Publications by authors named "Leon E Jessen"

7 Publications

  • Page 1 of 1

TCRMatch: Predicting T-Cell Receptor Specificity Based on Sequence Similarity to Previously Characterized Receptors.

Front Immunol 2021 11;12:640725. Epub 2021 Mar 11.

La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States.

The adaptive immune system in vertebrates has evolved to recognize non-self antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared seven metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensive -mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.
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http://dx.doi.org/10.3389/fimmu.2021.640725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991084PMC
March 2021

T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes.

Nat Biotechnol 2018 Nov 19. Epub 2018 Nov 19.

Department of Micro and Nanotechnology, Technical University of Denmark, Lyngby, Denmark.

The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T-cell recognition. Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements. Here we present a 'one-pot' strategy for determining the interactions that govern TCR recognition of peptide-major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide-MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development.
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http://dx.doi.org/10.1038/nbt.4303DOI Listing
November 2018

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 09;50(9):1343

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0197-6DOI Listing
September 2018

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 08 16;50(8):1072-1080. Epub 2018 Jul 16.

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
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http://dx.doi.org/10.1038/s41588-018-0157-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068780PMC
August 2018

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Am J Hum Genet 2018 01;102(1):88-102

MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777980PMC
January 2018

Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses.

Am J Respir Crit Care Med 2018 03;197(5):589-594

1 Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Rationale: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations.

Objectives: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood.

Methods: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses.

Measurements And Main Results: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages.

Conclusions: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.
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http://dx.doi.org/10.1164/rccm.201705-1021OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005238PMC
March 2018

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

Sci Rep 2017 05 22;7(1):2224. Epub 2017 May 22.

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.
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http://dx.doi.org/10.1038/s41598-017-01977-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440386PMC
May 2017