title: Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy.
abstract: Antibodies (Abs) to donor HLA (donor-specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue-restricted self-antigens (self-Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self-Ags, Collagen-IV (Col-IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col-IV and FN by enzyme-linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN-γ), IL-17 or IL-10 by ELISPOT. Development of Abs to self-Ags following KTx increased the risk for TG with an odds ratio of 22 (p-value = 0.001). Abs to self-Ags were IgG and IgM isotypes. Pretransplant Abs to self-Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self-Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col-IV and FN specific CD4+ T cells secreting IFN-γ and IL-17 with reduction in IL-10. We conclude that development of Abs to self-Ags is a risk factor and having both DSA and Abs to self-Ags increases the risk for TG. The increased frequency of self-Ag-specific IFN-γ and IL-17 cells with reduction in IL-10 demonstrate tolerance breakdown to self-Ags which we propose play a role in the pathogenesis of TG.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: N
authors.initials: N
authors.lastname: Angaswamy
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.forename: V
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: J
authors.initials: J
authors.lastname: Gaut
authors.forename: S
authors.initials: S
authors.lastname: Anwar
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: D
authors.initials: D
authors.lastname: Phelan
authors.forename: J R
authors.initials: JR
authors.lastname: Wellen
authors.forename: S
authors.initials: S
authors.lastname: Shenoy
authors.forename: W C
authors.initials: WC
authors.lastname: Chapman
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D024141:Collagen Type IV / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005353:Fibronectins / Q000276:immunology*; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000097:blood* / Q000276:immunology; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D016207:Cytokines; D005353:Fibronectins; D006680:HLA Antigens; D007518:Isoantibodies
keywords: Alloimmunity; Collagen-IV; autoimmunity; fibronectin; kidney transplantation; transplant glomerulopathy