factor. The lack of MHC class II expression in this cell line is caused by some other defect. The results of our analysis indicate that at least two different factors are involved in regulation of MHC class II gene expression.

Azacitidine↗

PubMed2006

Identification and analysis of MHC class II DRB1 (Patr-DRB1) alleles in chimpanzees.

The MHC-DRB1 gene is known to display the most extensive allelic polymorphisms among MHC class II genes. We attempted the selective identification of chimpanzee (Pan troglodytes) DRB1 (Patr-DRB1) alleles using the polymerase chain reaction (PCR) technique in three steps: first, we performed Patr-DRB1*02 lineage-specific 8-kb PCR for *02 lineage detection in each chimpanzee; second, we performed 620-bp PCR for amplification of full-length exon 2; and finally, we carried out an insert check using the pattern of microsatellite repeat length variability. In the genomic DNA of 23 chimpanzees, nine Patr-DRB1 alleles containing two new alleles were detected. Our approach provides a relatively effective method of identifying Patr-DRB1 alleles in individual chimpanzees and should also contribute to our understanding of the features of MHC molecules in non-human primates.

Alleles↗

PubMed2005

Dissection of the genetic complexity of arthritis using animal models.

Rheumatoid arthritis (RA) is a chronic inflammatory disease directed towards peripheral joints. As all common diseases it is associated with several genes and a multitude of environmental factors. In addition, in similarity with most other complex diseases, it is defined only on the basis of clinical signs and symptoms, it is therefore more properly classified as a syndrome rather than a distinct disease entity. This complexity of RA has led to difficulties in finding the underlying genes. In spite of large efforts it is still only the MHC class II region that reaches genome wide significance in confirmed studies. However, this has been known for decades and we are still unable to conclusively identify the underlying gene/s. We hypothesize that an MHC class II gene is involved and although we have detailed knowledge on both structure and function we do not know its possible pathogenic role in RA. In this review I will argue for the usefulness of animal models as a tool to identify genes and pathways associated with disease. The examples to be discussed are genes controlling the oxidative burst pathways and MHC class II genes.

Animals↗

PubMed1991

IFN-gamma induces the expression of the genes for MHC class II I-A beta and tumor necrosis factor through a protein kinase C-independent pathway.

The mechanism of gene expression for the MHC I-A beta and TNF genes was studied in murine bone marrow macrophages. The treatment of macrophages with PMA stimulated the expression of TNF, but not I-A beta, suggesting that the TNF gene is responsive to activators of protein kinase C whereas the I-A beta gene is not. The treatment of macrophages with IFN-gamma led to an increase in the level of RNA for both TNF and I-A beta. The increase in expression of I-A beta and TNF, induced by IFN-gamma, was blocked by naphthalenesulfonamide or phenothiazine (trifluoperazine) but was not affected by the addition of isoquinolinesulfonamide or sphingosine. These results suggest that the induced expression of I-A beta and TNF by IFN-gamma is mediated by a pathway that is protein kinase C independent. This was supported by the finding that calcium ionophores were also able to induce the gene expression of both TNF and I-A beta. We observed that when both IFN-gamma and PMA were added to the macrophages, the level of RNA for TNF increased to a higher level than the level seen when either agent alone was added to the cells. In contrast, the addition of both IFN-gamma and PMA to macrophages had an inhibitory effect on the expression of the I-A beta gene. These results further emphasize the complex nature of gene regulation during the activation of macrophages.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1988

The functional link between the immune suppression gene and Mhc class II molecules.

The immune response to bovine insulin (BI) in the rat is controlled by the major histocompatibility complex (Mhc)-linked immune response gene (Ir-BI) and immune suppression gene (Is-BI). In the present study, we investigated the low responsiveness to BI in the WKAH rat (RT1k) and attempted to explore the functional link between Is-BI and Mhc class II molecules. Lymph node cells (LNC) from the low responder (WKAH) rats responded well to BI when a large amount of antigen was added to the culture in vitro or after OX8-bearing (OX8+) T cells were eliminated. These LNC, after the elimination of OX8+ cells, could show the RT1.Dk-restricted proliferative response upon in vitro challenge with BI, BI-B chain, or pork insulin. In addition, OX8+ T cells, which were activated with BI and antigen-presenting cells (APC) in vitro, suppressed the anti-BI response of W3/25-bearing proliferating T cells from BI-immunized rats. The results have demonstrated that proliferating T-cell repertoires do exist to BI, which recognize BI-B chain in the context of RT1.Dk molecules in the WKAH rat, and that the state of low responsiveness is mediated to a great extent by antigen-specific OX8+ suppressor T (Ts) cells. Furthermore, the elimination of APC or the addition to RT1.Bk-specific monoclonal antibody in the in vitro secondary activation culture of Ts cells diminished the suppressive activity of OX8+ Ts cells. In the induction phase of Ts cells it therefore seems to be necessary for these cells to recognize BI together with RT1.Bk molecules on APC.

Animals↗

PubMed2004

Gene expression in the elicitation phase of guinea pig DTH and CHS reactions.

Delayed-type hypersensitivity (DTH) reactions are divided into classical DTH induced by protein antigens and contact hypersensitivity (CHS) induced by haptens. It has been reported that different cytokines and T cell subsets are involved in the induction of each DTH reaction. We previously isolated many genes whose expression is elevated during elicitation of skin DTH reaction in guinea pigs. In this study, we focused on the expression of tryptophanyl-tRNA synthetase (WRS), ferritin heavy chain and major histocompatibility complex (MHC) class II genes to investigate the different regulatory mechanisms in classical DTH and CHS. Furthermore, the expression of various cytokines and chemokines was examined. WRS expression in classical DTH was higher than that in CHS, and the expression of interferon-gamma but not that of transforming growth factor-beta showed similar patterns. MHC class II mRNA increased only in classical DTH. The differential expression of WRS and MHC class II genes in classical DTH might be caused by the differential expression of interferon-gamma and/or the involvement of CD4(+) T cells in classical DTH, respectively. In contrast, the expression of ferritin heavy chain and interleukin-1beta was elevated in CHS, and also by treatment with dinitrochlorobenzene in unsensitized guinea pigs, and expression of both was correlated.

Animals↗

PubMed1995

Differential transcription elements direct expression of HLA-DQ genes.

Regulation of class II MHC gene expression, including the HLA-DQ genes, is primarily at the level of transcription. Locus-specific control of DQ gene transcription is both tissue-specific and developmentally regulated and relies on complex mechanisms involving specific DNA-protein interactions. Electrophoretic mobility shift and DNase I protection assays demonstrate the presence of unique nuclear protein interactions with the consensus W and Y box elements in the DQB1 promoter region in DQ-negative cell lines. Based on these and other recent studies, a multistage model of DQ gene regulation is outlined to account for specific patterns of DQ gene expression.

Cell Line↗

PubMed1998

The MHC class II transactivator (CIITA) requires conserved leucine charged domains for interactions with the conserved W box promoter element.

The class II transactivator CIITA is required for transcriptional activation of the major histocompatibility complex (MHC) class II genes. Aside from an N-terminal acidic transcriptional activation domain, little is known about how this factor functions. Extensive mutagenesis of CIITA was undertaken to identify structural motifs required for function. The ability of mutants to activate a reporter gene under the control of MHC class II conserved W-X-Y or X-Y regulatory elements was determined. Two mutants displayed differential activity between the two promoters, activating transcription with the W-X-Y but not the X-Y elements. All mutants were tested for their ability to interfere with wild-type CIITA activity. Five CIITA mutant constructions were able to down-regulate wild-type CIITA activity. Three of these mutants contained targeted disruptions of potential functional motifs: the acidic activation domain, a putative GTP-binding motif and two leucine charged domains (LCD motifs). The other two contained mutations in regions that do not have homology to described proteins. The characterization of CIITA mutants that are able to discriminate between promoters with or without the W box strongly suggests that CIITA requires such interactions for function. The identification of LCD motifs required for CIITA function brings to light a previously undefined role of these motifs in CIITA function.

Amino Acid Substitution↗

PubMed2006

Linkage mapping and physical localization of the major histocompatibility complex region of the marsupial Monodelphis domestica.

We used genetic linkage mapping and fluorescence in situ hybridization (FISH) to conduct the first analysis of genic organization and chromosome localization of the major histocompatibility complex (MHC) of a marsupial, the gray, short-tailed opossum Monodelphis domestica. Family based linkage analyses of two M. domestica MHC Class I genes (UA1, UG) and three MHC Class II genes (DAB, DMA, and DMB) revealed that these genes were tightly linked and positioned in the central region of linkage group 3 (LG3). This cluster of MHC genes was physically mapped to the centromeric region of chromosome 2q by FISH using a BAC clone containing the UA1 gene. An interesting finding from the linkage analyses is that sex-specific recombination rates were virtually identical within the MHC region. This stands in stark contrast to the genome-wide situation, wherein males exhibit approximately twice as much recombination as females, and could have evolutionary implications for maintaining equality between males and females in the ability to generate haplotype diversity in this region. These analyses also showed that three non-MHC genes that flank the MHC region on human chromosome 6, myelin oligodendrocyte glycoprotein (MOG), bone morphogenetic protein 6 (BMP6), and prolactin (PRL), are split among two separate linkage groups (chromosomes) in M. domestica. Comparative analysis with eight other vertebrate species suggests strong conservation of the BMP6-PRL synteny among birds and mammals, although the BMP6-PRL-MHC-ME1 synteny is not conserved.

Animals↗

PubMed1989

Association of class I, II, and III MHC gene products with systemic lupus erythematosus. Results of a Central European multicenter study.

Class I, II, and III MHC gene products were examined in 248 Central European SLE patients. The previously reported association with HLA-A1, -B8 and -DR3, and C4AQ0 alleles was confirmed. The frequency of HLA-DR2 was also slightly elevated in SLE patients, while no increase in C4BQ0 alleles was observed. Additional findings were a significantly increased frequency of HLA-B13 and a significant decrease of HLA-B44.

Alleles↗