title: Anti-LG3 Antibodies Aggravate Renal Ischemia-Reperfusion Injury and Long-Term Renal Allograft Dysfunction.
abstract: Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Yang
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Dieudé
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hamelin
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Hénault-Rondeau
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.|Department of Pathology, CHU Ste-Justine, Université de Montréal, Montreal, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Patey
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Turgeon
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Lan
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Pomerleau
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Quesnel
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Chan
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hébert
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.|Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.|Université de Montréal, Montreal, QC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Cardinal
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D051799:Delayed Graft Function / Q000097:blood / Q000209:etiology* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006085:Graft Survival / Q000276:immunology*; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011379:Prognosis; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D019812:Heparan Sulfate Proteoglycans; C071927:perlecan
keywords: autoimmunity; basic (laboratory) research/science; clinical research/practice; complement biology; delayed graft function (DGF); immunobiology; ischemia reperfusion injury (IRI); kidney (allograft) function/dysfunction; kidney transplantation/nephrology