RT Journal Article
SR Electronic
T1 Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B are Increased in Patients with Kidney Allograft Antibody-Mediated Rejection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.02.408922
DO 10.1101/2020.12.02.408922
A1 Sergi Clotet-Freixas
A1 Max Kotlyar
A1 Caitriona M. McEvoy
A1 Chiara Pastrello
A1 Sonia Rodríguez-Ramírez
A1 Sofia Farkona
A1 Heloise Cardinal
A1 Mélanie Dieudé
A1 Marie-Josée Hébert
A1 Yanhong Li
A1 Olusegun Famure
A1 Peixuen Chen
A1 S. Joseph Kim
A1 Emilie Chan
A1 Igor Jurisica
A1 Rohan John
A1 Andrzej Chruscinski
A1 Ana Konvalinka
YR 2020
UL http://biorxiv.org/content/early/2020/12/02/2020.12.02.408922.abstract
AB Antibody-mediated rejection (AMR) causes >50% of late kidney graft losses. Although donor-specific antibodies (DSA) against HLA cause AMR, antibodies against non-HLA antigens are also linked to rejection. Identifying key non-HLA antibodies will improve our understanding of antibody-mediated injury.We analyzed non-HLA antibodies using protein microarrays in sera from 91 kidney transplant patients with AMR, mixed rejection, acute cellular rejection (ACR), or acute tubular necrosis (ATN). IgM and IgG antibodies against 134 non-HLA antigens were measured pre-transplant, at the time of biopsy-proven diagnosis, and post-diagnosis. Findings were validated in 60 kidney transplant patients from an independent cohort.Seventeen non-HLA antibodies were significantly increased (p<0.05) in AMR and mixed rejection compared to ACR or ATN pre-transplant, nine at diagnosis and six post-diagnosis. AMR and mixed cases showed significantly increased pre-transplant levels of IgG anti-Ro/SS-A and anti-CENP-B, compared to ACR. Together with IgM anti-CENP-B and anti-La/SS-B, these antibodies were also significantly increased in AMR/mixed rejection at diagnosis. Increased IgG anti-Ro/SS-A and anti-CENP-B pre-transplant and at diagnosis, and IgM anti-La/SS-B at diagnosis, were associated with the presence of microvascular lesions, but not with tubulitis or interstitial/total inflammation. All three antibodies were associated with the presence of class-II DSA (p<0.05). Significantly increased IgG anti-Ro/SS-A in AMR/mixed compared to ACR (p=0.01), and numerically increased IgM anti-CENP-B (p=0.05) and anti-La/SS-B (p=0.06), were validated in the independent cohort.This is the first study that implicates autoantibodies against Ro/SS-A and CENP-B in AMR. These non-HLA antibodies may participate in the crosstalk between autoimmunity and alloimmunity in kidney AMR.SIGNIFICANCE STATEMENT Antibody-mediated rejection (AMR) causes >50% of kidney graft losses. Although donor-specific antibodies against HLA cause AMR, antibodies against non-HLA antigens are also linked to rejection. Serum samples of 91 kidney transplant patients were analyzed using protein arrays against 134 non-HLA antigens. AMR and mixed rejection cases showed significantly increased pre-transplant levels of IgG anti-Ro/SS-A and anti-CENP-B, compared to acute cellular rejection. Together with IgM anti-CENP-B and anti-La/SS-B, these antibodies were significantly increased in AMR/mixed rejection at diagnosis and were validated in a second, independent cohort. Increased IgG anti-Ro/SS-A, IgG anti-CENP-B and IgM anti-La/SS-B were associated with the presence of microvascular lesions and anti-HLA class-II antibodies. This is the first study to implicate anti-Ro/SS-A, anti-La/SS-B and anti-CENP-B autoantibodies in AMR.Competing Interest StatementDr. Igor Jurisica reports receiving personal fees from Canadian Rheumatology Association, grants and nonfinancial support from IBM, and personal fees from Novartis, outside the submitted work.