title: MICA variant promotes allosensitization after kidney transplantation.
abstract: MHC class I-related chain A (MICA) antigens are surface glycoproteins strongly implicated in innate immunity, and the MICA gene is highly polymorphic. Clinical observations suggest a role for donor MICA antigens expressed on transplant endothelial cells in the alloimmune response, but the effect of MICA genotype is not well understood. Here, we investigated the immunologic effect of the A5.1 mutation, related to the common MICA*008 allele. Compared with wild-type endothelial cells (ECs), homozygosity for MICA A5.1 associated with an endothelial phenotype characterized by 7- to 10-fold higher levels of MICA mRNA and MICA proteins at the cell surface, as well as exclusive release in exosomes instead of enzymatic cleavage. Mechanistically, we did not detect quantitative changes in regulatory microRNAs. Functionally, A5.1 ECs enhanced NKG2D interaction and natural killer cell activation, promoting NKG2D-dependent lysis of ECs. In kidney transplant recipients, polyreactive anti-MICA sera bound preferentially to ECs from MICA A5.1 donors, suggesting that MICA*008(A5.1) molecules are the preferential antigenic determinants on ECs of grafts. Furthermore, the incidence of MICA A5.1 mismatch revealed a statistically significant association between donor MICA A5.1 and both anti-MICA sensitization and increased proteinuria in kidney recipients. Taken together, these results identify the A5.1 mutation as an immunodominant factor and a potential risk factor for transplant survival.
authors.affiliation: Centre de Recherche en Transplantation et Immunologie, LabEx Transplantex, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Tonnerre
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gérard
authors.forename: Mathias
authors.initials: M
authors.lastname: Chatelais
authors.forename: Caroline
authors.initials: C
authors.lastname: Poli
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Allard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cury
authors.forename: Céline
authors.initials: C
authors.lastname: Bressollette
authors.forename: Anne
authors.initials: A
authors.lastname: Cesbron-Gautier
authors.forename: Béatrice
authors.initials: B
authors.lastname: Charreau
mesh_terms: D000328:Adult; D000368:Aged; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology*; D007519:Isoantigens / Q000235:genetics / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D061251:Primary Cell Culture; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012307:Risk Factors; D050794:STAT1 Transcription Factor / Q000276:immunology; D014019:Tissue Donors; D014158:Transcription, Genetic / Q000235:genetics; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D007519:Isoantigens; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor
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