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Els Goulmy - One of the best experts on this subject based on the ideXlab platform.
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Minor Histocompatibility Antigen H-Y Is Expressed on Human Hematopoietic Progenitor Cells
2016Co-Authors: Els Goulmy, Willem Fibbe, See Profile, Paul J. Voogt, Willemien F. J. Veenhof, J. Frederik H. FalkenburgAbstract:Minor Histocompatibility Antigen H-Y is expressed on human hematopoietic progenitor cell
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IMMUNOBIOLOGY General
2016Co-Authors: Joke Den M. M. Haan, Tuna Mutis, Els Blokl, Ad P. Ijzerman, Els GoulmyAbstract:T-cell receptor antagonists to immunomodulate HLA-A2–restricted Minor Histocompatibility Antigen HA-1–specific T-cell response
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GENE THERAPY
2016Co-Authors: Mirjam H M Heemskerk, Els Goulmy, Michel G D Kester, Manja Hoogeboom, Roelof A. De Paus, Roel Willemze, J. Frederik H. FalkenburgAbstract:Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of Minor Histocompatibility Antigen HA-2–specific T-cell receptor complexes expressing a conserved alpha joining regio
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Graft-versus-host driven graft-versus-leukemia effect of Minor Histocompatibility Antigen HA-1 in chronic myeloid leukemia patients
Leukemia, 2010Co-Authors: Tuna Mutis, Ronald Brand, D Gallardo, A. Van Biezen, Dietger Niederwieser, Els GoulmyAbstract:Graft-versus-host driven graft-versus-leukemia effect of Minor Histocompatibility Antigen HA-1 in chronic myeloid leukemia patients
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The relevance of Minor Histocompatibility Antigens in solid organ transplantation.
Current opinion in organ transplantation, 2009Co-Authors: Miranda P. Dierselhuis, Els GoulmyAbstract:Disparities in Minor Histocompatibility Antigens between HLA-matched organ and hematopoietic stem cell donors and recipients create the risks of graft failure and graft-versus-host disease (GvHD) respectively. A decade ago, technical advances combined with genomic information resulted in the identification of the chemical nature of the first series of Minor Histocompatibility Antigens, facilitating their molecular typing. A new era of research had begun in exploring the role of Minor Histocompatibility Antigens in physiological and nonphysiological settings. Here we summarize, to the best of our knowledge, human studies on the relevance of Minor Histocompatibility Antigens in solid organ transplantation with a main focus on renal allografting. The Minor Histocompatibility Antigen HY is associated with acute rejection, and male grafts in female recipients have reduced graft survival; both cellular and humoral responses are observed. Studies on autosomal Minor Histocompatibility Antigens on graft rejection are less conclusive; their role in transplant tolerance, however, offers perspective. Information on the clinical relevance of Minor Histocompatibility Antigen allo-immune responses in solid organ allografting is still scarce. The possible implications of the Minor Histocompatibility allo-immune responses for future clinical practice in solid organ transplantation are discussed in relation to their possible detrimental or beneficial effects on the host.
Stanley R Riddell - One of the best experts on this subject based on the ideXlab platform.
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A single Minor Histocompatibility Antigen encoded by UGT2B17 and presented by human leukocyte Antigen-A*2902 and -B*4403.
Transplantation, 2007Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R RiddellAbstract:T-cell responses to Minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human Minor Histocompatibility Antigen that is recognized by CD8 cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this Minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. An HLA-B*4403-restricted CD8 CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The Minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant Minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.
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a single Minor Histocompatibility Antigen encoded by ugt2b17 and presented by human leukocyte Antigen a 2902 and b 4403
Transplantation, 2007Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R RiddellAbstract:Background. T-cell responses to Minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human Minor Histocompatibility Antigen that is recognized by CD8+ cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this Minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. Methods. An HLA-B*4403-restricted CD8+ CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The Minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. Results. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. Conclusions. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant Minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.
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human Minor Histocompatibility Antigen specific cd8 t cells are found predominantly in the cd45ra cd62l naive t cell subset
Blood, 2005Co-Authors: Marie Bleakley, Audrey Mollerup, Colette Chaney, Michele Brown, Stanley R RiddellAbstract:Graft versus host disease (GVHD) after allogeneic stem cell transplant (SCT) is initiated by the activation of alloreactive T cells by host dendritic cells (DC) in lymphoid tissue. Studies in murine models have demonstrated that selective depletion of naive T cells abrogates GVHD in major and Minor Histocompatibility Antigen (miH) mismatched SCT and provides for rapid reconstitution of memory T cell responses to pathogens. This suggests the memory subset may lack a sufficient repertoire of alloreactive T cells or fail to localize to sites where GVHD is initiated. If such a strategy were effective in humans, morbidity from GVHD would be reduced, but the graft versus leukemia (GVL) effect might be compromised. To explore the potential of this approach in humans, we developed a novel limiting dilution assay using DC as stimulator cells in vitro to analyze the frequency and repertoire of human miH reactive T cells in highly purified naive and memory T cell subsets obtained from HLA identical volunteer donor pairs. For each pair, mature DC were derived by differentiation of CD14+ monocytes in vitro from one volunteer, and pure (>97%) populations of naive (CD62L+, CD45 RA+, CD45RO-) and memory (CD45RO+) CD8 T cells were obtained by FACS sorting of CD8 enriched PBMC from the respective HLA identical sibling. Memory and naive T cells were cultured for 12 days in 96 well plates at a range of concentrations with DC at a 30:1 ratio and IL12 (10 ng/ml), and IL15 (10 ng/ml) was added on day 7. On day 12, the wells were screened against target cells from each volunteer in a chromium release assay (CRA) to quantitative T cells with reactivity against miH. All wells with reactivity in this screening assay were subsequently expanded using anti CD3 antibody and IL2 and retested by CRA to validate the results of the screening assay. In multiple experiments using different HLA matched pairs, T cells with specific and reproducible cytotoxic activity (>15% lysis) against target cells from the DC donor but not autologous targets were only isolated from wells plated with naive CD8 T cells, and there was no reproducible cytotoxicity from wells plated with memory T cells. This data demonstrates that miH specific CD8 T cells are found predominantly, and possibly exclusively, in the naive T cell subset in humans. This data is consistent with a dramatically reduced repertoire of miH alloreactive T cells in the memory T cell pool and supports the development of protocols to prevent GVHD by selective depletion of CD45RA+ CD8+ T cells from the hematopoietic cell graft. However, T cells specific for miH also contribute to the GVL effect and CD45RA depletion would be expected to compromise antileukemic activity. Using the above approach for isolating miH specific CTL from naive CD8 T cells, we have found a diverse repertoire of alloreactivity in most cultures and identified a subset of T cell lines and clones specific for miH presented selectively on hematopoietic cells. These T cells recognize primary ALL and AML samples that express the restricting HLA allele in vitro. MiH specific T cell clones can be reliably generated by this method using DC derived from monocytes of patients with advanced leukemia. Thus, it may be feasible to utilize this approach to isolate T cells specific for hematopoietic restricted miH for adoptive therapy as an adjunct to CD45RA depletion to preserve the GVL effect and allow separation of GVL from GVHD.
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an alternative transcript of the pane1 gene encodes a Minor Histocompatibility Antigen that is selectively expressed in resting cd19 cells and b cll
Blood, 2005Co-Authors: Anthony G Brickner, Stanley R Riddell, Jeffrey K Mito, Xin Feng, Tetsuya Nishida, Liane Fairfull, Robert E Ferrell, Kenneth A Foon, Edus H WarrenAbstract:We recently identified an HLA-A3-restricted Minor Histocompatibility Antigen (mHAg) encoded by an alternative transcript (transcript k ) of the PANE1 gene within an exon unique from all other PANE1 transcripts. Differential CTL recognition of mHAg+ and mHAg− cells is due to a single nucleotide polymorphism that replaces an arginine codon (CGA) with a translation termination codon (TGA). Cytotoxicity assays revealed robust recognition of HLA-A3+ EBV-LCL, minimal recognition of unfractionated peripheral blood mononuclear cells and PHA-stimulated T-cell blasts (PHA-T), and no recognition of dermal fibroblasts. To determine whether the restricted tissue distribution of the mHAg correlated with transcript k expression, we developed a real-time quantitative PCR assay to specifically detect transcript k . In normal tissues, expression was highest in spleen, low in all other tissues examined, and undetectable in dermal fibroblasts. Analysis of resting and activated peripheral blood cell fractions revealed very high expression levels in resting CD19+ cells, intermediate levels in EBV-LCL and resting CD4+ and CD8+ cells, and very low levels in activated CD19+ cells as well as resting and activated mononuclear cells, CD14+ cells, and activated CD4+ and CD8+ cells. EBV-LCL from mHAg− TGA homozygotes express significantly lower transcript k levels (p=0.043; Student’s t test) than mHAg+ EBV-LCL, suggesting the possibility of nonsense-mediated decay. The preferential expression of transcript k in normal resting CD19+ cells prompted us to investigate expression in malignant CD19+ cells. In a small sample of CD19+ acute lymphoblastic leukemia cells, we observed low-level expression comparable to that of activated normal CD19+ cells. In contrast, we observed high-level expression in CD19+ B-CLL cells comparable to or greater than that of normal resting CD19+ cells, and far greater than the levels in any other cell type tested. CTL cytotoxicity assays of a subset of HLA-A3+, mHAg+ B-CLLs revealed that they uniformly presented the mHAg encoded by PANE1 transcript k . Our finding that transcript k was selectively expressed in resting CD19+ cells and CD19+ B-CLL contradicted a previous report (Bierie et al. , Gene Expression Patterns 4:389, 2004) that the longest PANE1 transcript (transcript c ) is preferentially expressed in activated lymphoid cells. We therefore evaluated transcript c expression in the same panel of samples, and confirmed that it was selectively expressed in activated CD19+ cells, with very low levels in resting CD19+ and primary B-CLL cells. Thus, PANE1 transcripts k and c display reciprocal expression in resting and activated CD19+ cells and primary CD19+ B-CLL cells. To determine if activation of CD19+ cells would increase expression of transcript c and decrease expression of transcript k , we evaluated the effect of CD40L stimulation in 6 primary B-CLL samples. In all samples tested, CD40L stimulation led to a profound decrease in transcript k expression, and a significant increase in transcript c expression. These studies suggest distinct roles for different PANE1 isoforms in resting versus activated CD19+ cells, and identify PANE1 as a potential therapeutic target in B-CLL.
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a human Minor Histocompatibility Antigen resulting from differential expression due to a gene deletion
Journal of Experimental Medicine, 2003Co-Authors: Makoto Murata, Edus H Warren, Stanley R RiddellAbstract:Minor Histocompatibility Antigens (Minor H Antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte Antigen identical hematopoietic stem cell transplantation. Only a few human Minor H Antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human Minor H Antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and Antigen-presenting cells. In contrast to previously defined human Minor H Antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating Minor H Antigens in humans.
Edus H Warren - One of the best experts on this subject based on the ideXlab platform.
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A single Minor Histocompatibility Antigen encoded by UGT2B17 and presented by human leukocyte Antigen-A*2902 and -B*4403.
Transplantation, 2007Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R RiddellAbstract:T-cell responses to Minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human Minor Histocompatibility Antigen that is recognized by CD8 cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this Minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. An HLA-B*4403-restricted CD8 CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The Minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant Minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.
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a single Minor Histocompatibility Antigen encoded by ugt2b17 and presented by human leukocyte Antigen a 2902 and b 4403
Transplantation, 2007Co-Authors: Seitaro Terakura, Makoto Murata, Edus H Warren, Alessandro Sette, John Sidney, Tomoki Naoe, Stanley R RiddellAbstract:Background. T-cell responses to Minor Histocompatibility Antigens are mediators of graft-versus-host disease and organ graft rejection. We previously identified a human Minor Histocompatibility Antigen that is recognized by CD8+ cytotoxic T lymphocytes (CTLs) and encoded by the UDP glycosyltransferase 2 family, polypeptide B17 (UGT2B17) gene, which is highly expressed in the liver, colon, and small intestine. The UGT2B17 is presented by human leukocyte Antigen (HLA)-A*2902, and the immunogenicity of this Minor Histocompatibility Antigen results from differential protein expression in donor and recipient cells as a consequence of a UGT2B17 gene deletion. Methods. An HLA-B*4403-restricted CD8+ CTL clone was isolated from the same hematopoietic stem cell transplant recipient that exhibited an HLA-A*2902-restricted UGT2B17-specific response. The Minor Histocompatibility Antigen recognized by the HLA-B*4403-restricted clone was identified, and the ability of the peptide to be presented by HLA-B*4402 was examined. Results. The HLA-B*4403-restricted CTL clone recognized a peptide encoded by UGT2B17, which is identical to the peptide presented by HLA-A*2902. Peptide binding assays revealed this UGT2B17 peptide binds with comparable affinity to HLA-B*4402 as to HLA-B*4403. This patient had acute graft-versus-host disease involving liver and gastrointestinal tract, suggesting the T-cell response directed against UGT2B17 is involved in graft-versus-host disease. Conclusions. A single peptide encoded by UGT2B17 can be presented by HLA-A*2902, B*4402 and B*4403, and may serve as an immunodominant Minor Histocompatibility Antigen in individuals with these HLA alleles that undergo transplantation of stem cells or organ grafts from UGT2B17 disparate donors.
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an alternative transcript of the pane1 gene encodes a Minor Histocompatibility Antigen that is selectively expressed in resting cd19 cells and b cll
Blood, 2005Co-Authors: Anthony G Brickner, Stanley R Riddell, Jeffrey K Mito, Xin Feng, Tetsuya Nishida, Liane Fairfull, Robert E Ferrell, Kenneth A Foon, Edus H WarrenAbstract:We recently identified an HLA-A3-restricted Minor Histocompatibility Antigen (mHAg) encoded by an alternative transcript (transcript k ) of the PANE1 gene within an exon unique from all other PANE1 transcripts. Differential CTL recognition of mHAg+ and mHAg− cells is due to a single nucleotide polymorphism that replaces an arginine codon (CGA) with a translation termination codon (TGA). Cytotoxicity assays revealed robust recognition of HLA-A3+ EBV-LCL, minimal recognition of unfractionated peripheral blood mononuclear cells and PHA-stimulated T-cell blasts (PHA-T), and no recognition of dermal fibroblasts. To determine whether the restricted tissue distribution of the mHAg correlated with transcript k expression, we developed a real-time quantitative PCR assay to specifically detect transcript k . In normal tissues, expression was highest in spleen, low in all other tissues examined, and undetectable in dermal fibroblasts. Analysis of resting and activated peripheral blood cell fractions revealed very high expression levels in resting CD19+ cells, intermediate levels in EBV-LCL and resting CD4+ and CD8+ cells, and very low levels in activated CD19+ cells as well as resting and activated mononuclear cells, CD14+ cells, and activated CD4+ and CD8+ cells. EBV-LCL from mHAg− TGA homozygotes express significantly lower transcript k levels (p=0.043; Student’s t test) than mHAg+ EBV-LCL, suggesting the possibility of nonsense-mediated decay. The preferential expression of transcript k in normal resting CD19+ cells prompted us to investigate expression in malignant CD19+ cells. In a small sample of CD19+ acute lymphoblastic leukemia cells, we observed low-level expression comparable to that of activated normal CD19+ cells. In contrast, we observed high-level expression in CD19+ B-CLL cells comparable to or greater than that of normal resting CD19+ cells, and far greater than the levels in any other cell type tested. CTL cytotoxicity assays of a subset of HLA-A3+, mHAg+ B-CLLs revealed that they uniformly presented the mHAg encoded by PANE1 transcript k . Our finding that transcript k was selectively expressed in resting CD19+ cells and CD19+ B-CLL contradicted a previous report (Bierie et al. , Gene Expression Patterns 4:389, 2004) that the longest PANE1 transcript (transcript c ) is preferentially expressed in activated lymphoid cells. We therefore evaluated transcript c expression in the same panel of samples, and confirmed that it was selectively expressed in activated CD19+ cells, with very low levels in resting CD19+ and primary B-CLL cells. Thus, PANE1 transcripts k and c display reciprocal expression in resting and activated CD19+ cells and primary CD19+ B-CLL cells. To determine if activation of CD19+ cells would increase expression of transcript c and decrease expression of transcript k , we evaluated the effect of CD40L stimulation in 6 primary B-CLL samples. In all samples tested, CD40L stimulation led to a profound decrease in transcript k expression, and a significant increase in transcript c expression. These studies suggest distinct roles for different PANE1 isoforms in resting versus activated CD19+ cells, and identify PANE1 as a potential therapeutic target in B-CLL.
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disparity for a newly identified Minor Histocompatibility Antigen ha 8 correlates with acute graft versus host disease after haematopoietic stem cell transplantation from an hla identical sibling
British Journal of Haematology, 2003Co-Authors: Yoshiki Akatsuka, Edus H Warren, Victor H. Engelhard, Ming Tseh Lin, Paul J. Martin, John A. Hansen, Ted Gooley, Anthony G Brickner, David K Madtes, Toshitada TakahashiAbstract:Summary. We recently identified a new Minor Histocompatibility Antigen, termed HA-8, which is presented by human leucocyte Antigen (HLA)-A*0201 or HLA-A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA-A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte Antigen (HLA)-identical sibling was conducted to determine whether HA-8 disparity correlated with clinical outcome. HA-8 disparity was detected in 72 recipients, and grades II–IV graft-versus-host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA-8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1·8; 95% confidence interval, 1·0–3·1; P = 0·04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA-8 disparity was not sufficient to change other clinical outcomes.
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a human Minor Histocompatibility Antigen resulting from differential expression due to a gene deletion
Journal of Experimental Medicine, 2003Co-Authors: Makoto Murata, Edus H Warren, Stanley R RiddellAbstract:Minor Histocompatibility Antigens (Minor H Antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte Antigen identical hematopoietic stem cell transplantation. Only a few human Minor H Antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human Minor H Antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and Antigen-presenting cells. In contrast to previously defined human Minor H Antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating Minor H Antigens in humans.
Gerd Schmitz - One of the best experts on this subject based on the ideXlab platform.
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genomic organization of the human cholesterol responsive abc transporter abca7 tandem linkage with the Minor Histocompatibility Antigen ha 1 gene
Biochemical and Biophysical Research Communications, 2000Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd SchmitzAbstract:Abstract We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of ∼32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3′ gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5′ end of the coding region of the recently identified human Minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human Minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of ∼48 kb size on chromosome 19p13.3.
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Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the Minor Histocompatibility Antigen HA-1 gene.
Biochemical and biophysical research communications, 2000Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd SchmitzAbstract:We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of approximately 32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3' gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5' end of the coding region of the recently identified human Minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human Minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of approximately 48 kb size on chromosome 19p13.3.
Wolfgang E Kaminski - One of the best experts on this subject based on the ideXlab platform.
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Homozygosity for the 168His variant of the Minor Histocompatibility Antigen HA‐1 is associated with reduced risk of primary Sjögren's syndrome
European Journal of Immunology, 2004Co-Authors: Mariann Harangi, Evelyn Orso, Emese Kiss, Erika Zilahi, Jörg Marienhagen, Wolfgang E Kaminski, Margit Zeher, Martin Fleck, Zoltan Szekanecz, Charalampos AslanidisAbstract:The genes for the human ATP-binding cassette (ABC) transporter ABCA7 and the Minor Histocompatibility Antigen HA-1 are juxtaposed in close proximity on chromosome 19p13.3. The multispan transmembrane protein ABCA7 contains an extracellular domain that is recognized by antisera from patients with Sjogren's syndrome (“Sjogren-epitope”). Recent work from our laboratory demonstrating the involvement of ABCA7 in cellular ceramide and phosphatidylserine export suggests a role for this transporter in programmed cell death. In HA-1, a protein of unknown function, a His/Arg polymorphism (His168Arg), which constitutes the immunologic target for HA-1-specific cytotoxic T cells, has been causatively linked to graft-versus-host disease after allogeneic stem cell transplantation. Because these findings suggest a potential implication of ABCA7 and HA-1 in immune processes, we tested the hypothesis that allelic variants in both genes are associated with autoimmune disorders. We identified a total of 31 exonic single-nucleotide polymorphisms (SNP) in the ABCA7/HA-1 gene complex, nine of which represent non-synonymous nucleotide alterations. Genotypes of ABCA7 and HA-1 SNP were determined in three distinct Caucasian populations of patients with primary Sjogren's syndrome and ethnically matched controls. Comparison of allele frequencies between these groups revealed that the incidence of the HA-1 168His allele is significantly lower in Sjogren's syndrome patients than in controls (p
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genomic organization of the human cholesterol responsive abc transporter abca7 tandem linkage with the Minor Histocompatibility Antigen ha 1 gene
Biochemical and Biophysical Research Communications, 2000Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd SchmitzAbstract:Abstract We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of ∼32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3′ gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5′ end of the coding region of the recently identified human Minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human Minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of ∼48 kb size on chromosome 19p13.3.
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Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the Minor Histocompatibility Antigen HA-1 gene.
Biochemical and biophysical research communications, 2000Co-Authors: Wolfgang E Kaminski, Armin Piehler, Gerd SchmitzAbstract:We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of approximately 32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3' gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5' end of the coding region of the recently identified human Minor Histocompatibility Antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human Minor Histocompatibility Antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of approximately 48 kb size on chromosome 19p13.3.