title: A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection.
abstract: Immune responses to human leucocyte antigen (HLA) and self-antigen collagen V (Col-V) have been proposed in the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome, BOS) following human lung transplantation (LTx). In this study, we defined the role for the shift in immunodominant epitopes of Col-V in inducing T helper phenotype switch leading to immunity to Col-V and BOS. Sera and lavage from BOS(+)  LTx recipients with antibodies to Col-V were analysed. Two years prior to BOS, patients developed antibodies to both Col-V,α1(V) and α2(V) chains. However, at clinical diagnosis of BOS, antibodies became restricted to α1(V). Further, lung biopsy from BOS(+) patients bound to antibodies to α1(V), indicating that these epitopes are exposed. Fourteen Col-V peptides [pep1-14, pep1-4 specific to α1(V), pep5-8 to α1,2(V) and pep9-14 to α2(V)] which bind to HLA-DR4 and -DR7, demonstrated that prior to BOS, pep 6, 7, 9, 11 and 14 were immunodominant and induced interleukin (IL)-10. However, at BOS, the response switched to pep1, 4 and 5 and induced interferon (IFN)-γ and IL-17 responses, but not IL-10. The T helper (Th) phenotype switch is accompanied by decreased frequency of regulatory T cells (T(regs) ) in the lavage. LTx recipients with antibodies to α1(V) also demonstrated increased matrix metalloproteinase (MMP) activation with decreased MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP), suggesting that MMP activation may play a role in the exposure of new Col-V antigenic epitopes. We conclude that a shift in immunodominance of self-antigenic determinants of Col-V results in induction of IFN-γ and IL-17 with loss of tolerance leading to autoimmunity to Col-V, which leads to chronic lung allograft rejection.
authors: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: V
authors: V
authors: Tiriveedhi
authors: N
authors: N
authors: Angaswamy
authors: D
authors: D
authors: Brand
authors: J
authors: J
authors: Weber
authors: A G
authors: AG
authors: Gelman
authors: R
authors: R
authors: Hachem
authors: E P
authors: EP
authors: Trulock
authors: B
authors: B
authors: Meyers
authors: G
authors: G
authors: Patterson
authors: T
authors: T
authors: Mohanakumar
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D024042:Collagen Type I / Q000276:immunology*; D024062:Collagen Type V / Q000276:immunology*; D019175:DNA Methylation; D004789:Enzyme Activation; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D007519:Isoantigens / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D001324:Autoantigens; D024042:Collagen Type I; D024062:Collagen Type V; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016056:Immunodominant Epitopes; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D007519:Isoantigens; D010446:Peptide Fragments; D007371:Interferon-gamma; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9