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Query: UNIPROT:P06889 (Mol)
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Reversal of autoimmune disease with monoclonal antibodies to polymorphic determinants associated with class II gene products of the major histocompatibility complex (MHC) and to T-cell receptor variable region segments has been demonstrated in animal models. Recent studies have shown that it is also possible to use mutant peptides to block recognition of self-antigen associated with MHC by T-cells that mediate autoimmune disease. These mutant peptides have been used to prevent the model autoimmune condition experimental allergic encephalomyelitis. The possibility of extending these approaches to human disease is discussed.
Mol Biol Med 1990 Aug
PMID:Development of antigen-specific therapies for autoimmune disease. 223 45

The human major histocompatibility complex contains approximately 20 class I genes, pseudogenes, and gene fragments. These include the genes for the three major transplantation antigens, HLA-A, HLA-B, and HLA-C, as well as a number of other genes or pseudogenes of unknown biological significance. Most of the latter have C + G-rich sequences in their 5' ends that are unmethylated in the B-lymphoblastoid cell line 3.1.0. We investigated one of these genes, HLA-H, in more detail. The gene is, overall, strongly homologous in sequence to HLA-A but differs in several potentially significant ways, including changes in conserved promoter sequences, a single-base deletion producing a translation termination codon in exon 4, and a region of sequence divergence downstream of the transcribed portion of the gene. Nevertheless, mouse L cells transfected with the gene accumulated small amounts of apparently full-length polyadenylated RNA. A portion of this RNA begins at the transcription site predicted by analogy to certain class I cDNA clones, while another portion appears to begin shortly upstream. L cells transfected with a hybrid gene containing the first three exons of HLA-H and the last five exons of HLA-B27 accumulated full-length HLA transcripts at the same level as cells transfected with an HLA-B27 gene; both levels are at least 15- to 20-fold higher than that directed by HLA-H alone. In addition, we isolated a cDNA clone for HLA-H that contains a portion of intron 3 attached to a normally spliced sequence comprising exons 4 through 8. These results suggest that low levels of translatable mRNA for the truncated class I heavy chain encoded by HLA-H are produced under physiologic circumstances and that sequences 3' of intron 3 decrease the levels of stable transcripts.
Mol Cell Biol 1990 Jan
PMID:Transcription analysis, physical mapping, and molecular characterization of a nonclassical human leukocyte antigen class I gene. 229 3

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.
Mol Cell Biol 1990 Mar
PMID:Two DNA-binding proteins discriminate between the promoters of different members of the major histocompatibility complex class II multigene family. 230 71

Anti-H-2.33 [(B10.D2 X A)F1 anti-B10.A(5R)], which predominantly contains antibodies recognizing H-2Kb and IAb molecules, was found to be cytotoxic against DMLM 1678, a B-cell leukemia of SJL/J (H-2s) origin. The antiserum precipitated a typical class I (H-2-like) molecule from labeled tumor cell preparations as judged by molecular mass, papain susceptibility and association with beta 2-microglobulin. Sequential immunoprecipitation studies revealed that it was distinct from either H-2Ks or H-2Ds, the 2 molecules expressing the private antigens of the H-2s haplotype. Absorption analysis using congenic mice mapped the gene controlling the expression of the novel molecule telomeric to the S-region within the major histocompatibility complex.
Mol Immunol 1985 Aug
PMID:A novel H-2s class I molecule expressed on a B-cell leukemia from SJL/J mice. 241 49

Molecular analysis of the heterodimeric T-cell antigen receptor of insulin-specific class II-restricted T-cell hybridomas (THys) derived from C57BL/6 (B6) wild-type and B6.C-H-2bm12 (bm12) mutant mice revealed that such T cells use a diverse V gene repertoire. Analysis of three THys that use related V genes, however, showed a number of novel features. Two THys that share major histocompatibility complex restriction use V alpha genes that are 98.6% homologous. Two THys sharing the same antigen fine specificity use a particular germ line V beta D beta J beta combination. A 21-base-pair deletion in the 5' segment of the J beta gene occurs in one THy, suggesting a novel mechanism for generating diversity in T-cell antigen receptor beta genes. The first amino acid encoded by N sequences at the V-D junction is conserved in a pair of T cells which recognize identical antigenic epitopes. The implications of these findings for the structural mechanisms underlying major histocompatibility complex-restricted antigen-specific T-cell recognition are discussed.
Mol Cell Biol 1987 May
PMID:Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice. 243 99

Moloney murine leukemia virus (M-MuLV) and Moloney murine sarcoma virus (M-MSV) exert a regulatory effect on the class I genes of the murine major histocompatibility complex (MHC). We have previously shown that M-MuLV infection of mouse fibroblasts results in a substantial increase in cell surface expression of H-2K, H-2D, and H-2L proteins, whereas M-MSV, upon coinfection of the same cells, is apparently able to override the MuLV-induced increase in H-2 expression. As a result of this modulation, immune recognition of the infected cells is profoundly altered. Our efforts have been directed toward elucidating the molecular basis for this phenomenon. We report here that stimulation of interferon production as a result of infection with MuLV does not occur and, therefore, is not the cause of MuLV-induced enhancement of MHC expression. Control of H-2 class I and beta 2-microglobulin gene expression by M-MuLV, and probably by M-MSV, takes place at the transcriptional level as indicated by nuclear runoff studies and analysis of steady-state mRNA levels. Our demonstration that M-MuLV controls expression of widely separated endogenous cellular genes (those coding for H-2D, H-2K, H-2L, and beta 2-microglobulin), transfected class I MHC genes, and unintegrated chimeric genes consisting of fragments of class I MHC genes linked to sequences encoding a procaryotic enzyme, chloramphenicol acetyltransferase, suggests that M-MuLV exerts its effect in trans and not by proviral integration in the vicinity of the H-2 gene complex. Finally, we show that the sequences of at least one MHC gene, which are responsive to trans regulation by M-MuLV, lie within 1.2 kilobases upstream of the initiation codon for that gene.
Mol Cell Biol 1987 Jul
PMID:Murine retroviruses control class I major histocompatibility antigen gene expression via a trans effect at the transcriptional level. 244 Dec 41

The retrotransposon micropia was first described from Y-chromosomal fertility genes of Drosophila hydei. Screening a Drosophila melanogaster genomic library yielded several clones representing micropia elements in D. melanogaster. The DNA sequences of two elements from D. hydei (micropia-DhMiF2 and micropia-DhMiF8) and two elements from D. melanogaster (micropia-Dm2 and micropia-Dm11) permitted a detailed analysis of the spatial organization of micropia constituents. Micropia represents the typical gene organization represented by "core"-protein domains followed by a protease, reverse transcriptase, RNase and integrase domain. New features of the micropia family compared with other retrotransposons are: (1) a region of similarity to class I major histocompatibility complex antigens of mammals; (2) only one main open reading frame of about 4000 bases length; (3) a non-protein-coding region of about 500 base-pairs length between the 3' end of the open reading frame and the 5' start of the 3' long terminal repeat. This region includes 32 base-pair tandem repeats; (4) within the long terminal repeats, 82 base-pair tandem repeats with four potential ecdysteroid receptor binding sites. Because micropia combines many evolutionary features of different viruses, non-viral transposable elements, chromosomal genes and repetitive sequence organizations, this retrotransposon may be seen as a "minigenome" reflecting evolutionary principles of the construction of genomic components.
J Mol Biol 1988 Nov 20
PMID:Micropia: a retrotransposon of Drosophila combining structural features of DNA viruses, retroviruses and non-viral transposable elements. 246 89

Primary cultures are introduced as a method for an immunocytochemical and functional characterization of epithelial cells (ECs) from human thymic epithelial tumors. Neoplastic ECs were obtained after enzymatic digestion of the tumor tissue with dispase. The ECs were kept in culture for up to 1.5 months. Over this period a progressive decline in their proliferation rate was observed. In all five cases studied, ECs showed a co-expression of keratin and vimentin intermediate filaments in vitro as well as strong expression of major histocompatibility complex (MHC)-class I antigens and a progressive loss of MHC-class II antigens. Acetylcholine receptor (AchR)-epitopes were detected immunohistochemically by using monoclonal antibodies (mAbs) to the cytoplasmic site of the alpha-chain if the AchR. Epitopes were found in three of five thymomas in vivo and to a varying degree in all five cases in vitro.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Primary cultures of human thymic epithelial tumors. Morphological and immunocytochemical characterization. 247 51

Proteolytic processing of specific antigen was studied using Epstein Barr virus transformed B-lymphoblastoid cells expressing membrane IgG against tetanus toxin. As previously reported (Watts, C., and H.W. Davidson. 1988. EMBO (Eur. Mol. Biol. Organ.) J. 7:1937-1945), receptor-mediated endocytosis of monovalent antigen bound at 0 degrees C began immediately upon shifting the cells to 37 degrees C. In contrast, degradation of antigen, assessed either by the release of acid-soluble radiolabel into the incubation medium, or by SDS-PAGE analysis of total cell-associated antigen, proceeded after a lag of 10-20 min. Degradation was abolished by exposure of the cells to metabolic inhibitors, or by incubation at 20 degrees C, and inhibited in a dose-dependent fashion by chloroquine and by the lysosomal protease inhibitors leupeptin, E-64, and pepstatin A. Analysis of the cell-associated radiolabel by SDS-PAGE and autoradiography after incubations at 37 degrees C revealed the time-dependent generation of distinct antigen fragments. Virtually quantitative immunoprecipitation of these fragments was obtained using a monoclonal anti-human IgG antibody, indicating that the antigen/mIg complex is the initial substrate for processing. We show that the pattern of fragmentation observed varies from one B cell line to another (a) depending on the epitope through which the antigen is bound and endocytosed and (b) depending on whether additional epitopes in the antigen are complexed with anti-tetanus Fabs. The implications of these results for the presentation of major histocompatibility complex restricted antigen fragments, and for intracellular trafficking of ligand/receptor complexes are discussed.
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PMID:Epitope-directed processing of specific antigen by B lymphocytes. 247 83

Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant decrease in mRNA encoding the Ia proteins which persists for at least 18 h. Within the upstream regulatory region of A alpha k, an NF-kappa B-like binding site is present. We have identified an LPS-induced DNA-binding protein in extracts from athymic mice whose spleens consist predominantly of B cells. Binding activity is present in low levels in unstimulated spleen cells and is increased by LPS treatment. This protein binds to two sites in a regulatory region of the Ia A alpha k gene, one of which contains the NF-kappa B-like binding site. DNA fragments containing these sites cross-compete for protein binding. Analysis by DNase I footprinting identified a target binding sequence, named the LPS-responsive element. Although this target sequence contains an NF-kappa B-like binding site, competition with a mutant oligonucleotide demonstrated that bases critical for NF-kappa B binding are not required for binding of the LPS-inducible protein. Therefore, we hypothesized that this inducible protein represents a new mediator of LPS action, distinct from NF-kappa B, and may be one mechanism to account for the decrease in mRNA encoding the Ia proteins.
Mol Cell Biol 1989 Aug
PMID:A lipopolysaccharide-induced DNA-binding protein for a class II gene in B cells is distinct from NF-kappa B. 247 82


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