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PubMed2002

Murine NFX.1: isolation and characterization of its messenger RNA, mapping of its chromosomal location and assessment of its developmental expression.

We have previously isolated (by expression cloning) a human cDNA, termed NFX.1, encoding a nucleic acid-binding protein that interacts with the conserved X1 box cis-element first discovered in class II major histocompatibility complex (MHC) genes. Functional studies involving expression of NFX.1 and assessment of expression from class II reporter constructs and endogenous class II MHC genes indicated that the factor could repress transcription of class II MHC genes. Subsequent studies have extended the biological significance of the factor, indicating that it plays an important role in neuronal development. Indeed, the reiterated RING finger motifs in the central domain of the polypeptide strongly suggest that NF-XI is a probable E3 ubiquitin protein ligase, indicating that the protein may have multiple activities. Here we report the cloning of the mouse homologue of the human NfX.1 cDNA: m-Nfx.1. Comparison of the deduced primary sequence of mouse and human NFX.1 proteins shows very high homology and confirms that m-NFX.1 contains the conserved cysteine-rich DNA-binding motif first described in human NFX.1 (95% homology). Expression of MHC class II genes is substantially reduced following expression of m-NFX.1, which confirms that we have isolated the functional murine homologue of human NfX.1 cDNA. Further evidence comes from the mapping of m-Nfx.1 gene to the proximal region of mouse chromosome 4, a region syntenic to the location of human Nfx.1 (short arm of chromosome 9). Expression profiling shows that m-NFX.1 is expressed ubiquitously in both adult tissues and during development, supporting the hypothesis that it may have yet-undescribed roles in distinct biological processes.

Aging↗

PubMed1995

Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis.

Collagen-induced arthritis (CIA) is an animal model of auto immune polyarthritis, sharing similarities with rheumatoid arthritis (RA). Paradoxally, susceptibility to mouse CIA is controlled by the H2A loci (DQ homologous) while RA is linked to HLA.DR genes (H2E homologous). We recently showed that the E beta d molecule prevents CIA development in susceptible H2q mice. We addressed the question of whether H2Eb polymorphism will influence CIA incidence as HLA.DRB1 polymorphism does in RA. In F1 mice, only H2Ebd and H2Ebs molecules showed protection. Using recombinant B10.RDD (Ebd/b) mice, we found that CIA protection was mediated by the first domain of the E beta d molecule. Using peptides covering the third hypervariable region of the E beta chain, we found a perfect correlation between presentation of E beta peptides by the H2Aq molecule and protection on CIA. Therefore, the mechanism by which H2Eb protects against CIA seems to rely on the affinity of E beta peptides for the H2Aq molecule.

Amino Acid Sequence↗

PubMed1996

Structure and organization of pig MHC class II DRB genes: evidence for genetic exchange between loci.

The pig major histocompatibility complex DRB genes were studied by polymerase chain reaction (PCR) amplification of exon 2 from eight domestic pigs and two European wild boars. Sequence comparisons together with a phylogenetic analysis showed the existence of at least three DRB genes of which only one appears to be expressed. The two putative DRB pseudogenes contained deletions in exon 2, making it possible to confirm the presence of three non-allelic DRB genes by analyzing the length polymorphism of the amplified PCR products. The expressed gene shows allelic polymorphism at the same positions as in the human DRB1 gene. In addition, this pig gene shows extensive allelic polymorphism at positions 84-88, whereas, e.g., human DRB genes do not. Surprisingly, the two putative DRB pseudogenes also display a considerable amount of allelic polymorphism, albeit of a different character as compared with the expressed DRB gene. Short stretches of sequences are shared between individual alleles at different loci. These sequence similarities cannot be due to natural selection, since two of the three DRB genes involved are polymorphic pseudogenes constituting allelic series that have diverged after the inactivation event. Instead, the results indicate that the sequences have been exchanged between the DRB genes by intergenic recombination.

Animals↗

PubMed1997

Retinoblastoma protein expression facilitates chromatin remodeling at the HLA-DRA promoter.

The major histocompatibility complex (MHC) class II genes encode a series of heterodimeric cell surface glycoproteins that bind peptide antigen. The MHC class II/peptide complex is bound by the T-cell receptor of CD4(+) T cells, thereby stimulating an immune response. The MHC class II genes are coordinately regulated by conserved promoter elements and are inducible by IFN-gamma. Furthermore, IFN-gamma induction of the MHC class II genes in solid human tumor lines requires retinoblastoma protein (Rb). In vivo footprinting analyses of the HLA-DRA gene, which encodes the heavy chain subunit of the human MHC class II molecule, HLA-DR, revealed that Rb facilitates occupancy of multiple HLA-DRA promoter elements. Detecting the effect of Rb on HLA-DRA promoter occupancy in vivo required IFN-gamma treatment. However, use of a variation on the in vivo footprinting technique, nuclei footprinting, which assays for promoter occupancy in isolated nuclei, revealed that expression of Rb facilitates promoter occupancy even in the absence of IFN-gamma. These results indicate that expression of Rb leads to modification of the chromatin environment of the HLA-DRA promoter independently of transcription.

Chromatin↗

PubMed1995

Nested PCR allows the characterization of TaqI and PstI RFLPs in the second exon of the caprine MHC class II DRB gene.

A nested polymerase chain reaction (PCR) method has been developed to obtain a specific amplification of the second exon of the caprine MHC class II DRB gene. The specificity of this method has been verified by cloning and sequencing the PCR product and comparing its sequence to 21 previously published caprine DRB second exon allelic variants. Nucleotide identity between this sequence (Caae-DRB23) and other caprine DRB alleles ranged between 85.6% (Caae-DRB22) and 96.5% (Caae-DRB5). Caae-DRB5 and Caae-DRB23 sequences diverged in five amino acid substitutions (70, 71, 73, 74, 78), all of them placed at the antigen binding site. Likewise, the restriction polymorphism of the caprine DRB second exon has been analyzed and two different restriction patterns have been found depending on the presence or absence of a TaqI site and a PstI site at positions 122 bp and 241 bp of the PCR product respectively. TaqI and PstI RFLPs were also analyzed in other artiodactyla species. While PstI RFLP was found not only in goats but also in cattle, sheep and pigs, TaqI RFLP was only detected in goats. In all of these species close associations were detected between the presence of TaqI and PstI restriction sites and amino acid substitutions at positions 40 and 78 respectively, suggesting that PCR restriction fragment length polymorphism (RFLP) could be a useful tool in relating amino acid substitutions at critical positions with disease resistance.

Amino Acid Sequence↗

PubMed1997

I-A beta gene expression regulation in macrophages derived from mice susceptible or resistant to infection with M. bovis BCG.

The innate capacity of mice to control mycobacterial multiplication early after infection is controlled by the resistant allele of the Nramp-1/Bcg gene. The Bcg gene seems to be involved in a pathway leading to macrophage activation. It differentially affects the ability of BCG-resistant and -susceptible strains of mice to express important macrophage genes including Major Histocompatibility Complex (MHC) class II genes. An inhibition of Nramp1 gene by Nramp1-ribozyme transfection in macrophages resulted in the impairment of MHC class II gene induction by IFN gamma. In this study, we have investigated the molecular mechanisms involved in IFN-gamma-induced MHC class II expression using macrophages derived from mice resistant or susceptible to mycobacterial infections (B10R and B10S, respectively). We have found that the difference in the IFN gamma-induced Ia surface protein expression between B10R and B10S macrophages correlate with a higher rate of I-A beta gene transcription. We have also studied the binding of proteins prepared from nuclear extracts of non-stimulated and IFN-gamma-stimulated B10R and B10S macrophages to the S, X and Y cis-acting elements of the I-A beta promoter. Differences observed in protein binding to the X box may explain the difference in transcription activation of the I-A beta gene. We have also found that I-A alpha and I-A beta mRNA half-lives measured in IFN gamma-stimulated cells are significantly longer in B10R, compared to B10S macrophages. Overall, our data suggest that both transcriptional and posttranscriptional regulatory mechanisms are responsible for the more efficient expression of I-A beta gene in macrophages carrying a resistant allele of Nramp1 gene.

Animals↗

PubMed1998

A radiation hybrid map of BTA23: identification of a chromosomal rearrangement leading to separation of the cattle MHC class II subregions.

Bovine chromosome 23 (BTA23) contains the bovine major histocompatibility complex (MHC) and is thus of particular interest because of the role of MHC genes in immunity. Previous studies have shown cattle MHC class II genes to be subdivided into two distinct subregions separated by a variable genetic distance of 15-30 cM. To elucidate the genetic events that resulted in the present organization of the class II and other MHC genes, a framework radiation hybrid (RH) map of BTA23 was developed by testing DNA samples from a 5000 rad whole genome RH panel. Twenty-six markers were screened with an average retention frequency of 0.27, ranging from 0.14 to 0.42. Total length of the chromosome was 220 cR5000, with 4.1 cR5000/cM when compared to linkage data. Gene orders for the markers common to both the RH framework map and the consensus framework linkage map are identical. Large centiray intervals, D23S23-D23S7, DYA-D23S24 and CYP21-D23S31, were observed compared to linkage distances. These data may indicate a much larger physical distance or suppression of recombination in the interval separating the class II subregions and also within the class I region than previously estimated. Comparison of 13 Type I genes conserved between BTA23 and the human homolog HSA6p suggests the occurrence of an inversion encompassing the centromeric half of the bovine chromosome, thus explaining the large distance between the bovine class IIa and IIb clusters. These results exemplify the power of RH mapping in solving problems in comparative genomics and evolution. Furthermore, noncongruence of the genetic and physical RH map distances indicates that caution must be observed in using either resource alone in searching for candidate genes controlling traits of economic importance.

Animals↗

PubMed2004

Genetic drift outweighs balancing selection in shaping post-bottleneck major histocompatibility complex variation in New Zealand robins (Petroicidae).

The Chatham Island black robin, Petroica traversi, is a highly inbred, endangered passerine with extremely low levels of variation at hypervariable neutral DNA markers. In this study we investigated variation in major histocompatibility complex (MHC) class II genes in both the black robin and its nonendangered relative, the South Island robin Petroica australis australis. Previous studies have shown that Petroica have at least four expressed class II B MHC genes. In this study, the sequences of introns flanking exon 2 of these loci were characterized to design primers for peptide-binding region (PBR) sequence analysis. Intron sequences were comprised of varying numbers of repeated units, with highly conserved regions immediately flanking exon 2. Polymerase chain reaction primers designed to this region amplified three or four sequences per black robin individual, and eight to 14 sequences per South Island robin individual. MHC genes are fitness-related genes thought to be under balancing selection, so they may be more likely to retain variation in bottlenecked populations. To test this, we compared MHC variation in the black robin with artificially bottlenecked populations of South Island robin, and with their respective source populations, using restriction fragment length polymorphism analyses and DNA sequencing of the PBR. Our results indicate that the black robin is monomorphic at class II B MHC loci, while both source and bottlenecked populations of South Island robin have retained moderate levels of variation. Comparison of MHC variation with minisatellite DNA variation indicates that genetic drift outweighs balancing selection in determining MHC diversity in the bottlenecked populations. However, balancing selection appears to influence MHC diversity over evolutionary timescales, and the effects of gene conversion are evident.

Amino Acid Sequence↗

PubMed1998

Polymorphism of the HLA class II loci in Siberian populations.

The populations that colonized Siberia diverged from one another in the Paleolithic and evolved in isolation until today. These populations are therefore a rich source of information about the conditions under which the initial divergence of modern humans occurred. In the present study we used the HLA system, first, to investigate the evolution of the human major histocompatibility complex (MHC) itself, and second, to reveal the relationships among Siberian populations. We determined allelic frequencies at five HLA class II loci (DRB1, DQA1, DQB1, DPA1, and DPB1) in seven Siberian populations (Ket, Evenk, Koryak, Chukchi, Nivkh, Udege, and Siberian Eskimo) by the combination of single-stranded conformational polymorphism and DNA sequencing analysis. We then used the gene frequency data to deduce the HLA class II haplotypes and their frequencies. Despite high polymorphism at four of the five loci, no new alleles could be detected. This finding is consistent with a conserved evolution of human class II MHC genes. We found a high number of HLA class II haplotypes in Siberian populations. More haplotypes have been found in Siberia than in any other population. Some of the haplotypes are shared with non-Siberian populations, but most of them are new, and some represent "forbidden" combinations of DQA1 and DQB1 alleles. We suggest that a set of "public" haplotypes was brought to Siberia with the colonizers but that most of the new haplotypes were generated in Siberia by recombination and are part of a haplotype pool that is turning over rapidly. The allelic frequencies at the DRB1 locus divide the Siberian populations into eastern and central Siberian branches; only the former shows a clear genealogical relationship to Amerinds.

Alleles↗

PubMed1991

New class II-like genes in the murine MHC.

Major histocompatibility complex (MHC) class I molecules present endogenous antigens to CD8+ (cytotoxic) T cells. MHC class II molecules present primarily exogenously derived antigens to CD4+ T cells. Three new genes (Ma, Mb1 and Mb2) located between the Pb and Ob genes of the murine MHC have properties indicating that they are members of the MHC class II gene family, but they are the most divergent class II members so far identified and are almost as closely related in sequence to class I genes as they are to the known class II genes.

Amino Acid Sequence↗

PubMed2005

The multigenic structure of the MHC locus contributes to positive selection efficiency: a role for MHC class II gene-specific restriction.

The study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of I-E molecule in the thymic cortex increases positive selection efficiency of CD4 cells by approximately 50%. We show that increments in positive selection attributable to either the I-A and I-E genes are not due to increased MHC class II expression in the thymic cortex and are not affected by the number of MHC alleles. Collectively, our findings imply that MHC class II gene-restricted TCR specificities significantly contribute to positive selection efficiency, introducing the notion that multigenic structure of the MHC locus serves to increase selection of non-overlapping TCR repertoires.

Animals↗

PubMed1992

The turkey major histocompatibility complex: identification of class II genotypes by restriction fragment length polymorphism analysis of deoxyribonucleic acid.

Using a chicken Class II MHC clone in Northern blot analysis, tissue-specific expression of turkey Class II MHC genes was observed in the embryonic bursa of Fabricius as well as in the adult spleen. In contrast, there was no detectable expression in the embryonic liver, brain, or spleen. Southern blot analysis of BamHI-digested turkey DNA revealed two restriction fragment length polymorphism (RFLP) patterns that did not deviate significantly from single-gene Mendelian inheritance. Further analysis of PvuII-digested DNA from 325 turkeys showed four distinct RFLP patterns that segregated within the turkey lines studied. Because the chicken Class II MHC clone hybridized specifically to mRNA in immune-associated tissues, and because it identified polymorphisms among turkeys, the chicken clone is suggested to identify four turkey Class II MHC genotypes. The current study provides good evidence that RFLP analysis of DNA can be used as a means for molecular genotyping at the MHC in turkeys.

Animals↗

PubMed1993

Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity.

Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patients with IDDM, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosis, rheumatoid arthritis, and Sjogren's syndrome. Nondiabetic and non-insulin-dependent diabetes mellitus patients served as controls. MHC class I expression was measured with a conformationally dependent monoclonal antibody, W6/32. Freshly prepared PBLs from the autoimmune diseases studied and the corresponding fresh EBV-transformed B cell lines had decreased MHC class I expression compared with PBLs from normal volunteers and non-insulin-dependent (nonautoimmune) diabetic patients. Only 3 of more than 180 donors without IDDM or other clinically recognized autoimmune disease had persistently decreased MHC class I expression; one patient was treated with immunosuppressive drugs, and subsequent screening of the other two patients revealed high titers of autoantibodies, revealing clinically occult autoimmunity. Patients with nonautoimmune inflammation (osteomyelitis or tuberculosis) had normal MHC class I expression. Autoimmune diseases are characterized by decreased expression of MHC class I on lymphocytes. MHC class I expression may be necessary for self-tolerance, and abnormalities in such expression may lead to autoimmunity.

Adult↗

PubMed2001

Combinations of dominant-negative class II transactivator, p300 or CDK9 proteins block the expression of MHC II genes.

The class II transactivator (CIITA) regulates not only the transcription of HLA-DR, -DQ, -DP, but also invariant chain, DMA and DMB genes. A hybrid mutant CIITA protein, which contained residues from positions 302 to 1130 in CIITA fused to the enhanced green fluorescent protein (EdCIITA), inhibited the function of the wild-type protein. EdCIITA extinguished the inducible and constitutive expression of MHC II genes in epithelial cells treated with IFN-gamma and B lymphoblastoid cells respectively. Also, it blocked T cell activation by superantigen. This inhibition correlated with the localization of EdCIITA but not CIITA in the cytoplasm of cells. However, when EdCIITA was co-expressed with a dominant-negative form of the nucleoporin Nup214/CAN, it also accumulated in the nucleus. These data suggest that EdCIITA not only competes with the wild-type protein for the binding to MHC II promoters but sequesters a critical co-factor of CIITA in the cytoplasm. CIITA also recruits the histone acetyltransferase cAMP responsive element binding protein (CREB) binding protein and positive transcription elongation factor b (p-TEFb) for the transcription of MHC II genes. Dominant-negative p300 (DNp300) or CDK9 (DNCDK9) proteins inhibited the function of CIITA and of the DRA promoter. Thus, combinations of EdCIITA and DNp300 and/or DNCDK9 proteins extinguished the transcription of MHC II genes. They might become useful for future genetic therapeutic approaches in organ transplantation and autoimmune diseases.

Animals↗

PubMed1984

The nucleotide sequence of the murine I-E beta b immune response gene: evidence for gene conversion events in class II genes of the major histocompatibility complex.

We have determined the DNA sequence of the murine I-E beta b immune response gene of the major histocompatibility complex (MHC) of the C57BL/10 mouse and compared it with the sequence of allelic I-E and non-allelic I-A genes from the d and k haplotypes. The polymorphic exon sequences which encode the first extracellular globular domain of the E beta domain show approximately 8% nucleotide substitutions between the E beta b and E beta d alleles compared with only approximately 2% substitutions for the intron sequences. This suggests that an active mechanism such as micro gene conversion events drive the accumulation of these mutations in the polymorphic exons. The fact that several of the nucleotide changes are clustered supports this hypothesis. The E beta b and E beta k genes show approximately 2-fold fewer nucleotide substitutions than the E beta d/E beta b pair. The A beta bm12, a mutant I-A beta b gene from the C57BL/6 mouse, has been shown to result from three nucleotide changes clustered in a short region of the beta 1 domain, which suggests that a micro gene conversion event caused this mutation. We show here that the E beta b gene is identical to the non-allelic A beta bm12 DNA sequence in the mutated region and suggest, therefore, that the E beta b gene was the donor sequence for this intergenic transfer of genetic information. Diversity in class II MHC genes appears therefore to be generated, at least in part, by the same mechanism proposed for class I genes: intergenic transfer of short DNA regions between non-allelic genes.

Alleles↗

PubMed1987

Immunogenetics of collagen-induced arthritis.

CIA is a unique experimental model of disease, which may be particularly relevant to the study of RA, since it represents a true autoimmune reaction against a major joint component. Since it represents a model of the association of MHC genes and disease, it has a broad relevance to the study of disease, particularly the contribution of class II MHC genes to autoimmunity. This disease model has been demonstrated in three species, and a marked influence of immunogenetic control is apparent. Native type II collagen is a large protein with a genetically conserved structure, giving rise to a number of cross-reactive antigen epitopes between species. Susceptibility to CIA correlates with an Ir directed against certain epitopes, and this autoimmune response appears to be controlled by MHC-linked genes. In the mouse, susceptibility has been specifically associated with variations in the I-A beta chain. The immunogenetic control may be effected through the T-cell recognition of the collagen molecule, resulting in antibodies and reactive cells with a specificity for native autologous type II collagen. Although the specificity of the anti-type II collagen response is the critical element in the generation of the autoimmune reaction, production of a high level of antibody is important, as well as a complement-fixing isotype. Cell-mediated immunity to type II collagen contributes to the disease chronicity, either through the generation of inappropriate T help, or a suppressor defect, and the production of factors. However, the precise sequence of events, from antigen recognition to joint damage, has yet to be elucidated fully. Some aspects of this experimental model bear a striking resemblence to RA. Hopefully, this experimental model will provide valuable insights into the significance of collagen autoimmunity and the contribution of class II genes to the pathology of arthritic disease.

Animals↗

PubMed1992

Single base pair substitutions within the HLA-DRA gene promoter separate the functions of the X1 and X2 boxes.

The class II MHC genes are expressed on the surfaces of B cells, activated T cells, and macrophages and may be induced in other cell types by IFN-gamma. The control of class II gene expression has been shown to be mediated by a series of conserved cis-acting sequences (W, X1, X2, and Y boxes) located immediately 5' to the genes. Although these sequences are conserved, the bp that are important for transcriptional regulation have yet to be identified. To address this issue with regard to the MHC gene HLA-DRA, a series of single bp substitutions spanning the conserved upstream sequences was created and analyzed for their effects on transcription in both B cells and IFN-gamma-treated fibroblasts. In addition, the effects of X1 and X2 box mutations on DNA/protein interactions were examined and compared to the transcriptional data. The results of these studies show that each of the conserved elements participate in maximal expression in B cells and that W, X1, and X2 boxes are important for IFN-gamma induction and expression in fibroblasts. Interestingly, some of the bp changes that altered B cell expression did not alter expression and IFN-gamma induction in fibroblasts, suggesting that different or altered factors control the expression of these genes in the different cell types. Mutant templates designed to eliminate the binding of X1- and X2-specific DNA binding proteins in vivo suggest that these elements and their factors may interact to promote transcription.

B-Lymphocytes↗

PubMed1999

Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta.

The major histocompatibility complex (MHC) class II transactivator (CIITA) is the master regulatory factor required for appropriate expression of class II MHC genes. Understanding the expression of CIITA is key to understanding the regulation of class II MHC genes. This report describes the independent regulation of two distinct CIITA promoters by cytokines with opposing functions, gamma interferon (IFN-gamma) and transforming growth factor beta (TGF-beta). A functional analysis of deletion mutations of the upstream promoter (promoter III) identified an IFN-gamma-responsive region located approximately 5 kb from the transcriptional start site. An in vivo DNase I hypersensitivity analysis detected a hypersensitive site in this area which supports the relevance of this region. When the downstream promoter (promoter IV) was studied by in vivo genomic footprinting, IFN-gamma-induced changes at putative binding sites for STAT1, interferon regulatory factor 1 (IRF-1), and E-box proteins were seen. Gel shift and supershift analyses for IRF-1 confirmed the in vivo footprint results. The role of the IFN-gamma-inducible transcription factor STAT1 was examined functionally. Although both promoters were controlled by STAT1, promoter-specific regulation was exhibited. The IFN-gamma response of promoter III was completely dependent on STAT1 and not IRF-1, while promoter IV was partially activated by IRF-1 in the total absence of STAT1 expression. While both promoters were affected by TGF-beta, activation of promoter III by IFN-gamma was more severely diminished by TGF-beta treatment. The differential control of CIITA promoters by TGF-beta, IRF-1, and STAT1 may be important in refining regulation of class II MHC genes in different cell types and under different stimulatory conditions.

Base Sequence↗