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Malini Raghavan - One of the best experts on this subject based on the ideXlab platform.
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Catalytic site modifications of TAP1 and TAP2 and their functional consequences.
The Journal of biological chemistry, 2006Co-Authors: Christopher L. Perria, Philip E. Lapinski, Vijayalakshmi Rajamanickam, Malini RaghavanAbstract:Abstract The transporter associated with antigen processing (TAP), a member of the ATP binding cassette (ABC) family of transmembrane transporters, transports peptides across the endoplasmic reticulum membrane for assembly of major histocompatibility complex class I molecules. Two subunits, TAP1 and TAP2, are required for peptide transport, and ATP hydrolysis by TAP1·TAP2 complexes is important for transport activity. Two nucleotide binding sites are present in TAP1·TAP2 complexes. Compared with other ABC transporters, the first nucleotide binding site contains non-consensus catalytic site residues, including Asp668 in the Walker B region of TAP1 (in place of a highly conserved glutamic acid), and Gln701 in the switch region of TAP1 (in place of a highly conserved histidine). At the second nucleotide binding site, a glutamic acid (TAP2 Glu632) follows the Walker B motif, and the switch region contains a histidine (TAP2 His661). We found that alterations at Glu632 and His661 of TAP2 significantly reduced peptide translocation and/or TAP-induced major histocompatibility complex class I surface expression. Alterations of TAP1 Asp668 alone or in combination with TAP1 Gln701 had only small effects on TAP activity. Thus, the naturally occurring Asp668 and Gln701 alterations of TAP1 are likely to contribute to attenuated catalytic activity at the first nucleotide binding site (the TAP1 site) of TAP complexes. Due to its enhanced catalytic activity, the second nucleotide binding site (the TAP2 site) appears to be the main site driving peptide transport. A mechanistic model involving one main active site is likely to apply to other ABC transporters that have an asymmetric distribution of catalytic site residues within the two nucleotide binding sites.
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identification of domain boundaries within the n termini of tap1 and TAP2 and their importance in tapasin binding and tapasin mediated increase in peptide loading of mhc class i
Immunology and Cell Biology, 2005Co-Authors: Erik Procko, Malini Raghavan, Don C. Wiley, Gayatri Raghuraman, Rachelle GaudetAbstract:Before exit from the endoplasmic reticulum (ER), MHC class I molecules transiently associate with the transporter associated with antigen processing (TAP1/TAP2) in an interaction that is bridged by tapasin. TAP1 and TAP2 belong to the ATP-binding cassette (ABC) transporter family, and are necessary and sufficient for peptide translocation across the ER membrane during loading of MHC class I molecules. Most ABC transporters comprise a transmembrane region with six membrane-spanning helices. TAP1 and TAP2, however, contain additional N-terminal sequences whose functions may be linked to interactions with tapasin and MHC class I molecules. Upon expression and purification of human TAP1/TAP2 complexes from insect cells, proteolytic fragments were identified that result from cleavage at residues 131 and 88 of TAP1 and TAP2, respectively. N-Terminally truncated TAP variants lacking these segments retained the ability to bind peptide and nucleotide substrates at a level comparable to that of wild-type TAP. The truncated constructs were also capable of peptide translocation in vitro, although with reduced efficiency. In an insect cell-based assay that reconstituted the class I loading pathway, the truncated TAP variants promoted HLA-B*2705 processing to similar levels as wild-type TAP. However, correlating with the observed reduction in tapasin binding, the tapasin-mediated increase in processing of HLA-B*2705 and HLA-B*4402 was lower for the truncated TAP constructs relative to the wild type. Together, these studies indicate that N-terminal domains of TAP1 and TAP2 are important for tapasin binding and for optimal peptide loading onto MHC class I molecules.
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nucleotide interactions with membrane bound transporter associated with antigen processing proteins
Journal of Biological Chemistry, 2003Co-Authors: Philip E. Lapinski, Gayatri Raghuraman, Malini RaghavanAbstract:Abstract The transporter associated with antigen processing (TAP) contains two nucleotide-binding domains (NBD) in the TAP1 and TAP2 subunits. When expressed as individual subunits or domains, TAP1 and TAP2 NBD differ markedly in their nucleotide binding properties. We investigated whether the two nucleotide-binding sites of TAP1/TAP2 complexes also differed in their nucleotide binding properties. To facilitate electrophoretic separation of the subunits when in complex, we used TAP complexes in which one of the subunits was expressed as a fluorescent protein fusion construct. In binding experiments at 4 °C using the photo-cross-linkable nucleotide analogs 8-azido-[γ-32P]ATP and 8-azido-[α-32P]ADP, TAP2 was found to have reduced affinity for nucleotides compared with TAP1, when the two proteins were separately expressed. Complex formation with TAP1 enhanced the binding affinity of the TAP2 nucleotide-binding site for both nucleotides. Binding analyses with mutant TAP complexes that are deficient in nucleotide binding at one or both sites provided evidence for the existence of two ATP-binding sites with relatively similar affinities in TAP1/TAP2 complexes. TAP1/TAP2 NBD interactions appear to contribute at least in part to enhanced nucleotide binding at the TAP2 site upon TAP1/TAP2 complex formation. Binding analyses with mutant TAP complexes also demonstrate that the extent of TAP1 labeling is dependent upon the presence of a functional TAP2 nucleotide-binding site.
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Tapasin Interacts with the Membrane-spanning Domains of Both TAP Subunits and Enhances the Structural Stability of TAP1·TAP2 Complexes
The Journal of biological chemistry, 2002Co-Authors: Gayatri Raghuraman, Philip E. Lapinski, Malini RaghavanAbstract:Abstract The transporter associated with antigen processing (TAP) proteins are involved in transport of peptides from the cytosol into the endoplasmic reticulum. Two subunits, TAP1 and TAP2, are necessary and sufficient for peptide binding and peptide translocation across the endoplasmic reticulum membrane. TAP1 and TAP2 contain an N-terminal hydrophobic membrane-spanning region and a C-terminal nucleotide binding domain. Tapasin is an endoplasmic reticulum resident protein that has been found associated with the TAP subunits and shown to increase expression levels of TAP. Here we investigated TAP-tapasin interactions and their effects on TAP function in insect cells. We show tapasin binding to both TAP1 and TAP2 and to the corresponding nucleotide binding domain-exchanged chimeras as well as to a truncated TAP1·TAP2 complex containing just the membrane-spanning regions of TAP1 and TAP2. However, tapasin interactions with either the truncated TAP construct containing just the nucleotide binding domain are not observed. Tapasin is not required for high affinity peptide binding to TAP1·TAP2 complexes, and in fact, the presence of tapasin slightly reduces the affinity of TAP complexes for peptides. However, at near physiological temperatures, both tapasin and nucleotides stabilize the peptide binding site of TAP1·TAP2 complexes against inactivation, and enhanced thermostability of both TAP subunits is observed in the presence of tapasin. The enhanced structural stability of TAP1·TAP2 complexes in the presence of tapasin might explain the observations that tapasin increases TAP protein expression levels in mammalian cells.
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Walker A lysine mutations of TAP1 and TAP2 interfere with peptide translocation but not peptide binding.
The Journal of biological chemistry, 2000Co-Authors: Philip E. Lapinski, Richard R. Neubig, Malini RaghavanAbstract:We generated mutants of the transporter associated with antigen-processing subunits TAP1 and TAP2 that were altered at the conserved lysine residue in the Walker A motifs of the nucleotide binding domains (NBD). In other ATP binding cassette transporters, mutations of the lysine have been shown to reduce or abrogate the ATP hydrolysis activity and in some cases impair nucleotide binding. Mutants TAP1(K544M) and TAP2(K509M) were expressed in insect cells, and the effects of the mutations on nucleotide binding, peptide binding, and peptide translocation were assessed. The mutant TAP1 subunit is significantly impaired for nucleotide binding relative to wild type TAP1. The identical mutation in TAP2 does not significantly impair nucleotide binding relative to wild type TAP2. Using fluorescence quenching assays to measure the binding of fluorescent peptides, we show that both mutants, in combination with their wild type partners, can bind peptides. Since the mutant TAP1 is significantly impaired for nucleotide binding, these results indicate that nucleotide binding to TAP1 is not a requirement for peptide binding to TAP complexes. Peptide translocation is undetectable for TAP1.TAP2(K509M) complexes, but low levels of translocation are detectable with TAP1(K544M).TAP2 complexes. These results suggest an impairment in nucleotide hydrolysis by TAP complexes containing either mutant TAP subunit and indicate that the presence of one intact TAP NBD is insufficient for efficient catalysis of peptide translocation. Taken together, these results also suggest the possibility of distinct functions for TAP1 and TAP2 NBD during a single translocation cycle.
Myoung Hee Park - One of the best experts on this subject based on the ideXlab platform.
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association of tap1 and TAP2 genes with susceptibility to pulmonary tuberculosis in koreans
Apmis, 2015Co-Authors: Eun Youn Roh, Jong Hyun Yoon, Sue Shin, Eun Young Song, Myoung Hee ParkAbstract:Tuberculosis remains an important public health problem in Koreans. However, very few studies have reported on the genetic factors associated with TB susceptibility in Koreans. The aim of this study was to elucidate the genetic factors associated with susceptibility to pulmonary tuberculosis (PTB). We investigated the transporter associated with antigen processing -1 (TAP1) and TAP2 gene polymorphisms in 160 Korean PTB patients (categorized according to extent of lesion and TB medication history) and 210 controls. TAP2*C/E frequency was significantly increased in the PTB (pc = 0.004, OR = 2.28). TAP2*Bky2/C/E were enriched in the retreated, far-advanced and total PTB compared with the controls (pc = 0.015, OR = 3.27; pc = 0.019, OR = 2.56; pc = 2.8 × 10(-4) , OR = 2.42, respectively). In the comparison of TAP2 gene with the DRB1*08:03, which is associated with TAP2*Bky2 and PTB in Koreans, we demonstrated the hierarchy of these association factors. TAP2*C/E is independent factors as strong as DRB1*08:03, and TAP2*C/E interacts with DRB1*08:03, resulting in a striking combined association. Our results suggest that TAP2 gene has an association with PTB susceptibility, the extent of the lesion or recurrence. These associations are independent from and additive with DRB1*08:03.
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TAP1 and TAP2 gene polymorphisms and HLA-TAP haplotypes in Koreans based on 90 families.
Human immunology, 2005Co-Authors: Dong Hee Whang, Hyejin Park, Eun Youn Roh, Myoung Hee ParkAbstract:Abstract We have investigated the polymorphism of TAP genes and the distribution of human leukocyte antigen ( HLA )- TAP haplotypes in 90 Korean families (180 parents and 233 children), previously typed for HLA class II alleles. TAP1 (codons 333 and 637) and TAP2 (codons 379, 565, 577, 651, 665, and 687) typings were carried out by use of polymerase chain reaction–restriction fragment length polymorphism method. For TAP1 , four alleles (gene frequency: A 81.9%, B 15.0%, C 2.5%, D 0.5%) and for TAP2 , nine alleles ( A1 31.7%, A2 14.2%, B 32.5%, Bky2 6.1%, C 6.9%, D 2.5%, E 3.9%, G 0.8%, and H 1.4%) were detected. Sixteen different TAP1-TAP2 haplotypes were observed with frequencies > 0.5%, and we found that significant linkage disequilibrium was present between TAP1 and TAP2 loci ( p HLA-DRB1-DQB1 haplotypes were extended to TAP1 and TAP2 loci, much diversification of haplotypes was observed: 26 different DRB1-DQB1 haplotypes (frequencies > 0.8%) formed 90 different extended haplotypes. Eight recombinant haplotypes between DQB1 and DPB1 loci were observed, and most (seven of eight) of the recombinations occurred between TAP2 and DPB1 loci. These results add more evidence to the view that recombination hot spot is present within and around TAP gene region.
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association of tap1 and TAP2 gene polymorphisms with systemic sclerosis in korean patients
Human Immunology, 2005Co-Authors: Yeong Wook Song, Dong Hee Whang, Eun Bong Lee, Su Jin Kang, Fujio Takeuchi, Myoung Hee ParkAbstract:We sought to determine whether transporter associated with antigen processing (TAP) gene polymorphism is associated with susceptibility to systemic sclerosis (SSc). TAP1 and TAP2 gene polymorphisms were analyzed in 61 Korean patients with SSc and 100 ethnically matched healthy Koreans by polymerase chain reaction–restriction fragment length polymorphism. Human leukocyte antigen (HLA)-DRB1 genotyping data of the patients from our previous study was used for the assessment of independent role of TAP genes to SSc susceptibility. Patients were stratified according to anti–topoisomerase I (anti–topo I) antibody status and clinical subsets of diffuse and limited cutaneous SSc (dcSSc and lcSSc). TAP1 and TAP2 gene polymorphisms were associated with different subsets of SSc: TAP1*A/A genotype with anti–topo I–positive dcSSc (p = 0.01, p corrected = 0.04), TAP2*A1/C genotype with anti–topo I–positive lcSSc (p < 0.05), TAP2*Bky2 and *C alleles with anti–topo I–negative dcSSc (both p < 0.05), and TAP2*B/E genotype with anti–topo I–negative lcSSc (p = 0.004). Although TAP gene associations were generally weak, some associations (TAP2*A1/C, TAP2*C, and TAP2*B/E) with different subsets of SSc were independent of HLA-DR associations, revealing even stronger associations (TAP2*A1/C and TAP2*C) among individuals not possessing the risk HLA-DR alleles. These results suggest the possible role of TAP gene polymorphisms in the genetic susceptibility to SSc.
Robert Tampé - One of the best experts on this subject based on the ideXlab platform.
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assembly and function of the major histocompatibility complex mhc i peptide loading complex are conserved across higher vertebrates
Journal of Biological Chemistry, 2014Co-Authors: Andreas Hinz, Joachim Koch, Johanna Jedamzick, Valentina Herbring, Hanna Fischbach, Jessica Hartmann, David Parcej, Robert TampéAbstract:Abstract Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruit tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific.
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The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex
Journal of immunology (Baltimore Md. : 1950), 2008Co-Authors: Marieke C. Verweij, Danijela Koppers-lalic, Edwin Quinten, Sandra Loch, Florian Klauschies, Paul J. Lehner, Arend Mulder, Michael R. Knittler, Robert Tampé, Joachim KochAbstract:TAP translocates virus-derived peptides from the cytosol into the endoplasmic reticulum, where the peptides are loaded onto MHC class I molecules. This process is crucial for the detection of virus-infected cells by CTL that recognize the MHC class I-peptide complexes at the cell surface. The varicellovirus bovine herpesvirus 1 encodes a protein, UL49.5, that acts as a potent inhibitor of TAP. UL49.5 acts in two ways, as follows: 1) by blocking conformational changes of TAP required for the translocation of peptides into the endoplasmic reticulum, and 2) by targeting TAP1 and TAP2 for proteasomal degradation. At present, it is unknown whether UL49.5 interacts with TAP1, TAP2, or both. The contribution of other members of the peptide-loading complex has not been established. Using TAP-deficient cells reconstituted with wild-type and recombinant forms of TAP1 and TAP2, TAP was defined as the prime target of UL49.5 within the peptide-loading complex. The presence of TAP1 and TAP2 was required for efficient interaction with UL49.5. Using deletion mutants of TAP1 and TAP2, the 6+6 transmembrane core complex of TAP was shown to be sufficient for UL49.5 to interact with TAP and block its function. However, UL49.5-induced inhibition of peptide transport was most efficient in cells expressing full-length TAP1 and TAP2. Inhibition of TAP by UL49.5 appeared to be independent of the presence of other peptide-loading complex components, including tapasin. These results demonstrate that UL49.5 acts directly on the 6+6 transmembrane TAP core complex of TAP by blocking essential conformational transitions required for peptide transport.
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functional cysteine less subunits of the transporter associated with antigen processing tap1 and TAP2 by de novo gene assembly
FEBS Letters, 2003Co-Authors: Susanne Heintke, Joachim Koch, Barbara Seliger, Ulrike Ritz, Rupert Abele, Min Chen, Brigitte Lankatbuttgereit, Robert TampéAbstract:Within the adaptive immune system the transporter associated with antigen processing (TAP) plays a pivotal role in loading of peptides onto major histocompatibility (MHC) class I molecules. As a central tool to investigate the structure and function of the TAP complex, we created cysteine-less human TAP subunits by de novo gene synthesis, replacing all 19 cysteines in TAP1 and TAP2. After expression in TAP-deficient human fibroblasts, cysteine-less TAP1 and TAP2 are functional with respect to adenosine triphosphate (ATP)-dependent peptide transport and inhibition by ICP47 from herpes simplex virus. Cysteine-less TAP1 and TAP2 restore maturation and intracellular trafficking of MHC class I molecules to the cell surface.
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pairing of the nucleotide binding domains of the transporter associated with antigen processing
Journal of Biological Chemistry, 2000Co-Authors: Philip E. Lapinski, Robert Tampé, Gregory G Miller, Malini RaghavanAbstract:Abstract The transporter associated with antigen processing (TAP) comprises two structurally related subunits, TAP1 and TAP2, that form stable complexes in endoplasmic reticulum (ER) membranes. TAP complexes function in the translocation of peptides from the cytosol into the ER lumen for presentation by major histocompatibility complex class I molecules. Each TAP subunit contains an N-terminal membrane-spanning region with multiple membrane-spanning segments, and a C-terminal, cytosolic nucleotide binding region. To study the nature of the interactions occurring on the cytosolic face of TAP1/TAP2 complexes, we investigated quaternary associations mediated by two C-terminal fragments of human TAP1 (T1c, residues 452–748 and T1ctr, residues 472–748) and two C-terminal fragments of human TAP2 (T2c, residues 399–686 and T2ctr, residues 433–686). Each of these constructs contains the core nucleotide binding region as well as a long or short N-terminal extension. We show stable complex formation between T1c and T2c but not between T1ctr and T2ctr. The mechanistic implications of these results are discussed. We also show that each of the constructs except T1ctr interacts with wild type TAP1 and TAP2, indicating possibilities for homodimerization of TAP1 and TAP2, or of oligomerization of TAP1/TAP2 heterodimers on membranes.
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functional expression and purification of the abc transporter complex associated with antigen processing tap in insect cells
FEBS Letters, 1994Co-Authors: Thomas H Meyer, Robert Tampé, Peter Van Endert, Stephan Uebel, Bettina EhringAbstract:Using the baculovirus expression system the gene products of human tap1 and TAP2 were over-expressed as wild-type as well as oligohistidine fusion proteins in Spodoptera frugiperda (Sf9) insect cells. Both gene products were co-expressed within the same cells and were found enriched in microsomal membranes. Immunoprecipitation and immobilized metal affinity chromatography revealed complex formation between TAP1 and TAP2. The expressed TAP complex was shown to be functional by peptide translocation into microsomes of Sf9 cells. Peptide transport strictly requires TAP1 and TAP2 as well as ATP. For the first time the functional expression of the human TAP complex in insect cells has been demonstrated, indicating that additional cofactors of a highly developed immune system are not essential for peptide transport across microsomal membranes.
Shunichi Kumagai - One of the best experts on this subject based on the ideXlab platform.
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association of the TAP2 bky2 allele with presence of ss a ro and other autoantibodies in japanese patients with systemic lupus erythematosus
Lupus, 2003Co-Authors: Sugayo Kanagawa, Akio Morinobu, Masahiro Koshiba, G. Kageyama, Nobuhide Hayashi, Shin Yoshino, Yoshiaki Tokano, Hiroshi Hashimoto, Shunichi KumagaiAbstract:We previously reported that a new allele of transporter associated with antigen processing (TAP) 2 gene, TAP2*Bky2 (Val577), was significantly increased in Japanese patients with Sjogren’s syndrome (SS) and had a strong association with SS-A=Ro antibody production. In the present study, it was investigated whether the association of TAP2*Bky2 with SS-A=Ro antibody production was also found in Japanese patients with systemic lupus erythematosus (SLE). Polymorphisms of the TAP1 and TAP2 genes were determined in 114 Japanese SLE patients by the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) method. The allele frequencies of the TAP1 and TAP2 genes in SLE patients were not significantly different from those in controls, although the allele frequency of TAP2*Bky2 was slightly higher in SLE patients than in healthy control subjects (9.2% vs 5.5%, P = 0.126). The allele frequency of TAP2*Bky2 was significantly higher in SLE patients with oral ulcers than in those without. It was n...
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Association of the TAP2*Bky2 allele with presence of SS-A/Ro and other autoantibodies in Japanese patients with systemic lupus erythematosus
Lupus, 2003Co-Authors: Sugayo Kanagawa, Akio Morinobu, Masahiro Koshiba, G. Kageyama, Nobuhide Hayashi, Shin Yoshino, Yoshiaki Tokano, Hiroshi Hashimoto, Shunichi KumagaiAbstract:We previously reported that a new allele of transporter associated with antigen processing (TAP) 2 gene, TAP2*Bky2 (Val577), was significantly increased in Japanese patients with Sjogren’s syndrome (SS) and had a strong association with SS-A=Ro antibody production. In the present study, it was investigated whether the association of TAP2*Bky2 with SS-A=Ro antibody production was also found in Japanese patients with systemic lupus erythematosus (SLE). Polymorphisms of the TAP1 and TAP2 genes were determined in 114 Japanese SLE patients by the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) method. The allele frequencies of the TAP1 and TAP2 genes in SLE patients were not significantly different from those in controls, although the allele frequency of TAP2*Bky2 was slightly higher in SLE patients than in healthy control subjects (9.2% vs 5.5%, P = 0.126). The allele frequency of TAP2*Bky2 was significantly higher in SLE patients with oral ulcers than in those without. It was n...
A Arnaizvillena - One of the best experts on this subject based on the ideXlab platform.
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differential contribution of hla dr dq and TAP2 alleles to systemic lupus erythematosus susceptibility in spanish patients role of TAP2 01 alleles in ro autoantibody production
Annals of the Rheumatic Diseases, 1998Co-Authors: J M Martinvilla, M. Alvarez, J Martinezlaso, Narcisa Martinezquiles, M A Morenopelayo, M J Castropanete, M D De Juan, Juan J Gomezreino, A ArnaizvillenaAbstract:OBJECTIVE—To study the influence MHC class II and TAP2 alleles exert on systemic lupus erythematosus (SLE) susceptibility and on the clinical and serological manifestations of the disease, in a cohort of Spanish patients. METHODS—HLA-DR serological typing and HLA-DQA, DQB, and TAP2 DNA sequence specific oligotyping, were carried out in 85 unrelated Spanish SLE patients and 186 healthy controls. Autoantibodies detection was carried out by indirect immunofluorescence and counter immunoelectrophoresis. RESULTS—Total SLE group: the frequency of HLA-DR3 and HLA-DQA1*0501 is significantly increased in this group (pc<0.005, δ=0.34 and pc<0.005, δ= 0.45, respectively) although the highest δ value (δ=0.87) is obtained when the TAP2*01 alleles are considered. No DQB allele shows significant deviation from the control group. Renal damage: it mainly occurs in HLA-DR3 patients (pc<0.0005 and δ=0.72). HLA-DQA1*0501 (pc<0.05, δ=0.57) and DQB1*0201 (pc NS, δ=0.56) are weaker susceptibility factors. Ro+ (but not La) group: this autoantibody response is associated with TAP2*01 alleles in homozygosity (p<0.05, δ=0.81). Ro/La+ group: it has a different genetic background as HLA-DQA1*0501 (δ=1) and HLA-DQB1*0201 (δ=1) are the main susceptibility factors. CONCLUSIONS—A differential association between HLA-DR, DQA1, and DQB1 alleles and SLE or its clinical and serological manifestations are found. Furthermore, the associations are different to the ones reported in other ethnic groups. Finally, TAP2*01 group of alleles are associated with the highest susceptibility to SLE (higher than HLA-DR3) and may influence Ro (but not La) autoantibodies production, whereas HLA-DQA1*0501 and DQB1*0201 mediates concomitant Ro and La production. Keywords: TAP2 alleles; HLA class II alleles; systemic lupus erythematosus
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susceptibility to insulin dependent diabetes mellitus and short cytoplasmic atp binding domain TAP2 01 alleles
Tissue Antigens, 1994Co-Authors: J Martinezlaso, M. Alvarez, Gregorio Lledo, J M Martinvilla, Narcisa Martinezquiles, A ArnaizvillenaAbstract:TAP2 genes are placed within the HLA complex, have limited genetic variability and encode two main groups of peptide transporter proteins, the so-called TAP2*01 alleles, with a short ATP-binding domain, and the TAP2*0201 allele with a long domain. These transporters carry antigenic peptides from cytoplasm across the endoplasmic reticulum membrane to release them into nascent HLA class I molecules, which will then travel towards the plasma membrane. The shorter TAP2*01 alleles are present in 99% of diabetics and 90% of controls; these alleles may add slight, although significant and independent, susceptibility to diabetes, particularly in subjects carrying non-Asp 57 at beta DQ. Moreover, this increased susceptibility is not due to linkage disequilibrium with other HLA markers (i.e.: DR4), which does not exist in our Spanish population.
