scholarly journals TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Koshlan Mayer-Blackwell ◽  
Stefan Schattgen ◽  
Liel Cohen-Lavi ◽  
Jeremy C Crawford ◽  
Aisha Souquette ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Clinical Biomarkers ◽  
Tcr Repertoire ◽  
Open Source Software Package ◽  
Repertoire Sequencing ◽  
Tcr Diversity ◽  
Hla Genotype ◽  
New Framework

T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.

scholarly journals TCR meta-clonotypes for biomarker discovery with tcrdist3: quantification of public, HLA-restricted TCR biomarkers of SARS-CoV-2 infection

2020 ◽  
Author(s):  
Koshlan Mayer-Blackwell ◽  
Stefan Schattgen ◽  
Liel Cohen-Lavi ◽  
Jeremy Chase Crawford ◽  
Aisha Souquette ◽  
...  
Keyword(s):  
Open Source Software ◽  
Biomarker Discovery ◽  
Clinical Biomarkers ◽  
Repertoire Analysis ◽  
Tcr Repertoire ◽  
Open Source Software Package ◽  
Repertoire Sequencing ◽  
Tcr Diversity ◽  
Mechanistic Basis ◽  
New Framework

ABSTRACTAs the mechanistic basis of adaptive cellular antigen recognition, T cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages antigen-enriched repertoires to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires. We apply the framework to TCR data from COVID-19 patients, generating 1,915 public TCR meta-clonotypes from the 18 SARS-CoV-2 antigen-enriched repertoires with the strongest evidence of HLA-restriction. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 44% (845/1915) were significantly enriched among COVID-19 patients that expressed the putative restricting HLA allele, demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates workflows for distance-based TCR repertoire analysis.

scholarly journals Genetic and environmental determinants of human TCR repertoire diversity

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Chirag Krishna ◽  
Diego Chowell ◽  
Mithat Gönen ◽  
Yuval Elhanati ◽  
Timothy A. Chan
Keyword(s):  
T Cell ◽  
Adaptive Immune Response ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Mhc Molecules ◽  
Fitness Advantage ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Repertoire Sequencing ◽  
The Impact

Abstract T cell discrimination of self and non-self is the foundation of the adaptive immune response, and is orchestrated by the interaction between T cell receptors (TCRs) and their cognate ligands presented by major histocompatibility (MHC) molecules. However, the impact of host immunogenetic variation on the diversity of the TCR repertoire remains unclear. Here, we analyzed a cohort of 666 individuals with TCR repertoire sequencing. We show that TCR repertoire diversity is positively associated with polymorphism at the human leukocyte antigen class I (HLA-I) loci, and diminishes with age and cytomegalovirus (CMV) infection. Moreover, our analysis revealed that HLA-I polymorphism and age independently shape the repertoire in healthy individuals. Our data elucidate key determinants of human TCR repertoire diversity, and suggest a mechanism underlying the evolutionary fitness advantage of HLA-I heterozygosity.

scholarly journals Non-inherited maternal human leukocyte antigen alleles in susceptibility to familial rheumatoid arthritis

2008 ◽  
Vol 68 (1) ◽  
pp. 107-109 ◽  
Author(s):  
K A Guthrie ◽  
N R Tishkevich ◽  
J L Nelson
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Leukocyte Antigen ◽  
Age Of Onset ◽  
Human Leukocyte ◽  
Paternal Allele ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
The North ◽  
Significant Difference ◽  
Hla Genotype

Objectives:Some patients with rheumatoid arthritis (RA) lack RA-associated human leukocyte antigen (HLA) alleles. Prior studies investigated non-inherited maternal HLA alleles (NIMA) in RA risk with conflicting results.Methods:We examined NIMA in a large cohort of families from the North American Rheumatoid Arthritis Consortium (NARAC).Results:Among 620 patients with 1 or both parents having a HLA genotype, patients with RA informative for analysis included 176 without HLA-DRB1*04 and 86 without the HLA shared epitope (SE). The frequency of NIMA encoding HLA-DR4 or the SE was compared to the non-inherited paternal allele (NIPA). DR4-encoding NIMA vs NIPA revealed no significant difference (27% vs 20%). However, parity is known to modulate RA risk and analyses stratified by sex and age of onset showed significant variation among women. Interestingly, among women with onset <45 years DR4-encoding NIMA was increased compared to NIPA; among women ⩾45 years at onset the reverse was observed (31% vs 16% compared to 10% vs 60%, p = 0.008). DR4 encoding NIMA vs NIPA did not differ in men. The SE did not differ in men or women.Conclusions:Risk of RA was associated with HLA-DR4 encoding NIMA in younger-onset women but not in older-onset women or men. These observations could help explain conflicting prior results of NIMA in RA.

scholarly journals Human Leukocyte Antigen Genotype as a Marker of Multiple Sclerosis Prognosis

2019 ◽  
Vol 47 (2) ◽  
pp. 189-196 ◽  
Author(s):  
Andreas P. Lysandropoulos ◽  
Gaetano Perrotta ◽  
Thibo Billiet ◽  
Annemie Ribbens ◽  
Renaud Du Pasquier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Human Leukocyte Antigen ◽  
Visual Memory ◽  
Verbal Learning ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Lesion Volume ◽  
Leukocyte Antigen ◽  
Hla Genotype

ABSTRACT:Objective:In a previous pilot monocentric study, we investigated the relation between human leukocyte antigen (HLA) genotype and multiple sclerosis (MS) disease progression over 2 years. HLA-A*02 allele was correlated with better outcomes, whereas HLA-B*07 and HLA-B*44 were correlated with worse outcomes. The objective of this extension study was to further investigate the possible association of HLA genotype with disease status and progression in MS as measured by sensitive and complex clinical and imaging parameters.Methods:Hundred and forty-six MS patients underwent HLA typing. Over a 4-year period of follow-up, we performed three clinical and magnetic resonance imaging (MRI) assessments per patient, which respectively included Expanded Disability Status Scale, Multiple Sclerosis Severity Scale, Timed-25-Foot-Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, Brief Visual Memory Test, California Verbal Learning Test-II, and whole-brain atrophy, fluid-attenuated inversion recovery (FLAIR) lesion volume change and number of new FLAIR lesions using icobrain. We then compared the clinical and MRI outcomes between predefined HLA patient groups.Results:Results of this larger study with a longer follow-up are in line with what we have previously shown. HLA-A*02 allele is associated with potentially better MS outcomes, whereas HLA-B*07, HLA-B*44, HLA-B*08, and HLA-DQB1*06 with a potential negative effect. Results for HLA-DRB1*15 are inconclusive.Conclusion:In the era of MS treatment abundance, HLA genotype might serve as an early biomarker for MS outcomes to inform individualized treatment decisions.

scholarly journals Human genetic basis of coronavirus disease 2019

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hao Deng ◽  
Xue Yan ◽  
Lamei Yuan
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Genetic Basis ◽  
Human Leukocyte ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Leukocyte Antigen ◽  
Host Genetic ◽  
Considerable Morbidity ◽  
Novel Coronavirus ◽  
Hla Genotype

AbstractCoronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in considerable morbidity and mortality worldwide. COVID-19 incidence, severity, and mortality rates differ greatly between populations, genders, ABO blood groups, human leukocyte antigen (HLA) genotypes, ethnic groups, and geographic backgrounds. This highly heterogeneous SARS-CoV-2 infection is multifactorial. Host genetic factors such as variants in the angiotensin-converting enzyme gene (ACE), the angiotensin-converting enzyme 2 gene (ACE2), the transmembrane protease serine 2 gene (TMPRSS2), along with HLA genotype, and ABO blood group help to explain individual susceptibility, severity, and outcomes of COVID-19. This review is focused on COVID-19 clinical and viral characteristics, pathogenesis, and genetic findings, with particular attention on genetic diversity and variants. The human genetic basis could provide scientific bases for disease prediction and targeted therapy to address the COVID-19 scourge.

scholarly journals Predicting the Immunogenicity of T cell epitopes: From HIV to SARS-CoV-2

2020 ◽  
Author(s):  
Ang Gao ◽  
Zhilin Chen ◽  
Florencia Pereyra Segal ◽  
Mary Carrington ◽  
Hendrik Streeck ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
T Cell Epitopes ◽  
Population Coverage ◽  
Ctl Epitopes ◽  
Leukocyte Antigen ◽  
Immunodeficiency Virus ◽  
Hla Genotype ◽  
Hla Molecules ◽  
Do So

AbstractWe describe a physics-based learning model for predicting the immunogenicity of Cytotoxic T Lymphocyte (CTL) epitopes derived from diverse pathogens, given a Human Leukocyte Antigen (HLA) genotype. The model was trained and tested on experimental data on the relative immunodominance of CTL epitopes in Human Immunodeficiency Virus infection. The method is more accurate than publicly available models. Our model predicts that only a fraction of SARS-CoV-2 epitopes that have been predicted to bind to HLA molecules is immunogenic. The immunogenic CTL epitopes across all SARS-CoV-2 proteins are predicted to provide broad population coverage, but the immunogenic epitopes in the SARS-CoV-2 spike protein alone are unlikely to do so. Our model predicts that several immunogenic SARS-CoV-2 CTL epitopes are identical to those contained in low-pathogenicity coronaviruses circulating in the population. Thus, we suggest that some level of CTL immunity against COVID-19 may be present in some individuals prior to SARS-CoV-2 infection.

Abstract: P777 ASSOCIATIONS BETWEEN HUMAN LEUKOCYTE ANTIGEN (HLA) GENOTYPE AND ACUTE MYOCARDIAL INFARCTION

2009 ◽  
Vol 10 (2) ◽  
pp. e953
Author(s):  
H Björkbacka ◽  
E Lavant ◽  
G Fredrikson ◽  
O Melander ◽  
G Berglund ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Hla Genotype

scholarly journals Association Analysis of KIR/HLA Genotype with Liver Cirrhosis, Hepatocellular Carcinoma, and NUC Freedom in Chronic Hepatitis B Patients

2021 ◽  
Author(s):  
Satoru Joshita ◽  
Masao Ota ◽  
Hiroyuki Kobayashi ◽  
Shun-ichi Wakabayashi ◽  
Yuki Yamashita ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Hepatitis B ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Leukocyte Antigen ◽  
Patient Status ◽  
Positive Rate ◽  
Hla Genotype

Abstract Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. The proportion of the KIR2DS4/HLA-C2 pair was significantly higher in patients with liver cirrhosis (n = 40) than in those without (n = 240) (12.5% vs. 4.2%, odds ratio [OR] 3.29, P = 0.029). The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) (30.8% vs. 14.9%, OR 2.53, P = 0.015). The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusions, this study revealed significant KIR/HLA associations with progression to liver cirrhosis (KIR2DS4/HLA-C2), HCC development (KIR2DS3), and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients. KIR/HLA pairs may therefore play a role in HBV patient status.

scholarly journals P838 Characteristics of mucosal microbial composition of patients with inflammatory bowel disease susceptibility HLA genotype

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S649-S650
Author(s):  
A Hirano ◽  
J Umeno ◽  
T Torisu
Keyword(s):  
Human Leukocyte ◽  
Asian Population ◽  
Rrna Gene ◽  
16S Rrna Gene Sequences ◽  
Microbial Composition ◽  
Leukocyte Antigen ◽  
Hla Genotypes ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Hla Genotype

Abstract Background Although inflammatory bowel diseases (IBD) is presumed to develop as the result of dysregulated immune response to the intestinal microbiota in genetically susceptible hosts, the association between microbiota and genotypes in IBD patients remains unclear. The human leukocyte antigen (HLA)-Cw*1202-B*5201-DRB1*1502 haplotype has been reported to increase the susceptibility to ulcerative colitis (UC), and the HLA-DRB1#37Ser reduce the risk of Crohn’s disease (CD) in East Asian population. We investigated the association between IBD susceptibility HLA genotype and mucosal microbial composition to elucidate the pathogenesis of IBD. Methods Mucosal bioptic sampling was performed from the rectum under colonoscopy for the analysis of mucosal microbial composition among 54 IBD patients (27 patients with CD and 27 patients with UC). The mucosal microbial community structure was investigated using 16S rRNA gene sequences, and the structures were analysed using Qiime and LEfSe software. All patients were genotyped using the Affymetrix Japonica Array, and their HLA genotypes were determined by imputation based on the Japanese-specific references. Results Twelve CD patients had the HLA-DRB1#37Ser allele and 15 UC patients had the HLA-Cw*1202-B*5201-DRB1*1502 allele. Microbes of family Barnesiellaceae and genus Anaerofilum were more abundant in HLA-DRB1#37Ser allele carriers when compared with non-carriers among CD patients. Among UC patients, decreased abundance of the genus Acidaminococcus and increased abundance of genera Veillonella, SMB53, Lachnospira and Haemophilus was evident in HLA-Cw*1202-B*5201-DRB1*1502 allele carriers when compared with non-carriers. Conclusion IBD susceptibility HLA genotype might affect mucosal microbiota composition in both CD and UC.

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