PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules

Rheumatology ◽  
2019 ◽  
Vol 58 (11) ◽  
pp. 1942-1949 ◽  
Author(s):  
Jon Waarst Gregersen ◽  
Christian Erikstrup ◽  
Per Ivarsen ◽  
Rie Glerup ◽  
Elizabeth Krarup ◽  
...  
Keyword(s):  
Amino Acid ◽  
Peptide Binding ◽  
Amino Acid Sequences ◽  
Homogeneous Population ◽  
Exon 2 ◽  
Hla Alleles ◽  
Hypervariable Regions ◽  
Anca Associated Vasculitis ◽  
Increased Risk ◽  
Kidney Involvement

Abstract Objectives This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV. Methods We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2. Results Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8–9, 69, 76 and 84–87 within the hypervariable regions, but only positions 69 and 84–87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles. Conclusion PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove.

Characterization of the mouse thyrotrophin-releasing hormone receptor gene: an exon corresponds to a deletion in the rat cDNA

1993 ◽  
Vol 11 (2) ◽  
pp. 141-149 ◽  
Author(s):  
S M Duthie ◽  
P L Taylor ◽  
K A Eidne
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Stop Codon ◽  
Amino Acid Sequences ◽  
R Gene ◽  
Coding Region ◽  
Thyrotrophin Releasing Hormone ◽  
Exon 2 ◽  
Exon 4

ABSTRACT The cloning and characterization of the mouse TRH receptor (TRH-R) gene revealed an untranslated exon (exon 1), a single intron and an upstream dinucleotide repeat sequence (d(TG)16.d(AG)21) in the 5′ untranslated region (UTR). The coding region was contained almost entirely on a second exon (exon 2), with the final amino acid and stop codon at the COOH terminus of the gene encoded by a third exon (exon 3) flanked by two introns. The 3′ UTR was contained on the remainder of exon 3 and on the final exon (exon 4). Exon 3 (228 bp) corresponds exactly to a 228 bp deletion that exists in the rat TRH-R cDNA, but not in the mouse cDNA. The mouse TRH-R cDNA encodes a protein of 393 amino acids which is 96% homologous to the rat TRH-R protein of 412 amino acids, but is 19 amino acids shorter at its COOH terminus. The coding sequence for these 19 amino acids (plus 1 extra amino acid) does exist in the mouse TRH-R gene, but the sequence is encoded by exon 4, separated from the rest of the coding region by the stop codon and 223 bp of 3′ UTR on exon 3. Splicing of exon 3 in the mouse TRH-R gene would remove the last amino acid, the stop codon and the 223 bp of 3′ UTR, allowing transcription to continue into the 3′ UTR on exon 4, which encodes the 19 extra amino acids found in the rat cDNA. This would then result in an alternative 412 amino acid version of the mouse TRH-R protein, with 95% homology to the rat TRH-R. This study focused on the structural differences in the intracellular COOH-terminal tail of the receptor, which is known to be a functionally important domain in other members of the G protein-coupled receptor family. We have also recently characterized the human TRH-R cDNA, which revealed a third variant at the COOH terminus. Comparisons between mouse, rat and human TRH-Rs show that the amino acid sequences are virtually identical. However, significant differences between these species exist at the COOH terminus, with each TRH-R having a unique form of the COOH-terminal tail, beginning at exactly the same site and encoding 1, 20 and 6 amino acids in the mouse, rat and human respectively.

P1609HLA EPITOPE MATCHING IN KIDNEY TRANSPLANTATION AND PRACTICAL APPLICATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Irena Rambabova Bushljetikj ◽  
Goce Spasovski ◽  
Koco Dimitrovski
Keyword(s):  
Kidney Transplantation ◽  
Amino Acid ◽  
Acute Rejection ◽  
Amino Acid Sequences ◽  
Class I ◽  
Hla Dr ◽  
Increased Risk ◽  
Class 1 ◽  
Unrelated Donors ◽  
Hla Mismatches

Abstract Background and Aims HLA compatibility between donor and recipient is an important factor that influences graft outcomes after kidney transplantation. Increasing number of class I (HLA-AB) and class II (HLA-DR) mismatches are associated with an increased risk of acute rejection and graft loss. Recent developments have increased our understanding of the structural basis of HLA antigenicity and may allow accurate evaluation of the immunogenic potential of broad antigen HLA mismatches. The immunogenicity of HLA antigens is determined by continuous and discontinuous short sequences of amino acids that form the antibody-accessible regions within each HLA allele known as epitopes. HLAMatchmaker, a computer algorithm that calculates the number of epitope mismatches between donors and recipients by considering each HLA allele as a combination of distinct epitopes known as triplets (continuous amino acid sequences) or eplets (closely located contiguous amino acid sequences). Method A total number of 55 adult patients with LDKT were included in the study. The inclusion criteria: first transplantation of one organ - kidney, use of living donor related or unrelated, emotionally related (spouses) donor. Data concerning donor - sex, age of the donor, type of donation (related or unrelated donor), and data concerning the recipients: sex, age, hemodialysis vintage, underlying disease, type of immunosuppressive therapy, were analyzed. The number of eplet HLA mismatches for each recipient and donor pair at HLA class I (HLA-AB) and class II (HLA-DR) loci was calculated using HLAMatchmaker (Version 1.2) Results In our study we have included 55 patients. 44 patients have related and 11 have unrelated donors. From the group of related donors 31 patients were haploidentycal, with 3 HLA miss match, in the group of unrelated donors-recipients 5 of them have 6 miss match. According HLA MM triplets Class 1 + 2 &lt; or&gt; 20 we have devided 2 groups, but no statistical difference on the graft function was observed in the follow up period. Three acute rejections were reported in the group of patients with HLA miss match triplets Class 1 + 2&gt; 20. Conclusion An increasing number of epitope HLA mismatches is associated with an increased risk of acute rejection. Triplet HLA mismatches may provide better risk stratification for acute rejection and graft survival among those who are otherwise classified as low immunological risk at the broad antigen level.

scholarly journals Mechanisms of Variable p44 Expression by Anaplasma phagocytophilum

2003 ◽  
Vol 71 (10) ◽  
pp. 5650-5661 ◽  
Author(s):  
Quan Lin ◽  
Yasuko Rikihisa ◽  
Norio Ohashi ◽  
Ning Zhi
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Anaplasma Phagocytophilum ◽  
Hypervariable Region ◽  
Amino Acid Sequences ◽  
Hypervariable Regions ◽  
Tandem Genes ◽  
Flanking Regions ◽  
Passage Cell ◽  
Expression Status

ABSTRACT The human intragranulocytic bacterium Anaplasma phagocytophilum promotes variation of P44s, which are surface-exposed proteins encoded by a p44 multigene family. In the present study, the specific p44 gene expression loci in four strains of A. phagocytophilum were identified and it was determined that each consisted of four tandem genes, tr1, omp-1X, omp-1N, and p44. A putative σ70-type promoter was found upstream of tr1. The p44 genes include a central hypervariable region flanked by conserved regions. The hypervariable region sequence in the p44 expression locus was duplicated and, regardless of the expression status, conserved at another locus in both low- and high-passage cell cultures of strain NY-37. No significant differences in the hypervariable region were found when we compared p44 sequences, at the level of cDNA, within the expression locus and within other loci in the genomes of strains NY-37 and HZ. Similarly, in cDNA isolated from patients and from assorted cultures of strains NY-31, NY-36, and NY-37, hypervariable regions of 450 deduced amino acid sequences of various p44s within each strain were found to be identical, as were those of p44 sequences in the genome of strain HZ. These data suggest that variations in p44 sequences at the level of the p44 expression locus occur through unidirectional conversion of the entire (nonsegmental) p44 hypervariable region including flanking regions with a corresponding sequence copied from one of the conserved donor p44 genomic loci. The data suggest that the P44 antigenic repertoire within the hypervariable region is restricted.

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.

scholarly journals Allelic Diversity of Major Histocompatibility Complex Class II DRB Gene in Indian Cattle and Buffalo

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Sachinandan De ◽  
Raj Kumar Singh ◽  
Biswajit Brahma
Keyword(s):  
Amino Acid ◽  
Peptide Binding ◽  
Allelic Diversity ◽  
Zebu Cattle ◽  
Sequence Evolution ◽  
Substitution Pattern ◽  
Exon 2 ◽  
Allelic Sequence ◽  
Binding Regions ◽  
Indian Cattle

The present study was conducted to study the diversity of MHC-DRB3 alleles in Indian cattle and buffalo breeds. Previously reported BoLA-DRB exon 2 alleles of Indian Zebu cattle, Bos taurus cattle, buffalo, sheep, and goats were analyzed for the identities and divergence among various allele sequences. Comparison of predicted amino acid residues of DRB3 exon 2 alleles with similar alleles from other ruminants revealed considerable congruence in amino acid substitution pattern. These alleles showed a high degree of nucleotide and amino acid polymorphism at positions forming peptide-binding regions. A higher rate of nonsynonymous substitution was detected at the peptide-binding regions, indicating that BoLA-DRB3 allelic sequence evolution was driven by positive selection.

Amino Acid Substitution At Peptide-Binding Pockets of HLA Class I Molecules Adversely Impacts Hematopoietic Cell Transplantation Outcomes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 467-467
Author(s):  
Joseph Pidala ◽  
Tao Wang ◽  
Michael D Haagenson ◽  
Stephen Spellman ◽  
Medhat Askar ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Transplantation ◽  
Amino Acid Substitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Peptide Binding ◽  
Multivariable Analysis ◽  
Hla Class I ◽  
Class I ◽  
Increased Risk

Abstract Abstract 467 Background: While donor-recipient disparity at HLA loci is associated with greater risk for severe acute graft vs. host disease (GVHD) and inferior survival after unrelated donor allogeneic hematopoietic cell transplantation (HCT), the impact of amino acid substitution (AAS) at peptide binding pockets of the HLA molecule is incompletely understood. Methods: Adult and pediatric patients who received myeloablative or reduced intensity/non-myeloablative first unrelated bone marrow or peripheral blood stem cell transplantation for AML, ALL, CML or MDS between 1988 and 2009 were included. Donors and patients were fully high resolution matched for HLA-A, B, C, and DRB1 (8/8) or had single mismatch (7/8) at one HLA class I locus. Among 7/8 donor-recipient pairs, cases were categorized based on the presence or absence of the AAS of interest at positions 9, 77, 99, 116, or 156 of the class I molecule. In multivariable analysis accounting for patient, disease, and transplantation variables, we studied the independent impact of AAS at these residues on risk for grade III-IV acute GVHD, chronic GVHD, treatment-related mortality, primary malignancy relapse, and overall survival. We compared 7/8 donor-recipient pairs with AAS of interest to 7/8 pairs without these AAS in the primary analyses. Additionally, we performed this analysis restricted to each HLA class I locus. Results: Donor-recipient pairs were 8/8 matched (n=5282), 7/8 with AAS of interest (n=1713), or 7/8 without AAS of interest (n=318). In multivariable analysis, AAS at position 116 was associated with increased risk for grade III-IV acute GVHD (HR 1.21, 1.04–1.42, p=0.0165). No other significant association was detected between AAS studied and clinical outcomes. In multivariable analysis restricted to each class I HLA locus, we detected the following: Among 7/8 matched pairs with mismatch at HLA-C, AAS at position 116 was associated with increased risk for severe acute GVHD (HR 1.42, 1.13–1.79, p=0.0031) and inferior OS (HR 1.2, 1.01–1.41, p=0.0343). AAS at position 99 was associated with increased TRM (HR 1.37, 1.11–1.69, p=0.0037). Of 7/8 pairs with mismatch at HLA-B, AAS at position 9 was associated with increased chronic GVHD (HR 2.19, 1.31–3.66, p=0.0029). Specific amino acid substitution pairs with frequency > 30 were tested for association with HCT outcomes. None met the significance level of 0.00125, pre-specified for multiple comparisons. Conclusions: These results support the concept that AAS at key peptide-binding residues in the HLA class I molecule are associated with increased risk for severe acute GVHD and lower survival. Disclosures: No relevant conflicts of interest to declare.

Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity

2019 ◽  
Vol 105 (6) ◽  
pp. 1737-1747 ◽  
Author(s):  
Lara Frommer ◽  
Brigitte K Flesch ◽  
Jochem König ◽  
George J Kahaly
Keyword(s):  
Monte Carlo ◽  
Amino Acid ◽  
Peptide Binding ◽  
Class Ii ◽  
Hla Class Ii ◽  
Exon 2 ◽  
Allele Distribution ◽  
Autoimmune Thyroid ◽  
The Impact ◽  
Polyglandular Autoimmunity

Abstract Context The structure of the human leucocyte antigen (HLA) peptide-binding clefts strongly contributes to monoglandular and polyglandular autoimmunity (AP). Objective To investigate the impact of amino acid polymorphisms on the peptide-binding interactions within HLA class II and its association with AP. Design Immunogenetic study. Setting Tertiary referral center for autoimmune endocrine diseases. Subjects 587 subjects with AP, autoimmune thyroid disease (AITD), type 1 diabetes (T1D), and healthy unrelated controls were typed for HLA class II. Methods Amino acids within the peptide binding cleft that are encoded by HLA class II exon 2 were listed for all codon positions in all subjects. Overall comparisons between disease and control groups with respect to allele distribution at a given locus were performed by assembling rare alleles applying an exact Freeman Halton contingency table test with Monte-Carlo P values based on 150 000 samples. Results The Monte Carlo exact Fisher test demonstrated marked differences in all 3 loci, DQA1, DQB1, and DRB1 (P &lt; .0001) between AP and both AITD and controls, as well as between AP type II (Addison’s disease as a major endocrine component) and AP type III (T1D + AITD). Differences were also noted between AP and T1D pertaining to the DRB1 allele (P &lt; .041). Seven amino acid positions, DRB1-13, DRB1-26, DRB1-71, DRB1-74, DQA1-47, DQA1-56, and DQB1-57, significantly contributed to AP. Five positions in DQA1 (11, 47, 50, 56, and 69) completely correlated (P &lt; .0001). Conclusion Amino acid polymorphisms within HLA class II exon 2 mediate the AP risk and differentiate between thyroid and polyglandular autoimmunity.

scholarly journals Erythropoietin structure-function relationships: high degree of sequence homology among mammals

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1507-1516 ◽  
Author(s):  
D Wen ◽  
JP Boissel ◽  
TE Tracy ◽  
RH Gruninger ◽  
LS Mulcahy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structure Function ◽  
Disulfide Bridge ◽  
Cross Reactivity ◽  
Amino Acid Sequences ◽  
Exon 2 ◽  
Cdna Sequences ◽  
Intron 1 ◽  
Species Specific ◽  
High Degree

Abstract To investigate structure-function relationships of erythropoietin (Epo), we have obtained cDNA sequences that encode the mature Epo protein of a variety of mammals. A first set of primers, corresponding to conserved nucleotide sequences between mouse and human DNAs, allowed us to amplify by polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing of these fragments permitted the design of a second generation of species-specific primers. RNA was prepared from anemic kidneys and reverse-transcribed. Using our battery of species-specific 5′ primers, we were able to successfully PCR- amplify Epo cDNA from Rhesus monkey, rat, sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo proteins from these animals, in combination with known sequences for human, Cynomolgus monkey, and mouse, showed a high degree of homology, which explains the biologic and immunological cross-reactivity that has been observed in a number of species. Human Epo is 91% identical to monkey Epo, 85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos. There was full conservation of (1) the disulfide bridge linking the NH2 and COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic alpha- helices. In contrast, the short disulfide bridge (C29/C33 in humans) is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino acid replacements were conservative. The C-terminal part of the loop between the C and D helices showed the most variation, with several amino acid substitutions, deletions, and/or insertions. Calculations of maximum parsimony for intron 1/exon 2 sequences as well as coding sequences enabled the construction of cladograms that are in good agreement with known phylogenetic relationships.

scholarly journals HLA Alleles and Amino-Acid Signatures of the Peptide-Binding Pockets of HLA Molecules in Vitiligo

2012 ◽  
Vol 132 (1) ◽  
pp. 124-134 ◽  
Author(s):  
Archana Singh ◽  
Pankaj Sharma ◽  
Hemanta K. Kar ◽  
Vinod K. Sharma ◽  
Manoj K. Tembhre ◽  
...  
Keyword(s):  
Amino Acid ◽  
Peptide Binding ◽  
Hla Alleles ◽  
Binding Pockets ◽  
Hla Molecules

scholarly journals Erythropoietin structure-function relationships: high degree of sequence homology among mammals

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1507-1516 ◽  
Author(s):  
D Wen ◽  
JP Boissel ◽  
TE Tracy ◽  
RH Gruninger ◽  
LS Mulcahy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structure Function ◽  
Disulfide Bridge ◽  
Cross Reactivity ◽  
Amino Acid Sequences ◽  
Exon 2 ◽  
Cdna Sequences ◽  
Intron 1 ◽  
Species Specific ◽  
High Degree

To investigate structure-function relationships of erythropoietin (Epo), we have obtained cDNA sequences that encode the mature Epo protein of a variety of mammals. A first set of primers, corresponding to conserved nucleotide sequences between mouse and human DNAs, allowed us to amplify by polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing of these fragments permitted the design of a second generation of species-specific primers. RNA was prepared from anemic kidneys and reverse-transcribed. Using our battery of species-specific 5′ primers, we were able to successfully PCR- amplify Epo cDNA from Rhesus monkey, rat, sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo proteins from these animals, in combination with known sequences for human, Cynomolgus monkey, and mouse, showed a high degree of homology, which explains the biologic and immunological cross-reactivity that has been observed in a number of species. Human Epo is 91% identical to monkey Epo, 85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos. There was full conservation of (1) the disulfide bridge linking the NH2 and COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic alpha- helices. In contrast, the short disulfide bridge (C29/C33 in humans) is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino acid replacements were conservative. The C-terminal part of the loop between the C and D helices showed the most variation, with several amino acid substitutions, deletions, and/or insertions. Calculations of maximum parsimony for intron 1/exon 2 sequences as well as coding sequences enabled the construction of cladograms that are in good agreement with known phylogenetic relationships.

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