HLA-A amino acid polymorphism and delayed kidney allograft function

Kamoun, Malek; Holmes, John H.; Israni, Ajay K.; Kearns, Jane; Yang, Wei; Rosas, Sylvia E.; Joffe, Marshall M.; Li, Hongzhe; Feldman, Harold I.

doi:10.1073/pnas.0810308105

Cited by 16 publications

(14 citation statements)

References 31 publications

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“…The ability of alloreactive T cells to cross-react with nonself-MHC molecules is a major obstacle preventing successful organ transplantations (3)(4)(5). Two mechanisms, direct or indirect allorecognition, can be responsible for the rejection of a transplant by alloreactive T cells (6).…”

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confidence: 99%

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Kumar

Vahedi-Faridi

Merino

et al. 2009

Journal of Biological Chemistry

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The existence of cytotoxic T cells (CTL) cross-reacting with the human major histocompatibility antigens HLA-B14 and HLA-B27 suggests that their alloreactivity could be due to presentation of shared peptides in similar binding modes by these molecules. We therefore determined the crystal structures of the subtypes HLA-B*1402, HLA-B*2705, and HLA-B*2709 in complex with a proven self-ligand, pCatA (peptide with the sequence IRAAPPPLF derived from cathepsin A (residues 2-10)), and of HLA-B*1402 in complex with a viral peptide, pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236 -244) of Epstein-Barr virus). Despite the exchange of 18 residues within the binding grooves of HLA-B*1402 and HLA-B*2705 or HLA-B*2709, the pCatA peptide is presented in nearly identical conformations. However, pLMP2 is displayed by HLA-B*1402 in a conformation distinct from those previously found in the two HLA-B27 subtypes. In addition, the complexes of HLA-B*1402 with the two peptides reveal a nonstandard, tetragonal mode of the peptide N terminus anchoring in the binding groove because of the exchange of the common Tyr-171 by His-171 of the HLA-B*1402 heavy chain. This exchange appears also responsible for reduced stability of HLA-B14-peptide complexes in vivo and slow assembly in vitro. The studies with the pCatA peptide uncover that CTL cross-reactive between HLA-B14 and HLA-B27 might primarily recognize the common structural features of the bound peptide, thus neglecting amino acid replacements within the rim of the binding grooves. In contrast, structural alterations between the three complexes with the pLMP2 peptide indicate how heavy chain polymorphisms can influence peptide display and prevent CTL cross-reactivity between HLA-B14 and HLA-B27 antigens.T cells possessing the ability to recognize major histocompatibility complex (MHC) 2 molecules from another individual of the same species, also termed alloreactive T cells, may constitute up to 10% of the T cell pool of an individual, and their precursor frequency can be 100 -1,000-fold higher than that of self-restricted T cells directed against a foreign peptide (1, 2). The ability of alloreactive T cells to cross-react with nonself-MHC molecules is a major obstacle preventing successful organ transplantations (3-5). Two mechanisms, direct or indirect allorecognition, can be responsible for the rejection of a transplant by alloreactive T cells (6). In the first case, donor cells expressing MHC molecules are directly recognized by host T cells (7), whereas indirect allorecognition involves the presentation of peptides derived from donor proteins by MHC molecules of the host, followed by the detection of the complexes by the host T cells (8). However, although alloreactive T cells are very common and of great clinical importance, neither the primary basis for their existence nor the reasons underlying their cross-reactivity are sufficiently understood to draw general conclusions (9 -11). Only very few studies have addressed the structural basis for the recognition...

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confidence: 99%

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Kumar

Vahedi-Faridi

Merino

et al. 2009

Journal of Biological Chemistry

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“…It is broadly known that among them, genetic factors are of great importance [9,12,23]. There are also many promising studies focused on linkage between immune response mediators and cell status.…”

Section: Discussionmentioning

confidence: 99%

Joint Assessment of Donor and Recipient hTERT Gene Polymorphism Provides Additional Information for Early Kidney Transplantation Outcomes

et al. 2017

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BackgroundThere are several genes and genetic loci affecting telomere length, including hTERT gene and BICD1 gene as well as polymorphisms within chromosome 18. It has been demonstrated that the age of the donor is a negative factor associated with long-term kidney allograft function, and that post-transplant complications accelerate transplanted organ aging, thus contributing to estimated glomerular filtration rate (eGFR) decreases. The aim of this study was a joint assessment of donors’ and recipients’ hTERT and BICD1 genes as well as chromosome 18 polymorphisms with regard to early kidney transplantation outcomes.Material/MethodsThe study enrolled 74 pairs of Polish Caucasian kidney allograft cadaveric donors (60% male, mean age 45.99±14.62) and recipients (50.0% male, mean age 48.89±13.50). The transplantation procedure (Tx) was performed between 2001 and 2012. All samples were genotyped in duplicate using Real-Time PCR.ResultsThis study showed that rs2735940 hTERT CX-TT donor-recipient genotype pair was associated with almost five times higher odds (OR=4.82; 95% CI: 1.32–18; p=0.016) of delayed graft function (DGF), and that rs2735940 hTERT, rs2630578 BICD1, and rs7235755 chromosome 18 polymorphisms combined pairs were not associated with acute rejection (AR).ConclusionsIn conclusion, both the donor’s and the recipient’s rs2735940 hTERT gene polymorphism was associated with early graft function after transplantation. The odds of DGF were almost five times higher for a combination of CX (CT or CC) donor genotype and TT recipient genotype. Joint assessment of donor-recipient genotype pairs provides more information for prediction of early kidney transplantation outcomes.

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“…Allele‐level genotyping for human leukocyte antigen (HLA) loci is important for disease association studies , vaccine design , understanding the role of HLA amino acid polymorphisms in kidney allograft outcomes and HLA matching in hematopoietic stem cell transplantation (HSCT) . Furthermore, some studies suggest that transplants involving donors and recipients with matched haplotype phase might have decreased Graft‐versus‐host‐disease related morbidity rates .…”

Section: Introductionmentioning

confidence: 99%

Validation of statistical imputation of allele‐level multilocus phased genotypes from ambiguous HLA assignments

et al. 2014

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Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with average recall >76% when imputing HLA alleles from registry data. We simulated ambiguity generated by several HLA genotyping methods to evaluate the imputation performance on several levels of typing resolution. On average, imputation percent recall of allele-level HLA haplotypes was >95% for allele-level typing, >92% for intermediate resolution typing and >58% for serology (low-resolution) typing. Thus, allele-level HLA assignments can be imputed through the application of a set of statistical and population genetics inferences and with knowledge of haplotype frequencies and self-identified race and ethnicities.

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HLA-A amino acid polymorphism and delayed kidney allograft function

Abstract: HLA alleles ͉ kidney transplantation ͉ HLA mismatches ͉ MHC

Cited by 16 publications

References 31 publications

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Joint Assessment of Donor and Recipient hTERT Gene Polymorphism Provides Additional Information for Early Kidney Transplantation Outcomes

Validation of statistical imputation of allele‐level multilocus phased genotypes from ambiguous HLA assignments

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