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.