title: A stepwise breakdown of B-cell tolerance occurs within renal allografts during chronic rejection.
abstract: Autoantibodies detected after kidney transplantation may contribute to chronic rejection. We and others have previously described the organization of immune effectors into functional intragraft tertiary lymphoid tissue, a site where breakdown of B-cell tolerance may occur. To test this, we performed a comprehensive analysis of 26 chronically rejected kidney grafts. Antibodies were screened by indirect immunofluorescence on HEp2 cells, a procedure that detects antibodies to intracellular antigens, and monkey kidney sections, which detects kidney tissue autoantigens. The incidence of anti-HEp2 autoantibodies was significantly higher in graft explant culture supernatants than in patient sera. Reactivity against monkey kidney sections was detected in almost half of culture supernatants with anti-HEp2 autoantibodies. A local enrichment in T helper 17 and B-cell-activating factor (CD257) correlated with intragraft production of anti-HEp2 antibodies. A decrease in Tregs and a symmetric increase of activated OX40 (CD134)-expressing CD4+ T cells were found in grafts in which anti-kidney autoantibodies were produced. Thus, a stepwise breakdown of B-cell tolerance occurs within the graft during chronic rejection. Hence, the intragraft microenvironment interferes with peripheral deletion of autoreactive immature B cells that, in turn, produce antibodies against intracellular autoantigens. When intragraft immune regulation is insufficient, spreading of the local response against kidney autoantigens is favored.
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation Rénale et d'Immunologie Clinique, Lyon, France. olivier.thaunatpastu@free.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Thaunat
authors.forename: Stephanie
authors.initials: S
authors.lastname: Graff-Dubois
authors.forename: Nicole
authors.initials: N
authors.lastname: Fabien
authors.forename: Aurelie
authors.initials: A
authors.lastname: Duthey
authors.forename: Valerie
authors.initials: V
authors.lastname: Attuil-Audenis
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
authors.forename: Natcha
authors.initials: N
authors.lastname: Patey
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Morelon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D000882:Haplorhini; D006801:Humans; D007668:Kidney / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D053262:Receptors, OX40 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory; D058504:Th17 Cells; D023001:Transplantation Tolerance / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D016207:Cytokines; D053262:Receptors, OX40