24 results on '"Pando MJ"'
Search Results
2. HLA Homozygosity and Likelihood of Sensitization in Kidney Transplant Candidates.
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Rushakoff JA, Gragert L, Pando MJ, Stewart D, Huang E, Kim I, Jordan S, Lindblad K, Zhang X, Lalli P, Patel JK, Kobashigawa JA, and Kransdorf EP
- Abstract
Background: Homozygosity for HLAs has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization., Methods: We measured sensitization using the calculated panel reactive antibody value for a large cohort of 147 461 patients added to the US OPTN/United Network for Organ Sharing kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62 510 sensitized patients to 84 955 unsensitized controls., Results: We found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within mildly, highly, or extremely sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared with men, with attenuation of this effect in Black candidates. In a multivariable logistic model, the number of homozygous HLA loci interacted with female sex but not with other factors associated with sensitization, including recipient ethnicity and a history of prior kidney transplant., Conclusions: This study shows that HLA homozygosity is an innate genetic factor that affects the likelihood of HLA sensitization. Further research is needed to identify the immunologic mechanisms that underlie this observation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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3. Stem cell donor HLA typing improves CPRA in kidney allocation.
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Kransdorf EP, Pando MJ, Stewart D, Lindblad K, Bray R, Murphey C, Kaur N, Patel JK, Kim I, Zhang X, Maiers M, Kobashigawa JA, and Gragert L
- Subjects
- HLA Antigens, Histocompatibility Testing, Humans, Kidney, Stem Cells, Tissue Donors, Isoantibodies, Tissue and Organ Procurement
- Abstract
The Organ Procurement and Transplantation Network (OPTN) Kidney Allocation System provides a priority to sensitized candidates based on the calculated panel reactive antibody (CPRA) value. The human leukocyte antigen (HLA) haplotype reference panel used for calculation of the CPRA by the United Network for Organ Sharing (UNOS), the OPTN contractor, has limitations. We derived a novel panel from the National Marrow Donor Program HLA haplotype data set and compared the accuracy of CPRA values generated with this panel (NMDP-CPRA) to those generated from the UNOS panel (UNOS-CPRA), using predicted and actual deceased donor kidney offers for a cohort of 24 282 candidates. The overall accuracy for kidney offers was similar using NMDP-CPRA and UNOS-CPRA. Accuracy was slightly higher for NMDP-CPRA than UNOS-CPRA for candidates in several highly sensitized CPRA categories, with deviations in linkage disequilibrium for Caucasians and the smaller size of the UNOS panel as contributing factors. HLA data derived from stem cell donors yields CPRA values that are comparable to those derived from deceased kidney donors while improving upon several problems with the current reference panel. Consideration should be given to using stem cell donors as the reference panel for calculation of CPRA to improve equity in kidney transplant allocation., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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4. A blueprint for electronic utilization of ambiguous molecular HLA typing data in organ allocation systems and virtual crossmatch.
- Author
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Kaur N, Pinelli D, Kransdorf EP, Pando MJ, Smith G, Murphey CL, Kamoun M, Bray RA, Tambur A, and Gragert L
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- Humans, Patient Selection, HLA Antigens immunology, Histocompatibility Testing methods, Internet, Organ Transplantation, Software
- Abstract
Virtual crossmatch (VXM) compares a transplant candidate's unacceptable antigens to the HLA typing of the donor before an organ offer is accepted and, in selected cases, supplant a prospective physical crossmatch. However, deceased donor typing can be ambiguous, leading to uncertainty in compatibility prediction. We have developed a prototype web application that utilizes ambiguous HLA molecular typing data to predict which unacceptable antigens are present in the donor HLA genotype as donor-specific antibodies (DSA). The application compares a candidate's listed unacceptable antigens to computed probabilities of all possible two-field donor HLA alleles and UNOS antigens. The VIrtual CrossmaTch for mOleculaR HLA typing (VICTOR) tool can be accessed at http://www.transplanttoolbox.org/victor. We reanalyzed historical VXM cases where a transplant center's manual interpretation of molecular typing results influenced offer evaluation. We found that interpretation of ambiguous donor molecular typing data using imputation could one day influence VXM decisions if the DSA predictions were rigorously validated. Standardized interpretation of molecular typing data, if applied to the match run, could also change which offers are made. HLA typing ambiguity has been an underappreciated source of immunological risk in organ transplantation. The VICTOR tool can serve as a testbed for development of allocation policies with the aim of decreasing offers refused due to HLA incompatibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
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- 2020
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5. Comparison of sequence-specific oligonucleotide probe vs next generation sequencing for HLA-A, B, C, DRB1, DRB3/B4/B5, DQA1, DQB1, DPA1, and DPB1 typing: Toward single-pass high-resolution HLA typing in support of solid organ and hematopoietic cell transplant programs.
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Smith AG, Pereira S, Jaramillo A, Stoll ST, Khan FM, Berka N, Mostafa AA, Pando MJ, Usenko CY, Bettinotti MP, Pyo CW, Nelson WC, Willis A, Askar M, and Geraghty DE
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- Alleles, Humans, Genotyping Techniques, HLA Antigens genetics, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Histocompatibility Testing, Oligonucleotide Probes genetics, Organ Transplantation
- Abstract
Many clinical laboratories supporting solid organ transplant programs use multiple HLA genotyping technologies, depending on individual laboratory needs. Sequence-specific primers and quantitative polymerase chain reaction (qPCR) serve the rapid turnaround necessary for deceased donor workup, while sequence-specific oligonucleotide probe (SSOP) technology is widely employed for higher volumes. When clinical need mandates high-resolution data, Sanger sequencing-based typing (SBT) has been the "gold standard." However, all those methods commonly yield ambiguous typing results that utilize valuable laboratory resources when resolution is required. In solid organ transplantation, high-resolution typing may provide critical information for highly sensitized patients with donor-specific anti-HLA antibodies (DSA), particularly when DSA involve HLA alleles not discriminated by SSOP typing. Arguments against routine use of SBT include assay complexity, long turnaround times (TAT), and increased costs. Here, we compare a next generation sequencing (NGS) technology with SSOP for accuracy, effort, turnaround time, and level of resolution for genotyping of 11 HLA loci among 289 specimens from five clinical laboratories. Results were concordant except for SSOP misassignments in eight specimens and 21 novel sequences uniquely identified by NGS. With few exceptions, SSOP generated ambiguous results while NGS provided unambiguous three-field allele assignments. For complete HLA genotyping of up to 24 samples by either SSOP or NGS, bench work was completed on day 1 and typing results were available on day 2. This study provides compelling evidence that, although not viable for STAT typing of deceased donors, a single-pass NGS HLA typing method has direct application for solid organ transplantation., (© 2019 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)
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- 2019
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6. Mapping molecular HLA typing data to UNOS antigen equivalents.
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Kaur N, Kransdorf EP, Pando MJ, Maiers M, Ray B, Lee JH, Lalli P, Murphey CL, Bray RA, and Gragert L
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- Alleles, Computational Biology methods, Gene Frequency, HLA Antigens immunology, Humans, Software, United States, Web Browser, Chromosome Mapping, HLA Antigens genetics, Histocompatibility Testing methods
- Abstract
Background: Histocompatibility labs must convert molecular HLA typing data to antigen equivalencies for entry into the United Network for Organ Sharing (UNOS) UNet system. While an Organ Procurement and Transplantation Network (OPTN) policy document provides general guidelines for conversion, the process is complex because no antigen mapping table is available. We present a UNOS antigen equivalency table for all IPD-IMGT/HLA alleles at the A, B, C, DRB1, DRB3/4/5, DQA1, and DQB1 loci., Methods: An automated script was developed to generate a UNOS antigen equivalency table. Data sources used in the conversion algorithm included the World Marrow Donor Association (WMDA) antigen table, the HLA Dictionary, and UNOS-provided tables. To validate antigen mappings, we converted National Marrow Donor Program (NMDP) high resolution allele frequencies to antigen equivalents and compared with the UNOS Calculated Panel Reactive Antibodies (CPRA) reference panel., Results: Normalized frequency similarity scores between independent NMDP and UNOS panels for 4 US population categories (Caucasian, Hispanic, African American and Asian/Pacific Islander) ranged from 0.85 to 0.97, indicating correct antigen mapping. An open source web application (ALLele to ANtigen ("ALLAN")) and web services were also developed to map unambiguous and ambiguous HLA typing data to UNOS antigen equivalents based on NMDP population-specific allele frequencies (http://www.transplanttoolbox.org)., Conclusions: Computer-assisted interpretation of molecular HLA data may aid in reducing typing discrepancies in UNet. This work also sets a foundation for molecular typing data to be utilized directly in the UNet match run as well as the virtual crossmatch process at transplant centers., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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7. The role of complement-fixing donor-specific antibodies identified by a C1q assay after heart transplantation.
- Author
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Farrero Torres M, Pando MJ, Luo C, Luikart H, Valantine H, and Khush K
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- Adult, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Transplantation, Homologous, Complement C1q immunology, Graft Rejection immunology, Graft Survival immunology, HLA Antigens immunology, Heart Transplantation, Isoantibodies immunology, Tissue Donors
- Abstract
Background: The development of donor-specific antibodies (DSA) to human leukocyte antigens (HLA) has been associated with acute rejection and allograft failure after heart transplantation. Not all DSA, however, can fix complement., Methods: To determine the association between complement-fixing DSA and heart transplant outcomes, we retrospectively analyzed results obtained using the C1q solid-phase assay that specifically detects complement-fixing DSA in parallel with the standard IgG assay in 121 adult heart transplant recipients., Results: The 52 recipients who developed post-transplant DSA had a higher incidence of acute cellular rejection (58% vs 19%, P < .001) and antibody-mediated rejection (29% vs 7%, P < .001) than the 69 recipients without DSA. The 24 recipients with C1q+ DSA had more antibody-mediated rejection than the 28 recipients with C1q- DSA (46% vs 14%, P = .012), but there was no difference in the incidence of acute cellular rejection between these two groups. Patients with post-transplant DSA had higher mortality than patients with no DSA (29% vs 13%, P = .031), mainly due to increased incidence of acute rejection. No differences in survival were found between recipients with C1q+ DSA and C1q- DSA., Conclusions: Routine monitoring of DSA post-transplant, and their characterization using the C1q assay, may provide prognostic information for acute rejection after heart transplantation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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8. HLA Population Genetics in Solid Organ Transplantation.
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Kransdorf EP, Pando MJ, Gragert L, and Kaplan B
- Subjects
- Graft Rejection immunology, Graft Rejection prevention & control, Graft Survival, HLA Antigens immunology, Humans, Isoantibodies immunology, Models, Genetic, Organ Transplantation adverse effects, Risk Factors, Treatment Outcome, Genetics, Population, Graft Rejection genetics, HLA Antigens genetics, Histocompatibility, Organ Transplantation methods, Polymorphism, Genetic
- Abstract
HLAs are fundamental to the adaptive immune response and play critical roles in the cellular and humoral response in solid organ transplantation. The genes encoding HLA proteins are the most polymorphic within the human genome, with thousands of different allelic variants known within the population. Application of the principles of population genetics to the HLA genes has resulted in the development of a numeric metric, the calculated panel-reactive antibody (CPRA) that predicts the likelihood of a positive crossmatch as a function of a transplant candidate's unacceptable HLA antigens. The CPRA is an indispensible measure of access to transplantation for sensitized candidates and is used as the official measure of sensitization for allocation of points in the US Kidney Allocation System and Eurotransplant. Here, we review HLA population genetics and detail the mathematical basis of the CPRA. An understanding of these principles by transplant clinicians will lay the foundation for continued innovation in the care of sensitized patients.
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- 2017
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9. Calculated panel-reactive antibody predicts outcomes on the heart transplant waiting list.
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Kransdorf EP, Kittleson MM, Patel JK, Pando MJ, Steidley DE, and Kobashigawa JA
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- Adult, Cohort Studies, Female, HLA Antigens blood, Heart Failure mortality, Heart Failure surgery, Histocompatibility Testing, Humans, Male, Middle Aged, Predictive Value of Tests, United States, Heart Failure immunology, Heart Transplantation, Patient Selection, Tissue and Organ Procurement, Waiting Lists
- Abstract
Background: Sensitized heart transplant candidates spend more time and have higher mortality on the waiting list. Although the calculated panel-reactive antibody (CPRA) value is used to assign allocation priority to kidney transplant candidates in the United States, the relationship between CPRA and outcomes on the heart transplant waiting list is unknown., Methods: A data set of patients listed for heart transplant with unacceptable human leukocyte antigens (HLA) entered was obtained from the United Network for Organ Sharing. The study cohort was composed of 3,855 adult candidates listed for heart transplant between 2006 and 2013 with active waiting time. The cohort was divided into 5 groups by increasing CPRA. Outcomes were assessed using competing risks and sub-hazard regression analyses., Results: In each group of successively higher CPRA, the percentage of candidates who received a transplant decreased, whereas the percentage of those who were still waiting for a transplant increased, as did the percentage of those removed from the waiting list or had died. The group of candidates with a CPRA >80% displayed a markedly decreased incidence of transplantation (hazard ratio 0.37) and an increased risk of removal from the waiting list or death (hazard ratio 2.18) as compared to those with CPRA of ≤10%., Conclusions: Sensitized heart transplant candidates are at high risk of adverse outcomes on the heart transplant waiting list. Clinicians should strive to minimize the CPRA by maximizing specificity in the selection of HLA antigens to exclude. The optimal clinical approach for candidates with high CPRA requires further study., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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10. Corrigendum to "Calculated panel reactive antibody with decimals: A refined metric of access to transplantation for highly sensitized candidates" [Hum. Immunol. 78(3) (2017) 252-256].
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Kransdorf EP and Pando MJ
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- 2017
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11. Calculated panel reactive antibody with decimals: A refined metric of access to transplantation for highly sensitized candidates.
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Kransdorf EP and Pando MJ
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- HLA Antigens genetics, HLA Antigens immunology, Humans, Isoantibodies immunology, Reproducibility of Results, Waiting Lists, Histocompatibility Testing methods, Kidney Transplantation, Tissue Donors statistics & numerical data, Tissue and Organ Procurement methods, Tissue and Organ Procurement statistics & numerical data
- Abstract
The use of the calculated panel reactive antibody (CPRA) value and the implementation of allocation points for sensitized candidates by the United Network for Organ Sharing (UNOS) have improved access to kidney transplantation for highly sensitized candidates (98% CPRA and above). Despite this, a large population of highly sensitized candidates remain awaiting transplantation. To better define this population, we propose the use of two refinements of the standard UNOS CPRA, the CPRA with decimals or CPRAd, and the likelihood of a compatible donor (LCD). These refined metrics of the standard UNOS CPRA will allow transplant programs to describe their patients' access to transplantation with increased granularity and will help in decisions regarding the use of desensitization., (Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
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- 2017
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12. De novo donor-specific human leukocyte antigen antibodies early after kidney transplantation.
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Heilman RL, Nijim A, Desmarteau YM, Khamash H, Pando MJ, Smith ML, Chakkera HA, Huskey J, Valdez R, and Reddy KS
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- Adult, Aged, Antibodies immunology, Biopsy, Cohort Studies, Female, Graft Rejection immunology, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class II immunology, Histocompatibility Testing, Humans, Kidney Transplantation, Male, Middle Aged, Retrospective Studies, Time Factors, HLA Antigens immunology, Kidney Failure, Chronic immunology, Kidney Failure, Chronic surgery
- Abstract
Background: Our aim was to determine the incidence of de novo donor-specific human leukocyte antigen (HLA) antibody (dnDSA) during the first year after kidney transplantation and the impact of early dnDSA on acute rejection and protocol biopsy findings., Methods: We selected all patients who received a kidney transplant at our center between July 2010 and March 2012. Single antigen bead assay was performed at 1, 4 and 12 months after transplantation. Only DSAs with a mean fluorescence intensity (MFI) of greater 999 were included., Results: We included 245 kidney transplant recipients who did not have a DSA before transplantation. At 12 months, 8.2% of the patients developed dnDSA; 2.4% of them were to HLA class I and 6.5% to HLA class II. Of the 32 patients with a dnDSA at 1 or 4 months, only 8 (25%) persisted at 12 months. The risk of antibody-mediated rejection (AMR) was higher in the dnDSA group. For the dnDSA group with MFI of 3,000 or greater (compared with the group with MFI<3,000), the hazard ratio for AMR was 10.6 (95% confidence interval, 2.27-49.5). The cumulative incidence of AMR or mixed rejection at 1 year was 30% in the group with dnDSA MFI level of 3,000 or greater but only 4% for the group with dnDSA with MFI less than 3,000. On 1-year protocol biopsies, the dnDSA group showed more interstitial inflammation, tubulitis, and glomerulitis., Conclusion: We conclude that dnDSA occurring during the first posttransplantation year may be transient, and the risk of AMR is higher in patients with a dnDSA MFI level that is greater than 3,000.
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- 2014
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13. Co-evolution of human leukocyte antigen (HLA) class I ligands with killer-cell immunoglobulin-like receptors (KIR) in a genetically diverse population of sub-Saharan Africans.
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Norman PJ, Hollenbach JA, Nemat-Gorgani N, Guethlein LA, Hilton HG, Pando MJ, Koram KA, Riley EM, Abi-Rached L, and Parham P
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- Africa South of the Sahara, Black People, Child, Evolution, Molecular, Genetics, Population, HLA Antigens immunology, Haplotypes, Humans, Ligands, Malaria immunology, Malaria pathology, Molecular Sequence Data, Receptors, KIR immunology, HLA Antigens genetics, Killer Cells, Natural, Malaria genetics, Receptors, KIR genetics, Selection, Genetic
- Abstract
Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1-14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen., Competing Interests: The authors have declared that no competing interests exist.
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- 2013
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14. Genetic risk variants in African Americans with multiple sclerosis.
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Isobe N, Gourraud PA, Harbo HF, Caillier SJ, Santaniello A, Khankhanian P, Maiers M, Spellman S, Cereb N, Yang S, Pando MJ, Piccio L, Cross AH, De Jager PL, Cree BA, Hauser SL, and Oksenberg JR
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- Adult, Age of Onset, Alleles, Case-Control Studies, Female, Genetic Association Studies, Genotype, HLA-A Antigens genetics, HLA-DQ beta-Chains genetics, HLA-DRB1 Chains genetics, Humans, Male, Middle Aged, Multiple Sclerosis epidemiology, Black or African American genetics, Genetic Predisposition to Disease, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide
- Abstract
Objectives: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls)., Methods: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations., Results: The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans., Conclusion: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.
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- 2013
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15. Pregnancy-related human leukocyte antigen sensitization leading to cardiac allograft vasculopathy and graft failure in a heart transplant recipient: a case report.
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Ginwalla M, Pando MJ, and Khush KK
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- Adult, Arrhythmias, Cardiac immunology, Coronary Angiography, Coronary Artery Disease diagnosis, Coronary Artery Disease surgery, Cross Reactions, Female, Graft Rejection diagnosis, Graft Rejection surgery, Heart Failure immunology, Heart Transplantation adverse effects, Histocompatibility, Histocompatibility Testing, Humans, Immunosuppressive Agents therapeutic use, Pregnancy, Reoperation, Time Factors, Treatment Outcome, Cardiomyopathies surgery, Coronary Artery Disease immunology, Graft Rejection immunology, HLA Antigens immunology, Heart Transplantation immunology, Isoantibodies blood
- Abstract
In this report, we present a heart transplant recipient who developed cross-reactive paternal and donor-specific human leukocyte antigen (HLA) class II antibodies during pregnancy, leading to accelerated cardiac allograft vasculopathy and severe allograft dysfunction 17 years after transplantation. This resulted in acute heart failure and ventricular arrhythmias requiring repeat heart transplantation., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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16. Desensitization combined with paired exchange leads to successful transplantation in highly sensitized kidney transplant recipients: strategy and report of five cases.
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Yabu JM, Pando MJ, Busque S, and Melcher ML
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- Adult, Algorithms, Antibodies immunology, Female, Graft Rejection immunology, HLA Antigens immunology, Histocompatibility, Histocompatibility Testing, Humans, Kidney immunology, Kidney Failure, Chronic immunology, Kidney Failure, Chronic surgery, Male, Middle Aged, Desensitization, Immunologic methods, Graft Survival immunology, Kidney Failure, Chronic therapy, Kidney Transplantation immunology, Living Donors, Tissue and Organ Procurement methods
- Abstract
Sensitization remains a major barrier to kidney transplantation. Sensitized patients comprise 30% of the kidney transplant waiting list but fewer than 15% of highly sensitized patients are transplanted each year. Options for highly sensitized patients with an immunologically incompatible living donor include desensitization or kidney paired donation (KPD). However, these options when used alone may still not be sufficient to allow a compatible transplant for recipients who are broadly sensitized with cumulative calculated panel-reactive antibody (cPRA) > 95%. We describe in this report the combined use of both desensitization and KPD to maximize the likelihood of finding a compatible match with a more immunologically favorable donor through a kidney exchange program. This combined approach was used in five very highly sensitized patients, all with cPRA 100%, who ultimately received compatible living and deceased donor kidney transplants. We conclude that early enrollment in paired kidney donor exchange and tailored desensitization protocols are key strategies to improve care and rates of kidney transplantation in highly sensitized patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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17. Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection.
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Lopez-Vergès S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, and Lanier LL
- Subjects
- Acute Disease, Biomarkers metabolism, CD56 Antigen immunology, CD56 Antigen metabolism, CD57 Antigens biosynthesis, Cell Degranulation immunology, Cytomegalovirus metabolism, Cytomegalovirus Infections metabolism, GPI-Linked Proteins immunology, GPI-Linked Proteins metabolism, Gene Expression Regulation immunology, HLA-B Antigens immunology, HLA-B Antigens metabolism, Humans, Immunologic Memory, Killer Cells, Natural metabolism, NK Cell Lectin-Like Receptor Subfamily C biosynthesis, Organ Transplantation, Receptors, IgG immunology, Receptors, IgG metabolism, Receptors, KIR3DL1 immunology, Receptors, KIR3DL1 metabolism, Tissue Donors, Transplantation, Homologous, CD57 Antigens immunology, Cell Proliferation, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Killer Cells, Natural immunology, NK Cell Lectin-Like Receptor Subfamily C immunology
- Abstract
During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56(dim)CD16(+) NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94-NKG2C receptor and CD57 in CMV(+) donors. These CD57(+)NKG2C(hi) NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57(+)NKG2C(hi) NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57(+)NKG2C(hi) NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C(+) NK cells proliferated, became NKG2C(hi), and finally acquired CD57. Thus, we propose that CD57 might provide a marker of "memory" NK cells that have been expanded in response to infection.
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- 2011
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18. A multi-site study using high-resolution HLA genotyping by next generation sequencing.
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Holcomb CL, Höglund B, Anderson MW, Blake LA, Böhme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Pröll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Thiele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, and Erlich HA
- Subjects
- Alleles, Base Sequence, Double-Blind Method, Family Characteristics, Genotype, HLA Antigens analysis, Humans, Models, Biological, Molecular Sequence Data, Multicenter Studies as Topic, Sequence Analysis, DNA methods, Software, HLA Antigens genetics, High-Throughput Nucleotide Sequencing methods, Sequence Analysis, DNA trends
- Abstract
The high degree of polymorphism at human leukocyte antigen (HLA) class I and class II loci makes high-resolution HLA typing challenging. Current typing methods, including Sanger sequencing, yield ambiguous typing results because of incomplete genomic coverage and inability to set phase for HLA allele determination. The 454 Life Sciences Genome Sequencer (GS FLX) next generation sequencing system coupled with conexio atf software can provide very high-resolution HLA genotyping. High-throughput genotyping can be achieved by use of primers with multiplex identifier (MID) tags to allow pooling of the amplicons generated from different individuals prior to sequencing. We have conducted a double-blind study in which eight laboratory sites performed amplicon sequencing using GS FLX standard chemistry and genotyped the same 20 samples for HLA-A, -B, -C, DPB1, DQA1, DQB1, DRB1, DRB3, DRB4, and DRB5 (DRB3/4/5) in a single sequencing run. The average sequence read length was 250 base pairs and the average number of sequence reads per amplicon was 672, providing confidence in the allele assignments. Of the 1280 genotypes considered, assignment was possible in 95% of the cases. Failure to assign genotypes was the result of researcher procedural error or the presence of a novel allele rather than a failure of sequencing technology. Concordance with known genotypes, in cases where assignment was possible, ranged from 95.3% to 99.4% for the eight sites, with overall concordance of 97.2%. We conclude that clonal pyrosequencing using the GS FLX platform and CONEXIO ATF software allows reliable identification of HLA genotypes at high resolution., (© 2011 John Wiley & Sons A/S.)
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- 2011
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19. Interactions of NK cell receptor KIR3DL1*004 with chaperones and conformation-specific antibody reveal a functional folded state as well as predominant intracellular retention.
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Taner SB, Pando MJ, Roberts A, Schellekens J, Marsh SG, Malmberg KJ, Parham P, and Brodsky FM
- Subjects
- Antibodies, Monoclonal chemistry, Calreticulin chemistry, Calreticulin metabolism, Cell Line, Endoplasmic Reticulum chemistry, Endoplasmic Reticulum immunology, Endoplasmic Reticulum metabolism, HLA-B Antigens metabolism, Humans, Intracellular Fluid chemistry, Killer Cells, Natural chemistry, Ligands, Molecular Chaperones chemistry, Protein Binding immunology, Protein Conformation, Protein Transport immunology, Protein Unfolding, Receptors, KIR3DL1 chemistry, Stress, Physiological immunology, Antibodies, Monoclonal metabolism, Intracellular Fluid immunology, Intracellular Fluid metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Molecular Chaperones metabolism, Protein Folding, Receptors, KIR3DL1 metabolism
- Abstract
Variable interaction between the Bw4 epitope of HLA-B and the polymorphic KIR3DL1/S1 system of inhibitory and activating NK cell receptors diversifies the development, repertoire formation, and response of human NK cells. KIR3DL1*004, a common KIR3DL1 allotype, in combination with Bw4(+) HLA-B, slows progression of HIV infection to AIDS. Analysis in this study of KIR3DL1*004 membrane traffic in NK cells shows this allotype is largely misfolded but stably retained in the endoplasmic reticulum, where it binds to the chaperone calreticulin and does not induce the unfolded protein response. A small fraction of KIR3DL1*004 folds correctly and leaves the endoplasmic reticulum to be expressed on the surface of primary NK and transfected NKL cells, in a form that can be triggered to inhibit NK cell activation and secretion of IFN-γ. Consistent with this small proportion of correctly folded molecules, trace amounts of MHC class I coimmunoprecipitated with KIR3DL1*004. There was no indication of any extensive intracellular interaction between unfolded KIR3DL1*004 and cognate Bw4(+) HLA-B. A similarly limited interaction of Bw4 with KIR3DL1*002, when both were expressed by the same cell, was observed despite the efficient folding of KIR3DL1*002 and its abundance on the NK cell surface. Several positions of polymorphism modulate KIR3DL1 abundance at the cell surface, differences that do not necessarily correlate with the potency of allotype function. In this context, our results suggest the possibility that the effect of Bw4(+) HLA-B and KIR3DL1*004 in slowing progression to AIDS is mediated by interaction of Bw4(+) HLA-B with the small fraction of cell surface KIR3DL1*004.
- Published
- 2011
- Full Text
- View/download PDF
20. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
- Author
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Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, and Kingsmore SF
- Subjects
- Adolescent, Adult, Allelic Imbalance genetics, Breast metabolism, Breast Neoplasms genetics, CD4-Positive T-Lymphocytes metabolism, Case-Control Studies, CpG Islands genetics, DNA Copy Number Variations genetics, DNA Methylation genetics, Female, Genetic Predisposition to Disease genetics, Haplotypes genetics, Heterozygote, Humans, INDEL Mutation genetics, Lung metabolism, Lung Neoplasms genetics, Male, Polymorphism, Genetic genetics, Quantitative Trait Loci genetics, RNA, Messenger analysis, RNA, Messenger metabolism, Epigenesis, Genetic genetics, Genome, Human genetics, Multiple Sclerosis genetics, RNA, Messenger genetics, Twins, Monozygotic genetics
- Abstract
Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.
- Published
- 2010
- Full Text
- View/download PDF
21. KIR3DL1 polymorphisms that affect NK cell inhibition by HLA-Bw4 ligand.
- Author
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Carr WH, Pando MJ, and Parham P
- Subjects
- Alleles, Antibodies, Monoclonal, Antigens, CD genetics, Antigens, CD metabolism, Cell Line, Tumor, Cytotoxicity, Immunologic genetics, Histocompatibility Antigens Class I immunology, Humans, Killer Cells, Natural immunology, Leukocyte Immunoglobulin-like Receptor B1, Ligands, Molecular Sequence Data, Protein Structure, Tertiary, Receptors, Immunologic metabolism, Receptors, Immunologic physiology, Receptors, KIR, Receptors, KIR3DL1, HLA-B Antigens metabolism, Killer Cells, Natural physiology, Polymorphism, Genetic, Receptors, Immunologic genetics
- Abstract
The killer cell Ig-like receptor (KIR) gene family encodes MHC class I receptors expressed by NK cells and several T cell subpopulations. Factors contributing to human KIR haplotype diversity are differences in gene number, gene content, and allelic polymorphism. Whereas functional and clinical consequences of the first two factors are established, knowledge of the effects of KIR gene polymorphism is limited to special cases in which signaling function is reversed or cell surface expression lost. In this study we use retrovirally transduced human cell lines to show that 3DL1*002 is a stronger inhibitory receptor for HLA-Bw4 ligands than 3DL1*007. Analysis of mutant 3DL1*002 and 3DL1*007 molecules demonstrates that residue 238 in the D2 domain and 320 in the transmembrane region contribute to the difference in receptor strength. Neither position 238 nor 320 is predicted to interact directly with HLA-Bw4 ligand. This study also revealed that KIR3DL1 and LILRB1 both contribute to developing an inhibitory response to HLA-Bw4 ligands.
- Published
- 2005
- Full Text
- View/download PDF
22. The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1.
- Author
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Pando MJ, Gardiner CM, Gleimer M, McQueen KL, and Parham P
- Subjects
- Cell Line, Cell Membrane genetics, Cell Membrane immunology, Cell Membrane metabolism, Clone Cells, Endoplasmic Reticulum chemistry, Endoplasmic Reticulum genetics, Endoplasmic Reticulum immunology, Extracellular Space chemistry, Extracellular Space genetics, Extracellular Space immunology, Humans, Immunophenotyping, Jurkat Cells, Killer Cells, Natural immunology, Leucine chemistry, Leucine genetics, Polymorphism, Genetic immunology, Protein Structure, Tertiary genetics, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic chemistry, Receptors, KIR, Receptors, KIR3DL1, Serine chemistry, Serine genetics, Transfection, Alleles, Amino Acid Substitution genetics, Amino Acid Substitution immunology, Immunoglobulins chemistry, Immunoglobulins genetics, Killer Cells, Natural metabolism, Receptors, Immunologic biosynthesis, Receptors, Immunologic genetics
- Abstract
KIR3DL1 is an inhibitory HLA-B receptor of human NK and T cells that exhibits genetic and phenotypic polymorphism. KIR3DL1*004, a common allotype, cannot be detected on the surface of PBLs using the KIR3DL1-specific Ab DX9. The nature of this phenotype was investigated through comparison of 3DL1*004 with 3DL1*002, an allele giving high DX9 binding to cell surfaces. Analysis of Jurkat T cell transfectants with 3DL1*004 cDNA showed that 3DL1*004 is poorly expressed at the cell surface, but detectable intracellularly. Analysis of recombinant mutants made between 3DL1*004 and 3DL1*002 showed that polymorphism in Ig domains 0 and 1 (D0 and D1) causes the intracellular retention of 3DL1*004. Reciprocal point mutations were introduced into 3DL1*004 and 3DL1*002 at positions 44 and 86 of the D0 domain, where 3DL1*004 has unique residues, and at position 182 of the D1 domain, where 3DL1*004 resembles 3DL1*005, an allotype giving low DX9-binding phenotype. Leucine 86 in 3DL1*004 is the principal cause of its intracellular retention, with a secondary and additive contribution from serine 182. By contrast, glycine 44, which is naturally present in 3DL1*004, slightly increased cell surface expression when introduced into 3DL1*002. In 3DL1*004, the presence of leucine at position 86 corrupts the WSXPS motif implicated in proper folding of the KIR D0 Ig-like domain. This study demonstrates how a difference between KIR3DL1 allotypes in the D0 domain profoundly affects cell surface expression and function.
- Published
- 2003
- Full Text
- View/download PDF
23. Discovery of two novel variants of KIR2DS5 reveals this gene to be a common component of human KIR 'B' haplotypes.
- Author
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Vilches C, Pando MJ, Rajalingam R, Gardiner CM, and Parham P
- Subjects
- Haplotypes, Humans, Receptors, Immunologic classification, Receptors, KIR, Genetic Variation, Killer Cells, Natural metabolism, Receptors, Immunologic genetics
- Abstract
The gene encoding the non-inhibitory receptor KIR2DS5 has so far been represented by a single cDNA sequence, NKAT9. A previous study by polymerase chain reaction using sequence-specific primers (PCR-SSP) failed to detect NKAT9 in genomic DNA of 52 donors, which suggested that KIR2DS5 could be a rare gene. Here, we have characterized two novel variants of KIR2DS5 that differ from NKAT9 by 8 and 10 nucleotide substitutions. The frequency of KIR2DS5 was then re-assessed by PCR-SSP using primers specific for conserved sequences of all three known KIR2DS5 variants. We found KIR2DS5 is not a rare gene, but one present in 26% of 34 donors representing the major ethnic groups. Like other non-inhibitory KIR, the distribution of KIR2DS5 is restricted to the 'B' subset of KIR-gene haplotypes. Transcription of the KIR2DS5 gene was studied by reverse transcriptase (RT)-PCR in natural killer (NK) cells from one donor and shown to follow the clonal distribution seen for most other KIR genes.
- Published
- 2000
- Full Text
- View/download PDF
24. Genes encoding human killer-cell Ig-like receptors with D1 and D2 extracellular domains all contain untranslated pseudoexons encoding a third Ig-like domain.
- Author
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Vilches C, Pando MJ, and Parham P
- Subjects
- Adult, Base Sequence, DNA, Complementary, Humans, Molecular Sequence Data, Protein Biosynthesis, Protein Structure, Tertiary, Pseudogenes, Receptors, Immunologic chemistry, Receptors, Immunologic classification, Receptors, KIR, Receptors, KIR2DL1, Receptors, KIR2DL3, Receptors, KIR2DL4, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured, Exons, Killer Cells, Natural metabolism, Receptors, Immunologic genetics
- Abstract
Human killer-cell immunoglobulin-like receptors (KIR) show three types of organization of their extracellular domains: D0-D1-D2 in KIR3D, D1-D2 in the majority of KIR2D, and D0-D2 in KIR2DL4 and the novel KIR2DL5. The gene for a KIR2DL3 variant, which has a D1-D2 structure, has been shown previously to have a nonexpressed region (pseudoexon 3) that is paralogous to the exon encoding the D0 domain of other KIR. This pseudoexon is not expressed because it is skipped during splicing of pre-mRNA. In this study, we demonstrate that all eight genes encoding human KIR with D1-D2 configuration (KIR2DL1-KIR2DL3, KIR2DS1-KIR2DS5) have similarly untranslated pseudoexons. Whereas the pseudoexons of four of these KIR genes bear nonsense mutations and/or altered splicing sites, the pseudoexons in the other four KIR genes have no major structural abnormalities, indicating that other mechanisms are responsible for inactivation of their exons 3. A comparison of the sequences on pseudoexons 3 with the paralogous expressed exons suggests that an exonic splicing enhancer may be necessary for the expression of exon 3 in KIR genes.
- Published
- 2000
- Full Text
- View/download PDF
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