Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease
Abstract The association between human cytomegalovirus (hCMV) reactivation and the development of graft-versus-host-disease (GVHD) has been observed in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV-derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8 ± 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 ± 16121.8 matched MUD DRP peptides (Student’s T-test, p<0.001).In silicoanalysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins expressed at ≥10 RPKM). hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset with a subset analysis of 7 instances of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute + chronic GVHD (n=2) indicating cross reactive peptide expression within affected organs. We propose that based on our analysis and preliminary clinical correlations that hCMV immune cross-reactivity may cause antigenic mimicry of human alloreactive peptides triggering GVHD..
Medienart: |
Preprint |
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Erscheinungsjahr: |
2019 |
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Erschienen: |
2019 |
Enthalten in: |
bioRxiv.org - (2019) vom: 11. Sept. Zur Gesamtaufnahme - year:2019 |
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Sprache: |
Englisch |
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Beteiligte Personen: |
Hall, Charles [VerfasserIn] |
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Links: |
Volltext [kostenfrei] |
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doi: |
10.1101/066571 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
XBI000078476 |
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520 | |a Abstract The association between human cytomegalovirus (hCMV) reactivation and the development of graft-versus-host-disease (GVHD) has been observed in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV-derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8 ± 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 ± 16121.8 matched MUD DRP peptides (Student’s T-test, p<0.001).In silicoanalysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins expressed at ≥10 RPKM). hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset with a subset analysis of 7 instances of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute + chronic GVHD (n=2) indicating cross reactive peptide expression within affected organs. We propose that based on our analysis and preliminary clinical correlations that hCMV immune cross-reactivity may cause antigenic mimicry of human alloreactive peptides triggering GVHD. | ||
700 | 1 | |a Koparde, Vishal |e verfasserin |4 aut | |
700 | 1 | |a Jameson-Lee, Max |e verfasserin |4 aut | |
700 | 1 | |a Elnasseh, Abdelrhman |e verfasserin |4 aut | |
700 | 1 | |a Scalora, Allison |e verfasserin |4 aut | |
700 | 1 | |a Kobulnicky, Jared |e verfasserin |4 aut | |
700 | 1 | |a Serrano, Myrna |e verfasserin |4 aut | |
700 | 1 | |a Roberts, Catherine |e verfasserin |4 aut | |
700 | 1 | |a Buck, Gregory |e verfasserin |4 aut | |
700 | 1 | |a Neale, Micheal |e verfasserin |4 aut | |
700 | 1 | |a Nixon, Daniel |e verfasserin |4 aut | |
700 | 1 | |a Toor, Amir |e verfasserin |4 aut | |
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