Sustrato genético del rechazo mediado por anticuerpos tras el trasplante cardíacovariantes en genes de la cascada del complemento y de la biología de las células B

  1. Marrón Liñares, Grecia Manuela
Supervised by:
  1. Manuel Hermida Prieto Co-director
  2. Lucía Núñez Fernández Co-director

Defence university: Universidade da Coruña

Fecha de defensa: 11 May 2018

Committee:
  1. J. L. Gutiérrez Chico Chair
  2. Ángeles Castro Iglesias Secretary
  3. Raquel Marzoa Rivas Committee member

Type: Thesis

Teseo: 551953 DIALNET lock_openRUC editor

Abstract

One of the main problems involved in heart transplantation (HT) is the humoral response now termed antibody-mediated rejection (AMR), where complement cascade and B-cells play a key role. Thus, in this doctoral thesis, we explore the importance of genes related to complement pathway and B-cell biology in heart transplant patients and their donors that can yield diagnostic and prognostic information about AMR. For this purpose, genetic variants in 112 genes (51 complement pathway and 61 B-cell biology genes) were analyzed by next generation sequencing in 46 HT patients, 23 with and 23 without AMR and 28 donors, 14 donors from patients with and 14 donors from patients without AMR. We have identified 7 polymorphisms (SNPs) between groups which correlates with the development of AMR: 5 SNPs in receptors: 2 SNPs in complement genes (p.Gly54Asp- MBL2 and p.Asn428(p=)-CFP) and 3 SNPs in ITGA4 gene, related with B-cell biology [p.Thr615(p=), p.Gln878Arg y p.His961(p=)]. We have identified one SNP in donors in genes related with B-cell biology, p.Ile75Val-IL4Rα, which correlates with the development of AMR. Moreover, in the analysis of discrepancies between recipientdonor genotypes, we have identified another SNP, in this case in ADA gene (p.Val178(p=)), which is related with B-cell biology, associated with AMR. In addition, to examine the role of the variants p.Gly54Asp-MBL2, p.Asn428 (p =)-CFP and for the AGT-ITGA4 haplotype, expression studies were carried out, in patients with presence and absence of these variants, that corroborated their possible role in the development of the AMR. The most relevant conclusion of this study is that polymorphisms in HT receptors in MBL2 and CFP genes of the complement pathway and polymorphisms in ITGA4, IL4Rα, and ADA genes belonging to the B cells biology in HT receptors and in donors could have an important role in AMR.