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PubMed2004

Regulation of major histocompatibility complex class II gene expression in trophoblast cells.

Trophoblast cells are unique because they are one of the few mammalian cell types that do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to IFN-gamma. The absence of MHC class II antigen expression on trophoblast cells has been postulated to be one of the essential mechanisms by which the semi-allogeneic fetus evades immune rejection reactions by the maternal immune system. Consistent with this hypothesis, trophoblast cells from the placentas of women suffering from chronic inflammation of unknown etiology and spontaneous recurrent miscarriages have been reported to aberrantly express MHC class II antigens. The lack of MHC class II antigen expression on trophoblast cells is due to silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and IFN-gamma-inducible MHC class II gene transcription. Transfection of trophoblast cells with CIITA expression vectors activates both MHC class II and class Ia antigen expression, which confers on trophoblast cells both the ability to activate helper T cells, and sensitivity to lysis by cytotoxic T lymphocytes. Collectively, these studies strongly suggest that stringent silencing of CIITA (and therefore MHC class II) gene expression in trophoblast cells is critical for the prevention of immune rejection responses against the fetus by the maternal immune system. The focus of this review is to summarize studies examining the novel mechanisms by which CIITA is silenced in trophoblast cells. The elucidation of the silencing of CIITA in trophoblast cells may shed light on how the semi-allogeneic fetus evades immune rejection by the maternal immune system during pregnancy.

Animals↗
PubMed2000

Molecular characterization of major and minor MHC class I and II genes in B21-like haplotypes in chickens.

The major histocompatibility complex (MHC) sequences of three B21-like haplotypes deriving from very different origins including the Red Jungle Fowl Gallus Gallus gallus were compared with the MHC sequences of the standard B21 haplotype from Scandinavian White Leghorn Gallus domesticus. The present analysis reveals two cDNA sequences for B-F and two cDNA sequences for B-LB for every B21-like haplotype, including B21 itself. Contrary to expectation, no sequence polymorphism in the antigen-binding domains of the MHC genes, between the investigated haplotypes, was found. The relative level of MHC class I molecules on the surface of leukocytes measured by flow cytometry was also analysed and found to be low in Marek's Disease (MD)-resistant B haplotypes (B21 and B21-like) and high in MD-susceptible B haplotypes (B15 and B19). However, in heterozygous (resistant/susceptible) animals, the relative level was almost as high as in susceptible haplotypes.

Amino Acid Sequence↗
PubMed1992

Stimulatory effect of interleukin-1 beta on the interferon-gamma-dependent HLA-DR production.

Expression of major histocompatibility complex (MHC) class II genes is induced by interferon-gamma (IFN-gamma) in antigen-presenting cells. When human leukaemia THP-1 and PL-21 cells were pretreated with phorbol ester, IFN-gamma-dependent induction of MHC class II gene was markedly enhanced. To elucidate the mechanism of the phenomenon, we examined the effect of cytokines which were secreted from THP-1 cells by the treatment of phorbol ester. Among those cytokines, interleukin-1 beta (IL-1 beta) had a positive effect on IFN-gamma-dependent induction of MHC class II genes. In order to rule out the possibility that different clones of THP-1 cells respond independently to IFN-gamma or phorbol ester, we showed that all independent single clones expressed MHC class II and produced IL-1 beta by IFN-gamma or phorbol ester, respectively.

Culture Media↗
PubMed1999

Isolation and mapping of the rabbit DM genes.

Proper peptide presentation by major histocompatibility complex (MHC)-encoded class II antigens is dependent on the products of the MHC DM loci. We identified the rabbit orthologues (RLA-DMA and -DMB) of human HLA-DMA and -DMB and found that they have 76.9% and 78.8% identity with HLA-DMA and -DMB, respectively. Like classical class II MHC genes, RLA-DM genes are more closely related to human HLA-DM genes than to mouse H2-DM. Among the DM family, there is a high degree of variability at the amino terminus of the DMa chains, and length variability in the cytoplasmic tails of both DMalpha and DMbeta. The rabbit DM genes are coexpressed with class II genes in lymphoid tissues, as are the DM genes of other mammals. The RLA-DM locus maps to the class II region of the rabbit MHC, and is flanked by the DP and DOB loci. Despite having some similarities to class II genes of bony fishes, the DM family represents a separate branch of the MHC class II family.

Amino Acid Sequence↗
PubMed2000

Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B.

Expression of major histocompatibility complex (MHC) class II genes is controlled at the transcriptional level by at least four trans-acting genes, CIITA, RFXANK, RFX5, and RFXAP. Defects in these regulatory genes result in the absence of MHC class II molecule expression and, thereby, cause a combined immunodeficiency. MHC class II deficiency is inherited as an autosomal recessive trait. Since the first description of the disease, about 70 patients from 50 families have been reported. Forty-three of these families have been classified into four complementation groups: A, B, C, and D. In the largest group, B, the majority of patients are of North African origin. In two of these patients, the same mutation in the RFXANK gene (752delG-25) was identified. We performed a mutation analysis in 20 additional patients belonging to complementation group B and detected the 752delG-25 mutation in 17. All of these patients are of North African origin. A founder effect for this mutation was documented, since all tested patients, except one, display a common haplotype spanning the RFXANK locus.

Africa, Northern↗
PubMed2004

The S box of major histocompatibility complex class II promoters is a key determinant for recruitment of the transcriptional co-activator CIITA.

Tightly regulated expression of major histocompatibility complex (MHC) class II genes is critical for the immune system. A conserved regulatory module consisting of four cis-acting elements, the W, X, X2 and Y boxes, controls transcription of MHC class II genes. The X, X2, and Y boxes are bound, respectively, by RFX, CREB, and NF-Y to form a MHC class II-specific enhanceosome complex. The latter constitutes a landing pad for recruitment of the transcriptional co-activator CIITA. In contrast to the well defined roles of the X, X2, and Y boxes, the role of the W region has remained controversial. In vitro binding studies have suggested that it might contain a second RFX-binding site. We demonstrate here by means of promoter pull-down assays that the most conserved subsequence within the W region, called the S box, is a critical determinant for tethering of CIITA to the enhanceosome complex. Binding of CIITA to the enhanceosome requires both integrity of the S box and a remarkably stringent spacing between the S and X boxes. Even a 1-2-base pair change in the native S-X distance is detrimental for CIITA recruitment and promoter function. In contrast to current models, binding of RFX to a putative duplicated binding site in the W box is thus not required for either CIITA recruitment or promoter activity. This paves the way for the identification of novel factors mediating the contribution of the S box to the activation of MHC class II promoters.

Base Sequence↗
PubMed1989

Rabbit major histocompatibility complex. III. Multiple class II DR beta genes and restriction fragment length polymorphism of the class II alpha and beta genes.

Several class II alpha and beta chain genes of the rabbit MHC have been cloned and classified into three distinct subregions, R-DP, R-DQ and R-DR, based on their homology to the corresponding HLA-DP, -DQ and -DR genes. The organization of the rabbit MHC class II genes has now been studied in greater detail by analysing genomic DNA of an inbred III/J strain and several other RLA-D homozygous rabbits, with DNA probes derived from cloned R-DR beta genes. Eight previously cloned R-DR beta genes were shown to be allelic forms of five R-DR beta loci. Genomic blot analyses of DNA from seven rabbits homozygous for different RLA haplotypes revealed that the germline contains a total of approximately seven class II beta genes, one DQ beta, one DP beta and five DR beta. Extensive allelic polymorphism was identified by RFLP analysis using DQ and DR probes; limited RFLP was observed with DP probes. RFLP analyses allowed us to distinguish two haplotypes which had not been previously distinguished by MLR. Such RFLP analyses will be useful for identifying MHC 'compatible' rabbits for various immunobiological studies, including transplantation.

Animals↗
PubMed2002

Inhibition of class II trans-activator function by HIV-1 tat in mouse cells is independent of competition for binding to cyclin T1.

The Tat trans-activator protein from HIV-1 inhibits the function of the class II trans-activator protein (CIITA), resulting in reduced MHC class II gene transcription in human cells. Tat does so by competing with CIITA for binding to cyclin T1, a component of the transcriptional elongation complex PTEFb. Since Tat does not functionally interact with mouse cyclin T1, we decided to examine the ability of Tat to inhibit CIITA in mouse cells. We found that Tat inhibited CIITA activity in mouse cells though this inhibition was independent of cyclin T1. The inhibition required the transcriptional activation domain of CIITA, but did not involve alterations in MHC class II promoter occupancy. Although Tat blocked the interaction between CIITA protein and human cyclin T1, it had no effect on the binding between CIITA and mouse cyclin T1. Therefore, Tat can inhibit the ability of CIITA to activate transcription of MHC class II genes in mouse cells by a mechanism that appears to be distinct from that proposed for human cells.

3T3 Cells↗
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↗
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↗
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↗
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↗
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↗
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↗