The anti-drug antibody response is associated with amino acid variation within the HLADRB1 peptide-binding groove

2021 ◽  
Author(s):  
Teresa Tsakok
Keyword(s):  
Amino Acid ◽  
Antibody Response ◽  
Peptide Binding ◽  
Amino Acid Variation ◽  
Peptide Binding Groove ◽  
Binding Groove

HLA-DPA1 Polymorphism Is a Risk Factor for Graft-Versus-Host Disease Following Unrelated Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4181-4181
Author(s):  
Nina Lauterbach ◽  
Christien Voorter ◽  
Lisa Rybicki ◽  
Lotte Wieten ◽  
Ronald Sobecks ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lower Risk ◽  
Proportional Hazards ◽  
Peptide Binding ◽  
Cox Proportional Hazards ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Alpha Chain ◽  
Peptide Binding Groove ◽  
Binding Groove

Abstract Abstract 4181 Background: The HLA-DP molecule has been shown to be a target of allograft rejection and graft-versus-host-disease (GVHD) in HSCT. Nevertheless the way in which HLA-DP matching in HSCT should be approached remains unclear. Studies point out that some mismatched allele combinations result in a weaker alloreactive response than others, suggesting that epitope matching should be considered rather than allele matching. Most studies focus on the highly polymorphic beta chain of the DP molecule that is considered to play a dominant role in T cell interaction. Several groups have tried to identify immunogenic epitopes in the peptide binding groove of the beta chain to unravel DP immunogenicity, but there is no consensus on epitopes and amino acid residues. The alpha chain of the DP molecule is characterized by low polymorphism and therefore is considered less relevant in T cell recognition. Nonetheless, modeling studies identified amino acid position 31 in the peptide binding groove of the alpha chain as a potential immunogenic residue that influences peptide binding by the polymorphic residue Methionine (M) vs. Glutamine (Q). We hypothesized that HLA-DPA1 polymorphism at position 31 may impact patient outcomes after unrelated HSCT. Methods: Engraftment, GVHD, graft failure, relapse, and mortality had been analyzed in 81 patients who received HSCT in a single institute from 8/2003-12/2010 with a 10/10 matched unrelated donor. The median age was 47 years, and 58% were males. 30% had reduced-intensity conditioning and 70% were myeloablative. HLA-DPA1 polymorphism was determined using Luminex PCR-SSO method. Prognostic factors for outcomes were identified using Cox proportional hazards analysis. Variables analyzed included age, gender, co-morbidity, diagnosis, conditioning, cell source, donor characteristics, CMV serostatus, DPB1 mismatching, DPA1 polymorphism, and hematopoietic stem cell dose. Multivariable prognostic factors for each outcome were assessed using stepwise Cox proportional hazards. Results: Neither allele DPB1 mismatching nor recipient DPA1 allele polymorphism was associated with any of the outcome variables. Interestingly, in uni- and multivariable analysis homozygous M at position 31 (31M) of DPA1 in the donor was associated with a lower risk of acute GVHD compared to homozygous Q & heterozygous M/Q at position 31 (HR 0.54, P=0.031). Also, 31M donors, had a trend towards a lower risk of chronic GHVD (HR 0.52, P=0.08) and all-cause mortality (HR 0.63, P=0.11). Conclusion: With the limitation of the small population size, this is the first clinical study describing a potential role of amino acid polymorphism in the alpha chain of the HLA-DP molecule in unrelated HSCT. These results show an increased risk of donor DPA polymorphism for aGVHD and warrant further investigation in a larger cohort. Disclosures: No relevant conflicts of interest to declare.

HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease

2019 ◽  
Vol 80 (9) ◽  
pp. 731-738 ◽  
Author(s):  
Chisato Shimizu ◽  
Jihoon Kim ◽  
Hariklia Eleftherohorinou ◽  
Victoria J. Wright ◽  
Long T. Hoang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Kawasaki Disease ◽  
Peptide Binding ◽  
Amino Acid Substitutions ◽  
Peptide Binding Groove ◽  
Binding Groove

scholarly journals An amino acid motif in HLA-DRβ1 distinguishes patients with uveitis in juvenile idiopathic arthritis

2017 ◽  
Author(s):  
A.J.W. Haasnoot ◽  
M.W. Schilham ◽  
S.S.M. Kamphuis ◽  
P.C.E. Hissink Muller ◽  
A. Heiligenhaus ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Amino Acid ◽  
Genome Wide Association Study ◽  
Specific Interaction ◽  
Peptide Binding ◽  
A Genome ◽  
Increased Risk ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Female Specific

AbstractUveitis is a visually-debilitating disorder that affects up to 30% of children with juvenile idiopathic arthritis (JIA). To identify genetic susceptibility loci for uveitis in JIA, we conducted a genome-wide association study comparing 192 JIA-associated uveitis cases with 330 JIA individuals without uveitis. Two cohorts of JIA patients underwent genotyping and quality control. We used an HLA-specific imputation panel to impute HLA-specific amino acids and HLA types, and identified the amino acid serine at position 11 (serine-11) in HLA- DRB1 as associated to increased risk of uveitis (OR = 2.60, p = 5.43×10−10). The signal at serine-11 was female-specific (interaction of sex and serine-11, p = 0.0096). Serine-11 resides in the YST-motif (positions 10-12) in the peptide binding groove of HLA-DRB1. Quantitative binding affinity predictions revealed peptide-binding preferences that distinguish HLA-DRB1 allotypes with the YST-motif. Our findings highlight a genetically distinct, sexually-dimorphic feature of JIA-associated uveitis.

Peptide-Dependency of Alloreactive T Cell Clones after HLA-Mismatch Hematopoietic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3268-3268
Author(s):  
Seitaro Terakura ◽  
Makoto Murata ◽  
Kyoko Sugimoto ◽  
Momoko Suzuki ◽  
Akihiro Abe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Amino Acid ◽  
Cell Lines ◽  
Peptide Binding ◽  
Hematopoietic Stem ◽  
Peptide Specificity ◽  
Cos Cells ◽  
Peptide Binding Groove ◽  
Ifn Γ ◽  
Binding Groove

Abstract Donor-patient disparities at single or multiple HLA alleles increase the risks of graft rejection or severe graft-versus-host disease, which are crucial determinant for the outcome of hematopoietic stem cell transplant (HSCT). Cytotoxic T lymphocytes (CTLs) recognizing the mismatched major histocompatibility antigens, defined as alloreactive CTLs (allo-CTLs), are predominant mediators of the vigorous allo-response. In mice, allo-CTLs most probably recognize the peptide/MHC complex with a certain peptide dependency. However, in humans, the peptide dependency of those allo-CTLs is still unknown. To assess the peptide dependency of allo-CTLs after HLA-mismatch HSCT, we isolated CTL clones from a post-transplant patient who underwent HLA-mismatch HSCT. The donor was HLA-B One locus mismatch in GVH-vector (Recipient: B*5101, Donor: B*5201). Nine of 10 CTL clones recognized the COS cells transfected with HLA-B*5101 but not HLA-B*5201, and lysed donor-derived lymphoblastoid cells transfected with HLA-B*5101, suggesting these 9 CTLs were alloreactive. These CTLs showed different TCR-Vβ gene usage and variable region sequence, respectively. To address a possible contribution of peptides on the mismatched HLA molecule for the recognition by allo-CTLs, we generated the TAP-deficient cell lines, T2 and .174 cell lines, stably transfected with HLA-B*5101 molecule and tested as a target for a cytotoxicity assay by the allo-CTLs. All of the 9 allo-CTLs did not lyse T2-B*5101 and .174-B*5101 either, although the expression of HLA-B*5101 was confirmed >95% by flow cytometry analysis. This suggests that some particular peptides are likely to have importance for the recognition of allo-CTLs. The difference of amino acid sequence between HLA-B*5101 and B*5201 are only two amino acids at position 63 (B*5101:Asn, B*5201:Glu) and at position 67 (B*5101: Phe, B*5201: Ser). To examine which amino acid substitution makes the different recognition by these CTLs, we generated two chimeric genes termed Asn63Glu and Phe63Ser, transfected into COS cells, co-cultured with the CTLs and examined the IFN-γ release. All of the CTLs did not recognize COS cells with Phe67Ser, and 5 out of 9 CTLs recognized COS cells transfected with Asn63Glu. Because both the amino acid position 63 and 67 were localize on the α1-helix of peptide binding groove, the one amino acid substitution likely affects more local conformation around peptide binding groove. Substitutions localized on the α3-domain did not alter IFN-γ production of 9 allo-CTLs at all. Thus, we convinced that the peptide on HLA-B*5101 is essential for the recognition by the allo-CTLs, and allo-CTLs recognize certain peptide/HLA-B*5101 complex in the peptide-dependent manner. It is hypothesized that the strong allo-response after HLA-mismatch HSCT might associate with considerably low peptide specificity of allo-CTLs. To test the possible low peptide specificity of allo-CTLs, we synthesized 10 known peptides already shown to be presented on the HLA-B*5101 as candidate target pepitdes, pulsed onto T2-B*5101 and .174-B*5101, and tested the cytotoxicity by these allo-CTLs. However, all of the allo-CTLs did not lyse any of the peptides/T2- or .174-B*5101. This suggests allo-CTLs recognize the target with a sufficient specificity. In conclusion, a majority of CTLs after HLA-mismatch HSCT were alloreactive, and exhibit peptide-dependent recognition pattern with an extensive peptide-specific manner.

scholarly journals The strength of selection is consistent across both domains of the MHC class I peptide-binding groove in birds

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Piotr Minias ◽  
Ke He ◽  
Peter O. Dunn
Keyword(s):  
Mhc Class I ◽  
Peptide Binding ◽  
Variable Region ◽  
Molecular Data ◽  
Class I ◽  
Amino Acid Polymorphism ◽  
Exon 2 ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Avian Mhc

Abstract Background The Major Histocompatibility Complex (MHC) codes for the key vertebrate immune receptors responsible for pathogen recognition. Foreign antigens are recognized via their compatibility to hyper-variable region of the peptide-binding groove (PBR), which consists of two separate protein domains. Specifically, the PBR of the MHC class I receptors, which recognize intra-cellular pathogens, has two α domains encoded by exon 2 (α1) and exon 3 (α2) of the same gene. Most research on avian MHC class I polymorphism has traditionally focused exclusively on exon 3 and comparisons of selection between the two domains have been hampered by the scarcity of molecular data for exon 2. Thus, it is not clear whether the two domains vary in their specificity towards different antigens and whether they are subject to different selective pressure. Results Here, we took advantage of rapidly accumulating genomic resources to test for the differences in selection patterns between both MHC class I domains of the peptide-binding groove in birds. For this purpose, we compiled a dataset of MHC class I exon 2 and 3 sequences for 120 avian species from 46 families. Our phylogenetically-robust approach provided strong evidence for highly consistent levels of selection on the α1 and α2 domains. There were strong correlations in all selection measures (number of positively/negatively selected residues and dN/dS ratios) between both PBR exons. Similar positive associations were found for the level of amino acid polymorphism across the two domains. Conclusions We conclude that the strength of selection and the level of polymorphism are highly consistent between both peptide-binding domains (α1 and α2) of the avian MHC class I.

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