Crespo Barrio, MartaLlinàs-Mallol, LauraRedondo Pachón, María DoloresButler, CarrieGimeno Beltran, JavierPérez-Sáez, María JoséBurballa Tàrrega, Carla, 1988-Buxeda, AnnaArias Cabrales, Carlos EnriqueFolgueiras, MontserratSanz-Ureña, SaraValenzuela,Nicole M.Reed, Elaine F.Pascual Santos, Julio2022-07-282022-07-282021Crespo M, Llinàs-Mallol L, Redondo-Pachón D, Butler C, Gimeno J, Pérez-Sáez MJ, et al. Non-HLA antibodies and epitope mismatches in kidney transplant recipients with histological antibody-mediated rejection. Front Immunol. 2021 Jul 6; 12: 703457. DOI: 10.3389/fimmu.2021.7034571664-3224http://hdl.handle.net/10230/53872Background: correlation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved. Methods: we retrospectively assessed patients with transplant biopsies scored following Banff'15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT1R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMRh) with and without HLA-DSA. Results: one-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and AT1R-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMRhDSApos. Conclusions: in conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.application/pdfengCopyright © 2021 Crespo, Llinàs-Mallol, Redondo-Pachón, Butler, Gimeno, Pérez-Sáez, Burballa, Buxeda, Arias-Cabrales, Folgueiras, Sanz-Ureña, Valenzuela, Reed and Pascual. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) https://creativecommons.org/licenses/by/4.0/ . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fimmu.2021.703457AT1R antibodiesHLA antibodiesHLA epitope mismatchAntibody-mediated rejectionKidney transplantationNon-HLA antibodiesinfo:eu-repo/semantics/openAccess