title: Enhanced B Cell Alloantigen Presentation and Its Epigenetic Dysregulation in Liver Transplant Rejection.
abstract: T cell suppression prevents acute cellular rejection but causes life-threatening infections and malignancies. Previously, liver transplant (LTx) rejection in children was associated with the single-nucleotide polymorphism (SNP) rs9296068 upstream of the HLA-DOA gene. HLA-DOA inhibits B cell presentation of antigen, a potentially novel antirejection drug target. Using archived samples from 122 white pediatric LTx patients (including 77 described previously), we confirmed the association between rs9296068 and LTx rejection (p = 0.001, odds ratio [OR] 2.55). Next-generation sequencing revealed that the putative transcription factor (CCCTC binding factor [CTCF]) binding SNP locus rs2395304, in linkage disequilibrium with rs9296068 (D' 0.578, r(2) = 0.4), is also associated with LTx rejection (p = 0.008, OR 2.34). Furthermore, LTx rejection is associated with enhanced B cell presentation of donor antigen relative to HLA-nonidentical antigen in a novel cell-based assay and with a downregulated HLA-DOA gene in a subset of these children. In lymphoblastoid B (Raji) cells, rs2395304 coimmunoprecipitates with CTCF, and CTCF knockdown with morpholino antisense oligonucleotides enhances alloantigen presentation and downregulates the HLA-DOA gene, reproducing observations made with HLA-DOA knockdown and clinical rejection. Alloantigen presentation is suppressed by inhibitors of methylation and histone deacetylation, reproducing observations made during resolution of rejection. Enhanced donor antigen presentation by B cells and its epigenetic dysregulation via the HLA-DOA gene represent novel opportunities for surveillance and treatment of transplant rejection.
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: M
authors.initials: M
authors.lastname: Ningappa
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: C
authors.initials: C
authors.lastname: Ashokkumar
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: B W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Pathology, University of Pittsburgh, Division of Pediatric Pathology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: R
authors.initials: R
authors.lastname: Jaffe
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: G
authors.initials: G
authors.lastname: Mazariegos
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
authors.forename: D E
authors.initials: DE
authors.lastname: Weeks
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA.
authors.forename: S
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
authors.forename: R
authors.initials: R
authors.lastname: Ferrell
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Hillman Center for Pediatric Transplantation, Thomas E. Starzl Transplantation Institute, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh, PA.
authors.forename: R
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D047369:Chromatin Immunoprecipitation; D057890:Epigenomics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D006085:Graft Survival; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D007519:Isoantigens / Q000276:immunology*; D008107:Liver Diseases / Q000601:surgery; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014019:Tissue Donors
chemical_list: D006680:HLA Antigens; D007519:Isoantigens; D012333:RNA, Messenger
keywords: B cell biology; flow cytometry; genomics; immune; immunobiology; immunosuppression/immune modulation; liver transplantation/hepatology; monitoring; rejection:acute; translational research/science