title: IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.
abstract: Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury.
authors: Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France; carmen.lefaucheur@wanadoo.fr.
authors: Carmen
authors: C
authors: Lefaucheur
authors: Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France;
authors: Denis
authors: D
authors: Viglietti
authors: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
authors: Carol
authors: C
authors: Bentlejewski
authors: Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France; Department of Pathology, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors: Jean-Paul
authors: JP
authors: Duong van Huyen
authors: Methodology Unit (Research team 3181), University Hospital de Besançon, Besançon, France;
authors: Dewi
authors: D
authors: Vernerey
authors: Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France;
authors: Olivier
authors: O
authors: Aubert
authors: Department of Pathology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; and.
authors: Jérôme
authors: J
authors: Verine
authors: Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France;
authors: Xavier
authors: X
authors: Jouven
authors: Department of Kidney Transplantation, Necker Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France.
authors: Christophe
authors: C
authors: Legendre
authors: Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors: Denis
authors: D
authors: Glotz
authors: Paris Translational Research Center for Organ Transplantation, National Institute of Health and Medical Research, Mixed Research Unit-S970, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France.
authors: Alexandre
authors: A
authors: Loupy
authors: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
authors: Adriana
authors: A
authors: Zeevi
mesh_terms: D064591:Allografts / Q000276:immunology*; D000918:Antibody Specificity; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000145:classification* / Q000276:immunology*; D007674:Kidney Diseases / Q000276:immunology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000276:immunology*; D014019:Tissue Donors; D014181:Transplantation Immunology
chemical_list: D006680:HLA Antigens; D007074:Immunoglobulin G
keywords: acute allograft; immunology and pathology; kidney transplantation; rejection