The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands.
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ABSTRACT:
SUBMITTER: Hilton HG
PROVIDER: S-EPMC5510751 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Natural killer (NK) cells contribute to immunity and reproduction. Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.
| S-EPMC2774017 | biostudies-literature
Project description:Human leukocyte antigen (HLA)-DR15 is a haplotype associated with multiple sclerosis. It contains the two DRB* genes DRB1*1501 (DR2b) and DRB5*0101 (DR2a). The reported anchor motif of the corresponding HLA-DR molecules was determined in 1994 based on a small number of peptide ligands and binding assays. DR2a could display a set of peptides complementary to that presented by DR2b or, alternatively, a similar peptide repertoire but recognized in a different manner by T cells. It is known that DR2a and DR2b share some peptide ligands, although the degree of similarity of their associated peptidomes remains unclear. In addition, the contribution of each molecule to the global peptide repertoire presented by the HLA-DR15 haplotype has not been evaluated. We used mass spectrometry to analyze the peptide pools bound to DR2a and DR2b, identifying 169 and 555 unique peptide ligands of DR2a and DR2b, respectively. The analysis of these sets of peptides allowed the refinement of the corresponding binding motifs revealing novel anchor residues that had been overlooked in previous analyses. Moreover, the number of shared ligands between both molecules was low, indicating that DR2a and DR2b present complementary peptide repertoires to T cells. Finally, our analysis suggests that, quantitatively, both molecules contribute to the peptide repertoire presented by cells expressing the HLA-DR15 haplotype.
| S-EPMC5566978 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.
| S-EPMC8100314 | biostudies-literature
Project description:HLA DRB1*15:01 is overrepresentated in Parkinson's disease patients and binds with high affinity to the ⍺-synuclein peptide, 32-46. Immunization of humanized mice expressing HLA DRB1*15:01 with ⍺-syn32-46 induces enteric phenotypes similar to those of prodromal Parkinson's disease. We collected the ileum from HLA mice immunized with either Complete Freund's Adjuvant (CFA) with ⍺-syn32-46 or CFA alone, and sequenced the tissue with bulk RNA sequencing at 21 days post immunization to determine changes in gene expression.
2023-08-17 | GSE231873 | GEO
Project description:BACKGROUND:The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated. OBJECTIVES:To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS. METHODS:Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals. RESULTS:HLA-DRB1*15:01:01:01SG (OR?=?3.20, p?<?2.2E-16), HLA-DRB5*01:01:01 (OR?=?2.96, p?<?2.2E-16), and HLA-DRB5*01:01:01v1_STR1 (OR?=?8.18, p?=?4.3E-05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR?=?3.19, p?<?2.2E-16; OR?=?9.30, p?=?9.7E-05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR?=?0.64, p?=?0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR?=?1.66, p?=?4.9E-03). CONCLUSION:HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.
| S-EPMC6365219 | biostudies-literature
Project description:BackgroundThe polymorphisms of classical HLA-Ia and HLA-II loci have been associated with Posner-Schlossman syndrome (PSS) in the southern Chinese population. However, the associations of non-classical HLA-Ib (e.g., HLA-E and HLA-G) loci with PSS have not been reported for in the southern Chinese population. This study aimed to evaluate the associations of the HLA-E and HLA-G loci with PSS in a southern Chinese Han population group.MethodsNinety-seven unrelated patients with PSS and 90 ethnically matched control subjects were recruited from the Shenzhen Eye Hospital in China. The full-length sequences of HLA-E and HLA-G genes were amplified by long-range high-fidelity PCR, and the third exon of the HLA-E gene and the coding region of the HLA-G gene were sequenced.ResultsThe allele frequency of HLA-E*01:03 in patients with PSS was significantly higher than that in the control group (P=0.017, corrected P=0.034, OR =1.66). The genotype frequencies of HLA-E*01:01/01:03 and HLA-E*01:03/01:03 in the PSS group were significantly higher than that in the control group (P=0.027, OR =2.62; P=0.011, OR =3.05; respectively). There were no significant differences in the frequency of HLA-G alleles and genotypes between the two groups (all P>0.05). The haplotype frequency of HLA-E*01:03-G*01:01 in the PSS group was significantly higher than that in the control group (P=0.019, OR =1.63), although this association did not survive the Bonferroni correction (corrected P=0.13).ConclusionsThis study proved for the first time that HLA-E*01:03 and HLA-E*01:03-G*01:01 might be risk factors for PSS.
| S-EPMC6989981 | biostudies-literature
Project description:An inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV.We studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility.We found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility.These results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA-E recognition on the control of EBV infection and lymphomagenesis.
| S-EPMC4532421 | biostudies-literature
Project description:HLA-DR15 is a haplotype associated with multiple sclerosis. It contains the two DRB* genes DRB1*1501 (DR2b) and DRB5*0101 (DR2a). The reported anchor motif of the corresponding HLA-DR molecules was determined years ago based on a small number of peptide ligands and binding assays. DR2a could display a set of peptides complementary to that presented by DR2b or, alternatively, a similar peptide repertoire but recognized in a different manner by T cells. It is known that DR2a and DR2b share some peptide ligands, although the degree of similarity of their associated peptidomes remains unclear. In addition, the contribution of each molecule to the global peptide repertoire presented by the HLA-DR15 haplotype has not been evaluated. We used mass spectrometry to analyze the peptide pools bound to DR2a and DR2b, identifying 169 and 555 unique peptide ligands of DR2a and DR2b, respectively. The analysis of these sets of peptides allowed the refinement of the corresponding binding motifs revealing novel anchor residues that had been overlooked in previous analyses. Moreover, the number of shared ligands between both molecules was low, indicating that DR2a and DR2b present complementary peptide repertoires to T cells. Finally, our analysis suggests that, quantitatively, both molecules contribute to the peptide repertoire presented by cells expressing the HLA-DR15 haplotype.
2017-10-10 | PXD006534 | Pride
Project description:The HLA-B*27 peptidome has drawn significant attention due to the genetic association between some of the HLA-B*27 alleles and the inflammatory rheumatic disease ankylosing spondylitis (AS). The role of HLA-B*27 in this condition is not known yet. This study aims to expand the known limits of the HLA-B*27 peptidome in order to facilitate selection and testing of new peptides, possibly implicated with the disease. The HLA peptidomes of HeLa and C1R cell lines stably transfected with the AS-associated HLA-B*27:05 allele, the non-associated HLA-B*27:09 allele, or their mutants with Cysteine 67 replaced by Serine (C67S), were analyzed on a very large scale. In addition, the peptidomes of HLA-B*27:05 and HLA-B*27:05-C67S were analyzed from transgenic rats’ spleens. The results indicate that a fraction of HLA-B*27 peptides contain lysine at their second position (P2), in addition to the more commonly found peptides with arginine, or the less common glutamine located at this anchor position. Furthermore, the C67S mutation increases the percentages of peptides with glutamine or lysine at their P2 position, in both HLA-B*27:05 and HLA-B*27:09. Therefore, peptides with P2 lysine should be considered as valid ligands of HLA-B*27 molecules and taken into account while looking for candidate for arithrogenic peptides.
2018-04-10 | PXD007756 | Pride
Project description:The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.
| S-EPMC8041999 | biostudies-literature