Alteraciones genéticas de los Receptores Fc gamma y consecuencias funcionales de la ausencia de CD16

Abstract

Fc gamma receptors play an important role in immune responses by binding to the Fc region of IgG and activating mechanisms of cellular immunity including phagocytosis and cytotoxicity. One receptor that has been extensively studied especially since it is the only Fc receptor expressed by NK cells is FcγRIIIA (CD16A). In this thesis, the consequences of the absence of expression of CD16A have been studied. In an Ecuadorian family, three of its members inherited from the father a deletion of a region of the FCGR locus, which we call CNR5, that gives rise to a recombinant gene FCGR3B/A, and from the mother a deletion of the CNR2 region, which means the absence of the FCGR3A gene in this allele. These individuals do not express CD16A in their NK cells or in monocytes and CD16B/A mRNA is found only in polymorphonuclear cells, with no evidence of protein expression in these cells. In terms of function, as expected the absence of CD16A affects the ability of NK cells to perform their function of ADCC, but has no consequences for natural cytotoxicity, as compared to healthy individuals, both in vitro and in vivo. Elevated levels of EBV DNAemia in peripheral blood of the immunodeficient patient that have caused disease suggest that ADCC is important for immune control of replication of this virus. It has also been observed that CD16A is important in the expansion of “adaptive” NK cells. The study of this family led to analysis of genetic variability in the FCGR locus in ecuadorian populations. A search for new SNPs in FCGR3A gene identified two variants not previously described in the literature. Further, in a cohort of 70 individuals from Ecuador specific CNVs and SNPs were characterised by MLPA. The results obtained were similar to those of other Latin-American populations. However, we did not find any other individual with the recombinant gene FCGR3B/A, therefore the study was extended to focus on a specific population of Ecuador, the Llano Grande indigenous commune, the origin of this family. In the Llanogrande population 9.52% of individuals possessed the recombinant gene, and the proportions of genetic variables observed were likely a consequence of genetic drift because this commune has a propensity to inbreeding due to its social organization.