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PubMed2005

The MHC class II transactivator (CIITA) mRNA stability is critical for the HLA class II gene expression in myelomonocytic cells.

The human promyelocytic U937 cells express detectable levels of MHC class II (MHC-II) molecules. Treatment with 12-o--tetradecanoyl phorbol 13-acetate (TPA), inducing macrophage-like differentiation, produces a dramatic decrease of MHC-II expression as result of down-modulation of the activation of immune response gene 1 (AIR-1)-encoded MHC-II transactivator (CIITA). This event is specific, as MHC class I remains unaffected. Similar results are observed with U937 cells expressing an exogenous full-length CIITA. Molecular studies demonstrate that TPA treatment affects the stability of CIITA mRNA rather than CIITA transcription. Importantly, cis-acting elements within the distal 650 bp of the 1035-bp 3' untranslated region (3'UTR, nucleotides 3509-4543) are associated to transcript instability. Transcription inhibitors actinomycin D and 5,6-dichlororibofuranosyl benzimidazole, and the translation inhibitor cycloheximide significantly rescue the accumulation of CIITA mRNA in TPA-treated cells. A similar effect is also observed after treatment with staurosporine and the PKC-specific inhibitor GF109203X. The instability of CIITA mRNA produced by TPA in U937 cells is not seen in B cells. These results demonstrate the presence of an additional level of control of MHC-II expression in the macrophage cell lineage depending upon the control of CIITA mRNA stability, most likely mediated by differentiation-induced, 3'UTR-interacting factors which require kinase activity for their destabilizing function.

3' Untranslated Regions↗

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↗

PubMed1993

Class I associations and frequencies of class II HLA-DRB alleles by RFLP analysis in children with rheumatoid-factor-negative juvenile chronic arthritis.

A total of 94 patients with juvenile chronic arthritis (JCA) was tested for HLA class I by serology and for class II by RFLP typing. Early onset JCA (EOPA) is associated with HLA-A2, DR5 and DR8 in both males and females. The combination (joint occurrence) of these JCA associated alleles (A2, DR5, DR8) is frequently seen in patients with chronic iridocyclitis. Late onset pauciarticular disease has an increased frequency of HLA-B27, especially in males. Our data confirm that polyarticular JCA with early childhood onset (< or = 4 years) is associated with DR5 and DR8 and has a different immunogenetic background from polyarticular JCA with later childhood (> 4 years) onset (associated with DR4).

Adolescent↗

PubMed1985

Structure of a functional rabbit class I MHC gene: similarity to human class I genes.

Studies of rabbit major histocompatibility complex proteins have suggested that rabbits express only a single class I antigen, in contrast to most mouse strains (H-2K, D, and L) and man (HLA-A, -B, and -C), which express three. To explore the significance and the molecular basis of this apparent species difference, we have characterized the expressed class I protein and a corresponding cDNA clone from the rabbit cell line RL-5, which is derived from the inbred B/J rabbit strain. As an extension of these analyses, this report documents the genomic sequence of a gene, designated 19-1, which encodes the same histocompatibility antigen expressed in RL-5. The availability of the corresponding full-length cDNA and amino-terminal protein sequence indicates the fully functional nature of the 19-1 gene and allows presumptive assignment of the transcription start site and delineation of exon/intron boundaries. Comparisons of the rabbit gene with homologous human and mouse sequences reveal a striking similarity between 19-1 and human genes in both exon/intron organization and specific nucleotide sequences; this close similarity allows tentative identification of previously unrecognized transcriptional start sites in the human genes.

Animals↗

PubMed1988

Class II genes of miniature swine. I. Class II gene characterization by RFLP and by isolation from a genomic library.

Class II genes of miniature swine have been characterized by restriction fragment length polymorphism (RFLP) analysis and by analysis of a series of clones isolated from a lymphocyte genomic library. For RFLP analysis, DNA samples from three independent major histocompatibility complex homozygous lines and three intra-MHC recombinant lines were digested with a variety of restriction enzymes and analyzed in Southern blots using human cDNA probes for DP, DQ, DR, and DZ alpha genes, and DP, DQ, DR, and DO beta genes. One, or at most two, unique fragments were detected by hybridization with each of the human alpha probes tested. In contrast, multiple bands (five to six for most enzymes examined) were detected by each of the human beta probes tested, the majority of which were found to cross-react with at least three of these probes under conditions of moderate stringency. Genomic DNA from the SLAc haplotype was cloned into an EMBL-3 bacteriophage vector, and the corresponding genomic library was screened with each of these human cDNA probes. The class II genes thereby isolated from this library showed characteristics consistent with those anticipated from the RFLP analysis. Thus, unique alpha genes were obtained which showed no evidence of cross-hybridization, while beta genes showed extensive cross-hybridization and were frequently detected in the library by more than one human beta gene probe. These data are consistent with early evolutionary divergence of alpha genes, prior to mammalian speciation, and with continuing evolution of beta genes, with possible shared usage of these genes by different alpha loci. The data also imply that alpha genes can readily be assigned to loci homologous to their human counterparts, but that beta genes will require further mapping and/or sequence analysis to confirm assignments.

Animals↗

PubMed1976

Social class and group therapy in a working class population.

In a clinic in which the assignment of patients to therapy was demonstrated as not affected by social class and in which no patient was excluded as unsuitable, 45% of those referred to group therapy stayed 2 or more years. The only category that consistently correlated with not remaining in treatment was that of unemployment. When unemployed persons were included there appeared to be a significant correlation between a stay of 2 or more years and social class. When only employed persons were considered, this significance disappeared.

Adolescent↗

PubMed1995

The human antibody repertoire: heavy and light chain variable region gene usage in six alloantibodies specific for human HLA class I and class II alloantigens.

Peripheral blood B lymphocytes have been isolated from healthy individuals who were immunized with lymphocytes from HLA-incompatible donors and transformed with Epstein-Barr virus to produce human monoclonal cell lines specific for human HLA molecules. The cell lines have been previously characterized and are known to bind to various class I and class II alloantigens. In this report we describe the molecular characterization of the heavy and light chain variable region gene segments that are utilized by these monoclonal antibodies. Using the polymerase chain reaction and primer pairs specific for the respective constant region and VH or VL family, rearranged variable region gene segments were amplified from cDNA from individual cell lines. Products were then subcloned, sequenced and analysed for gene usage and apparent somatic mutation. The results show that the VH3 gene family predominates in a group of six heavy chains (four out of six) with one VH1 and one VH4 gene segment. The light chain variable region gene family usage is more diverse with 2 V kappa 3, 1 V kappa 1, 2 V lambda 2 and 1 V lambda 3. The extent of apparent somatic mutation is minimal, relative to our previous observations in a group of high affinity human monoclonal antibodies specific for pathogenic organisms.

Amino Acid Sequence↗

PubMed1999

Serum levels of beta-2-microglobulin-free heavy chain of HLA class I antigen in healthy individuals: relationship to their class I allotype.

An ELISA-based double determinant immunoassay has been established to measure the soluble beta2-microglobulin (beta2m)-free heavy chain (FHC) of the HLA-B, -C (and HLA-A3, -A28 and -A30) class I molecular complex in sera from 212 HLA-typed healthy unrelated individuals. FHC was calculated by means of a standard curve constructed using serial concentrations of beta2m-associated HLA-class I heavy chain (HLA-I)/FHC purified from cultured human lymphoid cell C1R-sB7-supernatant. The mean FHC concentration (+/-SD) was 0.25 mg/l (+/-0.2). Its median concentration did not statistically differ between males and females, though the male/female ratio was greater in the high secretor (FHC >0.45 mg/l; mean + 1SD) than in the low secretor group (FHC < 0.05 mg/l; mean - 1SD). FHC < 0.05 mg/l was statistically (Fisher's exact test) associated with HLA-B17 (p = 0.003); FHC > 0.45 mg/l was statistically associated with HLA-B35 (p = 0.003) and -Cw4 (p = 0.002). None of these allele-positive groups showed a mean FHC concentration 1.5 times higher than that of the corresponding allele-negative ones. This allotype-dependent HLA-B and C FHC enhancement was less marked than that previously reported for HLA-I in individuals carrying HLA-A9 (and its splits). These results indicate that FHC could be a more valuable marker when its levels are compared among individuals carrying different allotypes. Moreover the lack of correlation between FHC and HLA-I levels measured in 52 HLA-A3, -A28 or -A30 positive individuals suggests that the two molecules may be regulated by different metabolic pathways and their serum expression may have a different biological significance.

Alleles↗

PubMed2001

Pathogenesis of mousepox in H-2(d) mice: evidence for MHC class I-restricted CD8(+) and MHC class II-restricted CD4(+) CTL antiviral activity in the lymph nodes, spleen and skin, but not in the conjunctivae.

Genetically sensitive mice (i.e. H-2(d) haplotype) infected with a natural mouse pathogen named ectromelia virus (EV) can develop a mousepox. Virus replicates well in the skin, next in the draining lymph nodes (DLNs) and then in the spleen and liver, where it may induce extensive necrosis with strong inflammatory reaction. It is well known from the studies defined on some other viruses that a correlation, functional link and powerful help exist between MHC class I-restricted CD8(+) and MHC class II-restricted CD4(+) virus-specific cytotoxic T lymphocytes (CTLs). However, in the case of mousepox the role of CD4(+) CTLs is still controversial and some reports support the notion that induction of EV-specific CD4(+) CTLs is nonessential for the generation of virus-specific immune response. Consequently, this study was designed to evaluate EV-specific CD8(+) and CD4(+) CTL activity in the DLNs, spleen, skin and conjunctivae of BALB/c (H-2(d)) mice at 7 and 14 days p.i. with Moscow strain of EV. By using bulk cytotoxicity assay and immunosurgery of effector T cells with mAb specific for CD4(+) and/or CD8(+) T cells our data show that EV-specific CD8(+) CTLs predominated in DLNs and spleen at 7 days (67 and 66% of total CTLs, respectively) and 14 days p.i. (63 and 69% of total CTLs, respectively). In contrast, we found that EV clearance from the cutaneous lesions during mousepox is CD4(+) CTL-dependent at 7 days p.i. (59% of total CTLs), whereas at 14 days p.i. CD8(+) CTLs predominated in the epidermis, accounting for 72% of the total EV-specific CTLs. Our studies showed that the population of EV-specific CTLs is heterogeneous and contains cells of both phenotypes: CD8(+) and CD4(+). However, these effector cells did not express a similar tendency in cytotoxic activity in the DLNs, spleen and skin in comparison to the conjunctivae where EV-specific CD8(+) and CD4(+) CTLs were not detected at 7 days p.i. and at peak of mousepox conjunctivitis (14 days p.i.). Our results are discussed in terms of the value of EV to study antiviral CTL responses in the genetically susceptible host.

Animals↗

PubMed2002

Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA.

Familial aggregation, high relative risk to siblings, and segregation analysis, suggest genetic control of visceral leishmaniasis in Brazil. Class II gene effects in mice, and high circulating tumour necrosis factor alpha in humans, provide reasons to target HLA. Fifteen polymorphic markers across 1.03 Mb (DQB1 to TNFa) were genotyped (87 multicase families; 638 individuals). Model-based parametric analyses using single-point combined segregation and linkage in COMDS, or multi-point linkage in ALLEGRO, failed to detect linkage. Model-free nonparametric affected sibling pair (SPLINK) or NPL(all) score (ALLEGRO) analyses also failed to detect linkage. Information content mapping confirmed sufficient marker information to detect linkage. Analysis of simulated data sets demonstrated that these families had 100% power to detect NPL(all) scores of 5 to 6 (>LOD4; P < 0.00001) over the range (7% to 61%) of age-related penetrances for a disease susceptibility gene. The extended transmission disequilibrium test (TDT) showed no consistent allelic associations between disease and the 15 loci. TDT also failed to detect significant associations between extended haplotypes and disease, consistent with failure to detect significant linkage disequilibrium across the region. Linkage disequilibrium between adjacent groups of markers (HLADQ/DR; 82-1/82-3/-238bpTNFA; LTA/62/TNFa) was not accompanied by significant global haplotype TDT associations with disease. The data suggest that class II/III regions of HLA do not contain major disease gene(s) for visceral leishmaniasis in Brazil.

Animals↗

PubMed1988

Conserved upstream sequences of human class II major histocompatibility genes enhance expression of class II genes in wild-type but not mutant B-cell lines.

Class II major histocompatibility genes contain a conserved upstream sequence (CUS) that is important in the expression of these genes. This region has been divided into two major elements, the X box and the Y box. The ability of these elements to mediate transcription of a heterologous promoter was assayed upon transfection into a B-cell line (Raji), a class II-specific trans-acting factor-deficient B-cell line (RJ2.2.5 cells), and a T-cell line (Jurkat). The results showed that the X box element was responsible for directing tissue-specific expression when Raji cells were compared to Jurkat cells. The X box could not direct expression of the heterologous promoter in the trans-acting factor-deficient cell line, indicating that the X box is an ultimate target of the missing or defective factor in the RJ2.2.5 cell line. The Y box directed an equal but extremely low level of transcription in this system in both the mutant and wild-type B-cell lines, suggesting that this element is not involved in B-cell expression or as a target of the mutant factor.

B-Lymphocytes↗

PubMed1998

Identification of HLA class II-restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II-deficient mice.

T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4(+) human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab0) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/DQA*0301 (DQ8) alleles. In these animals, all CD4(+) T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis, and only a single hsp65 epitope, p1-20. DR3.Ab0 mice, immunized with bacillus Calmette-Guérin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab0 mice mounted a strong response to bacillus Calmette-Guérin but not to p1-20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171-200, 311-340, and 411-440. DR3.Ab0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51-70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab0 with the immunodominant peptides p1-20 and p51-70 induced T cell reactivity to M. tuberculosis. Thus, for two different Ags, T cells from DR3.Ab0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.

Amino Acid Sequence↗

PubMed1984

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12 neonatal females. Results of double thymus (B6 and bm12) engraftment excluded the possibility that this latter effect was caused by suppression. In addition, athymic bm1 mice were engrafted with thymuses from either B6 (Sendai CTL responder type) or syngeneic bm1 neonates (Sendai CTL nonresponder type). Again, both types of neonate thymuses restored T cell competence as measured by MHC/CTL responses to allogeneic cells. However, neither responder B6 nor nonresponder bm1 neonate thymus grafts allowed maturation of Sendai-specific CTL. In conclusion, the thymus dictates MHC specificity and immune response gene phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.

Animals↗

PubMed1990

Specialized functions of MHC class I molecules. I. An N-formyl peptide receptor is required for construction of the class I antigen Mta.

Maternally transmitted factor (Mtf) is a mitochondrial gene that controls the antigenic polymorphism of the MHC class I maternally transmitted antigen (Mta). Synthetic peptides from the NH2 terminus of the mitochondrially encoded NADH dehydrogenase subunit 1 (ND1) mimic Mtf peptide activity in an allele-specific manner. We show that the minimal ND1-alpha peptide length recognized by Mtaa-specific polyclonal CTLs was between 8 and 12 amino acids, while some Mtaa-specific CTL clones recognized a six amino acid peptide. The N-formyl group at the NH2 terminus of ND1 was essential for Mta activity. Competition experiments using N-substituted ND1-alpha peptides showed that an N-formyl peptide receptor on the target cell, which differs from the chemotactic peptide receptor, was required for Mta expression. The specificity of this receptor can account for the distinct immune restriction of Mta in which Mtf peptides are uniquely restricted by Hmt. It is possible that the Hmt gene product is the N-formyl peptide receptor itself and that it represents a class I antigen presentation molecule specialized for binding, transport, and immune presentation of N-formyl-peptide antigens of mitochondrial and prokaryotic origin.

Animals↗

PubMed1990

MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation.

Seven synthetic peptides corresponding to the polymorphic regions of the alpha and beta chains of the I-Ak molecule were examined for their ability to inhibit the presentation of foreign antigens to antigen-specific, I-A-restricted T cell hybridomas. Two of the peptides, representing the sequences found in the first and third polymorphic regions (PMR) of the A alpha k chain (alpha k-1 and alpha k-3) were capable of inhibiting the presentation of three different HEL-derived peptide antigens to their appropriate T cells. In addition, the alpha k-1 peptide inhibited the presentation of the OVA(323-339) immunodominant peptide to the I-Ad-restricted T cell hybridomas specific for it. Prepulsing experiments demonstrated that the PMR peptides were interacting with the APC and not with the T cell hybridomas. These observations were confirmed and extended by the demonstration that the alpha k-1 and alpha k-3 peptides blocked the direct binding of HEL(46-61) to purified I-Ak and that the alpha k-1 peptide blocked the binding of OVA(323-339) to I-Ad. The binding competition experiments suggest that the alpha k-1 peptide binds to the I-Ak molecule from which it was derived with a Kd approximately 10(-5) M, while the alpha k-3 peptide binds slightly less well. These combined data, suggesting that class II-derived peptides can bind to MHC class II molecules, including the autologous molecule from which they are derived, have important implications for the molecular basis of alloreactivity and autoreactivity. Further, they suggest a possible mechanism by which selecting elements, involving only MHC molecules, may be generated in the thymus.

Amino Acid Sequence↗

PubMed2001

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

Animals↗

PubMed2003

MHC class II enhanceosome: how is the class II transactivator recruited to DNA-bound activators?

MHC class II (MHCII) determinants play a crucial role in the immune response by presenting antigenic peptides to T cells. Their expression is controlled from compact promoters at the transcriptional level. Pre-assembled regulatory factor X (RFX) and nuclear factor Y (NFY) complexes form a platform on DNA. The class II transactivator (CIITA) can then be recruited through multiple protein-protein interactions. In this report, we defined domains of CIITA that are responsible for its interactions with these DNA-bound factors. Furthermore, using DNA-affinity precipitation, we demonstrated that although CIITA binds at least five activators, RFX5, RFXAP, RFXANK/B, NFYB and NFYC, its assembly on the promoter requires the addition of nuclear extracts. We conclude that not only does the platform bind DNA via multiple, spatially constrained nteractions, but that it can recruit only modified and/or complexed CIITA to MHCII promoters.

Amino Acid Sequence↗

PubMed1988

CpG islands and HTF islands in the HLA class I region: investigation of the methylation status of class I genes leads to precise physical mapping of the HLA-B and -C genes.

We have investigated the accessibility of the 5' CpG rich sequences (CpG islands) present in the 5' region of most if not all HLA class I genes to methylation sensitive rare cutter enzymes. We show that for HLA-A, -B, -C genes and a few other (but not all) class I sequences these CpG islands are unmethylated and therefore constitute HTF islands (CpG rich, unmethylated regions of DNA, usually associated with expressed genes). We then map precisely the HTF islands of the HLA-B and HLA-C genes and determine that they are separated by 130 Kb (in agreement with genetic data) and that these two genes are in the same transcriptional orientation on the chromosome.

Chromosome Mapping↗