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PubMed1979

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene.

Cytotoxic T lymphocytes (CTLs) can be generated if spleen cells from reovirus-infected mice are stimulated in vitro with syngeneic reovirus-infected cells. These cytolytic effector cells demonstrate: (i) serotype specificity (i.e., maximal cytolytic activity is observed on target cells infected with the serotype used to induce the CTLs) and (ii) H-2 restriction. The SI gene was shown to be the predominant viral gene determining the specificity of the cytotoxic T cells. This genome segment has previously been demonstrated to encode the viral hemagglutinin and determines reovirus cell tropism in the nervous system.

Animals↗
PubMed2000

Risk factors for inhibitor development in hemophilia A.

The development of anti-factor-VIII-antibodies represents the most serious complication of factor VIII concentrate therapy, affecting about 30% of patients with severe hemophilia A. The genetics of the patients, comprising the factor VIII gene mutation and the immune response genes (MHC), have been shown to influence the risk of inhibitor formation. Severe molecular defects within the factor VIII gene, such as intron 22 inversions, nonsense mutations and large deletions, are associated with a 7 to 10 times higher inhibitor prevalence than less severe molecular gene defects such as missense mutations. Unexpectedly, frame shift deletions within runs of adenine nucleotides showed a low inhibitor risk, although most of them result in a stop codon. The explanation of this phenomenon is the restoration of the reading frame in some factor VIII molecules by slippage errors of the polymerase enzymes. Within most mutation types subgroups with significantly different inhibitor risks can be defined, e.g. multi domain vs. single domain large deletions, yielding a total of 10 groups with different risks of inhibitor formation. Alleles of MHC class II genes showed a less impressive influence on inhibitor development. In two studies of patients with a homogenous factor VIII gene mutation, the alleles DQA0102, DQB0602 and DR15 occurred more frequently in patients with inhibitor than without inhibitor (relative risks ranging from 1.9 to 4.0) and therefore could be assigned as risk alleles. Inflammatory processes in early childhood are under discussion as being an environmental influence factor that may modify the immune response to a foreign antigen. Fixing the genetic predisposition by gene analysis will be one important tool in the future to assess further parameters that might influence inhibitor formation.

Genetic Predisposition to Disease↗
PubMed1999

Characterization of 18 new BoLA-DRB3 alleles.

The second exon of the bovine MHC class II DRB3 gene was amplified by polymerase chain reaction (PCR) from DNA samples of 568 zebu Brahman cattle (Bos indicus) from Martinique (French West Indies). Cloning of these PCR products allowed the isolation of both alleles from each animal, which were characterized by the PCR-restriction fragment length polymorphism (RFLP) technique using the restriction enzymes RsaI, BstYI and HaeIII. Four new PCR-RFLP patterns were obtained by digestion with RsaI. These patterns were named 'v', 'w', 'x' and 'y' continuing the accepted nomenclature. Sequencing of each allele allowed the identification of 18 new BoLA-DRB3 exon 2 nucleotide sequences and their deduced amino acid sequences.

Alleles↗
PubMed1984

Delineation of an immunoregulatory amplifier population recognizing autologous Ia molecules. Analysis with human T cell clones.

Autoreactive T lymphocytes were generated by culturing human peripheral blood mononuclear cells with an antigen-specific major histocompatibility complex (MHC)-restricted autologous inducer T cell, termed RW17C and subsequently cloned in soft agar. The majority of such clones (AC1-13) expressed the T3+T4+T8-T11+Ia+ phenotype and were directed at autologous class II MHC gene products found on B cells, macrophages, and B lymphoblastoid cells as judged by their proliferative response to the latter. For this recognition, the clones employed a T3-Ti molecular complex and a T4 structure analogous to those found on allospecific T cells. Perhaps more importantly, it was observed that the same AC1-13 autoreactive clones (AC) induced autologous B cells to produce high levels of immunoglobulin in the absence of exogenous antigen and could synergize with the RW17C clone to effect maximal B cell Ig production. These results support the notion that such autoreactive cells can function in a physiologic amplifier role by facilitating induction via an internal set of signals (i.e. autologous MHC).

Allergens↗
PubMed1994

[Current studies on the identification of susceptibility genes for IDDM in NOD mice].

Until recently, localization of genes involved in multifactorial diseases, such as diabetes, was thought to be impracticable. The recent development of microsatellite genetic markers detected by PCR has facilitated detailed genetic analysis of complex traits. Microsatellite markers have been utilized for genetic analysis of NOD mice which spontaneously develop autoimmune IDDM similar to the human disease. There is evidence for ten distinct loci that affect the development of insulitis and diabetes in NOD mice. One of these loci, designated Idd-1, has been linked to the MHC on chromosome 17. Transgenic mouse experiments have shown that Idd-1 is composed of MHC class II genes I-A beta and I-E alpha.

Animals↗
PubMed1988

T cell hybridomas define the class II MHC-restricted response to vesicular stomatitis virus infection.

T cell hybridomas with specificity for VSV (vesicular stomatitis virus)-infected cells were generated in an attempt to better define the la-restricted helper T cell response to VSV. The hybridomas were created by fusing BALB/c (H-2d) anti-VSV immune spleen cells to the murine thymoma BW 5147. These hybridomas produce IL-2 when stimulated with VSV-infected spleen cells. They were found to recognize viral antigens in association with I-Ad and, in addition, could also be stimulated by VSV-infected A20 cells (an Ia-positive B cell lymphoma of H-2d origin). The purified viral membrane glycoprotein, G protein, and Gs (secreted G protein that lacks the hydrophobic and intracytoplasmic domains) both stimulated IL-2 production when added to cultures of A20 and the hybridomas. These hybridomas therefore recognize a viral antigenic determinant on G protein. Since chemically-fixed antigen-presenting cells fail to stimulate the hybridomas after exogenous addition of purified G protein we can conclude that these T cell hybridomas recognize a processed form of the G protein. Stimulator cells created by expression in A20 of a transfected cDNA encoding G protein were also recognized. Recognition in this case was I-Ad-restricted, as anti-I-Ad monoclonal antibodies blocked stimulation, and an Ia-negative cell (P815) expressing a transfected G protein gene failed to stimulate the hybridomas. Even after paraformaldehyde fixation, G gene-transfected, Ia-positive cells could stimulate the hybridomas, suggesting that processing of this endogenously-synthesized antigen has occurred.

Animals↗
PubMed1999

Concerted evolution of two Mhc class II B loci in pheasants and domestic chickens.

The major histocompatibility complex (Mhc) of the ring-necked pheasant contains two polymorphic Mhc class II B genes. We show here, by screening of a cDNA library and RT-PCR from RNA, that both of these loci, Phco-DAB1 and Phco-DAB2, normally are transcribed in the spleen. They differ mainly in the 3' untranslated (UT) region, with the transcript lengths, not including the poly(A) tails, being 1,100 nt for DAB1 and 955 nt for DAB2. These two loci are orthologous to the B-LBI and B-LBII loci of the domestic chicken, respectively. DAB1 and DAB2 therefore seem to have evolved from a duplication before the split of the evolutionary lineages leading to the pheasant and the domestic chicken ca. 20 MYA. This is the first report of an orthologous relationship between avian Mhc genes. Yet, the third exons of DAB1 and DAB2 were identical in all available sequences and differed at 10 positions from the exon 3 sequences of B-LBI/B-LBII. The species-specific exon 3 suggests that DAB1 and DAB2 are subject to concerted evolution, i.e., interlocus genetic exchange. The exon 2 sequences show characteristic polymorphism, with hypervariable segments occurring in different combinations in different alleles. Given the divergence in the 3'UT region, the finding of the same exon 2 sequence at both the DAB1 and the DAB2 loci in one of the pheasant haplotypes also suggests that interlocus genetic exchange does occur. Accordingly, the exon 2 sequences tended to cluster irrespective of locus in the phylogenetic analyses. Genetic exchange simultaneously involving both exon 2 and exon 3 may be facilitated by the short length of the intervening intron (< 100 bp) in pheasants and domestic chickens compared with, e.g., humans (about 3 kb).

3' Untranslated Regions↗
PubMed2005

Identification of a novel substrate for tyrosine kinase in human testes.

Identification of genes specifically expressed in adult and fetal testes is important in furthering our understanding of testis development and function. In this study, a novel human specific transcript, designated NYD-SP10, was identified by hybridization of adult and fetal human testis probes with a human cDNA microarray. NYD-SP10 (GenBank Accession no. AF332192) was expressed at a higher level in adult testes than in fetal testes. Bioinformatic analysis illustrated NYD-SP10 is a splice variant of regulatory factor X4, while it is lack of RFX DNA-binding domain which binds to the X box of MHC class II genes. Most telling of all, NYD-SP10 uniquely possesses a tyrosine kinase phosphorylation site. Expression profiles demonstrated NYD-SP10 is specifically and strongly expressed in human adult testes and ejaculated spermatozoa. Taken together, these results suggest that NYD-SP10 is a novel testis-specific gene and it is possibly a novel substrate for tyrosine kinase and involved in the function of human spermatozoa, especially during capacitation.

Adult↗
PubMed1998

Severe B cell deficiency and disrupted splenic architecture in transgenic mice expressing the E41K mutated form of Bruton's tyrosine kinase.

To identify B-cell signaling pathways activated by Bruton's tyrosine kinase (Btk) in vivo, we generated transgenic mice in which Btk expression is driven by the MHC class II Ea gene locus control region. Btk overexpression did not have significant adverse effects on B cell function, and essentially corrected the X-linked immunodeficiency (xid) phenotype in Btk- mice. In contrast, expression of a constitutively activated form of Btk carrying the E41K gain-of-function mutation resulted in a B cell defect that was more severe than xid. The mice showed a marked reduction of the B cell compartment in spleen, lymph nodes, peripheral blood and peritoneal cavity. The levels in the serum of most immunoglobulin subclasses decreased with age, and B cell responses to both T cell-independent type II and T cell-dependent antigens were essentially absent. Expression of the E41K Btk mutant enhanced blast formation of splenic B cells in vitro in response to anti-IgM stimulation. Furthermore, the mice manifested a disorganization of B cell areas and marginal zones in the spleen. Our findings demonstrate that expression of constitutively activated Btk blocks the development of follicular recirculating B cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1993

A Y-box consensus sequence is required for basal expression of the human multidrug resistance (mdr1) gene.

Basal transcription of the human multidrug resistance (mdr1) promoter was studied by chloramphenicol acetyltransferase (CAT) reporter fusion gene analysis in two parental and doxorubicin-resistant human tumor cell lines. Deletion of mdr1 DNA sequences to -89 relative to the start of transcription (at +1) had little effect on expression. Deletion of nucleotide sequences from -89 to -70, however, resulted in a 5-10-fold reduction in mdrCAT expression. DNase I footprint analysis demonstrated that the region from -85 to -70 was protected from nuclease digestion using nuclear extracts from these cell lines. The sequence between -82 and -73 is perfectly homologous with the 10-base pair Y-box consensus sequence found in the promoters of all major histocompatibility complex class-II (MHC II) genes. The Y-box sequence in MHC II genes is required for accurate and efficient transcription and contains the sequence CCAAT in the reverse orientation (Dorn, A., Durand, B., Marfing, C., Le Meur, M., Benoist, C., and Mathis, D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 6249-6253). Mutations in the reverse CCAAT sequence of the Y-box consensus substantially reduced expression of an mdrCAT vector and eliminated nucleoprotein binding in an electrophoretic mobility shift assay. These results suggest that proteins which bind to the putative Y-box consensus sequence are critical for basal transcriptional regulation of the human mdr1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Cloning and sequence analysis of the human major histocompatibility complex gene DC-3 beta.

The DC antigen is one of the class II major histocompatibility antigens involved in the regulation of the immune response. This molecule is a heterodimer composed of an alpha and a beta chain. Southern blot analysis of several homozygous cell lines shows that there are two DC beta genes. The DC-3 beta gene, corresponding to a polymorphic restriction fragment, was cloned and sequenced and found to exist in five exons spanning 8 kilobase pairs of DNA. These exons correspond to the functional domains of the DC beta protein. Comparison of the beta 1 domains of known DC beta chains shows that the polymorphism is clustered in four regions. A similar comparison of the mouse A beta sequences shows only two prominent diversity regions. The DC beta chain sequences are eight amino acids shorter than the A beta chain sequences due to the elimination of a small exon by an aberrant splice acceptor.

Base Sequence↗
PubMed2005

Evolution of striated muscle: jellyfish and the origin of triploblasty.

The larval and polyp stages of extant Cnidaria are bi-layered with an absence of mesoderm and its differentiation products. This anatomy originally prompted the diploblast classification of the cnidarian phylum. The medusa stage, or jellyfish, however, has a more complex anatomy characterized by a swimming bell with a well-developed striated muscle layer. Based on developmental histology of the hydrozoan medusa this muscle derives from the entocodon, a mesoderm-like third cell layer established at the onset of medusa formation. According to recent molecular studies cnidarian homologs to bilaterian mesoderm and myogenic regulators are expressed in the larval and polyp stages as well as in the entocodon and derived striated muscle. Moreover striated and smooth muscle cells may have evolved directly and independently from non-muscle cells as indicated by phylogenetic analysis of myosin heavy chain genes (MHC class II). To accommodate all evidences we propose that striated muscle-based locomotion coevolved with the nervous and digestive systems in a basic metazoan Bauplan from which the ancestors of the Ctenophora (comb jellyfish), Cnidaria (jellyfish and polyps), as well as the Bilateria are derived. We argue for a motile tri-layered cnidarian ancestor and a monophyletic descent of striated muscle in Cnidaria and Bilateria. As a consequence, diploblasty evolved secondarily in cnidarian larvae and polyps.

Animals↗
PubMed1991

Chemically modified antigen-presenting cells induce T lymphocyte allospecific hyporesponsiveness.

We have investigated the interaction between murine T lymphocytes and allogeneic APC in an in vitro proliferative mixed leukocyte reaction. Our results demonstrate that freshly isolated potentially alloreactive murine splenic T lymphocytes, in primary culture, can be induced to develop a state of allospecific proliferative hyporesponsiveness in vitro by exposure to 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-modified allogeneic APC, a method similar to that previously used to induce nonresponsiveness in murine Ag-specific self-MHC-restricted T lymphocyte clones. This hyporesponsiveness was: specific for the allohaplotype of inducing APC, maintained for 96 h in vitro, not due to cellular inhibitory mechanisms, and associated with reduced ability to secrete IL-2 but not IL-3. Induction of this hyporesponsiveness was not due to altered expression of class II MHC gene products on the APC but was associated with markedly reduced T lymphocyte-APC adhesive interactions despite the lack of a detectable immunophenotypic change in lymphocyte function-associated Ag 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) expression on the modified APC. Therefore, we propose that TCR occupancy in the absence of normal T lymphocyte-APC adhesive clustering may induce T lymphocyte tolerance.

Animals↗
PubMed1997

Analysis of cytokine producing activity of intestinal intraepithelial T cells from TCR beta-chain and delta-chain mutant mice.

Intestinal intraepithelial T cells (IELs) expressing either gammadelta TCR or alphabeta TCR have been proposed to play an important role in the regulation of intestinal epithelia by producing cytokines that directly influence the adjoining intestinal epithelial cell (IEC) functions. To illuminate this issue, we utilized TCR mutant mice to obtain gammadelta IELs, alphabeta IELs and mixed gammadelta and alphabeta IELs from corresponding alphabeta T-cell-deficient (beta-/-), gammadelta T-cell-deficient (delta-/-) and wild-type (WT) littermate mice. The production of IFN-gamma by these IELs as well as the mRNA for IFN-gamma, TGF-alpha, TGF-beta1, TNF-alpha and TNF-beta in these IELs, in conjunction with the effect of produced cytokines on the expression of class II MHC molecules by the in vitro cell line IEC-6, were investigated. IFN-gamma and TNF-alpha [corrected] specific mRNA were detectable in all freshly isolated gammadelta, alphabeta and WT IELs. In addition to the IFN-gamma and TNF-alpha [corrected] mRNA, alphabeta and WT IELs that had been activated in culture plates coated with anti-CD3 mAb contained mRNA for TGF-beta1 and TNF-beta proteins. In the cultured gammadelta IELs, however, the signals for IFN-gamma and TNF-alpha [corrected] transcripts were weak, and mRNA for the latter two cytokines was almost undetectable. Supernatants from in vitro culturing of alphabeta and WT IELs but not gammadelta IELs induced class II MHC gene expression in IEC-6, whereas, in the presence of anti-IFN-gamma mAb, the same culture supernatants failed to do so. In fact, the concentration of IFN-gamma in supernatants from alphabeta and WT IEL cultures was ten- to twentyfold higher than that in the supernatant from the gammadelta IEL culture. Finally, TGF-alpha specific mRNA was not detectable in the gammadelta and alphabeta IELs even after in vitro activation. These results indicate that alphabeta IELs are superior to gammadelta IELs in the ability to produce IFN-gamma, TGF-beta1, TNF-alpha [corrected] and TNF-beta through TCR crosslinking primary in vitro stimulation.

Animals↗
PubMed2002

Differential splicing generates Tvl-1/RFXANK isoforms with different functions.

Earlier studies have shown that Tvl-1 gives rise to at least two differentially spliced mRNAs, one of which (Tvl-S) encodes a protein that lacks amino acids 91-112. DNA binding of RFX complexes assembled in the presence of Tvl-S is impaired. As a result, Tvl-S does not support the expression of Class II major histocompatibility complex (MHC) genes. Here, we show that the reason Tvl-S is inactive as a transcriptional regulator of Class II MHC genes is that the RFX complexes assembled in the presence of Tvl-S are unstable. Additionally, we show that interferon-gamma, which induces Class II MHC gene expression in 293 cells, promotes a shift in the splicing pattern of RFXANK/Tvl-1 toward the transcriptionally active Tvl-L isoform, suggesting that differential splicing of Tvl-1 is a signal-regulated process. Finally, we show that Tvl-1 regulates the expression of non-MHC genes. One such gene encodes the ephrin receptor EphA3. Since both Tvl-L and Tvl-S are identical in their ability to induce the expression of EphA3, we conclude that Tvl-1 regulates the expression of non-MHC genes by RFX-independent mechanisms.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Nucleotide sequence of the ring3 gene in the class II region of the mouse MHC and its abundant expression in testicular germ cells.

The RING3 (NAT) gene is the first and only locus with no obvious function associated with the immune system in the class II region of the human major histocompatibility complex. This gene is a homologue of the Drosophila homeotic gene female sterile homeotic (fsh) and encodes a nuclear serine-threonine kinase. To study more about the physiological function of the RING3 gene, we isolated a mouse homologue from a genomic library, determined its gene structure, and investigated its expression profile. The mouse Ring3 gene spans approximately 8 kb and consists of 12 exons encoding a 798-amino-acid protein, sharing as high as 96% amino acid identity with the human RING3 protein. Northern hybridization revealed that the Ring3 gene abundantly produced 3.8- and 3.0-kb transcripts in the testis but was weakly expressed with 4.6- and 3.8-kb transcripts in somatic tissues. It appears that testis-specific 3.0-kb transcript gives rise to a smaller size Ring3 protein resulting from the usage of the second ATG codon for translational initiation compared to the almost ubiquitous 4.6-kb transcript. In RNAs isolated from fractionated testicular germ cells, the two testicular mRNAs were detected exclusively in the fractions containing a large population of round spermatids and pachytene spermatocytes. Furthermore, in situ hybridization on cross sections of seminiferous tubules in the testis showed that the expression of the Ring3 gene was initiated at the pachytene spermatocyte stage during meiosis and persisted throughout the round spermatid stage during spermiogenesis. These results suggest that the Ring3 gene plays an important role in spermatogenesis.

Amino Acid Sequence↗
PubMed1992

A homologue of the Drosophila female sterile homeotic (fsh) gene in the class II region of the human MHC.

The RING3 gene maps in the class II region of the human major histocompatibility complex, at a CpG island distal of the HLA-DNA gene. RING3 cDNAs were obtained from a T cell cDNA library and the longest (4 kb) was sequenced. The sequence contained an open reading frame encoding a protein of 754 amino acids. A screen of protein databases revealed striking homology between the RING3 protein and the Drosophila female sterile homeotic gene (fsh) which is implicated in the establishment of segments in the early embryo. Partial sequence homology was also observed with some other proteins involved in cell cycle control (CCG1), cell division (ftsA) and regulation of cell growth (gamma interferons). This highly conserved gene may play an important role in human development. In addition, its location in the MHC class II region may be related to some HLA-associated diseases.

Amino Acid Sequence↗
PubMed2000

Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter.

Scaffold molecules interact with multiple effectors to elicit specific signal transduction pathways. CIITA, a non-DNA-binding regulator of class II major histocompatibility complex (MHC) gene transcription, may serve as a transcriptional scaffold. Regulation of the class II MHC promoter by CIITA requires strict spatial-helical arrangements of the X and Y promoter elements. The X element binds RFX (RFX5/RFXANK-RFXB/RFXAP) and CREB, while Y binds NF-Y/CBF (NF-YA, NF-YB, and NF-YC). CIITA interacts with all three. In vivo analysis using both N-terminal and C-terminal deletion constructs identified critical domains of CIITA that are required for interaction with NF-YB, NF-YC, RFX5, RFXANK/RFXB, and CREB. We propose that binding of NF-Y/CBF, RFX, and CREB by CIITA results in a macromolecular complex which allows transcription factors to interact with the class II MHC promoter in a spatially and helically constrained fashion.

Animals↗