Analysis of the intracellular traffic of IgG in the context of Down syndrome (trisomy 21)

R B Cejas,J G Blanco,M Tamaño-Blanco

doi:10.1038/s41598-021-90469-z

R B Cejas, J G Blanco + Show 1 more

Open Access

https://doi.org/10.1038/s41598-021-90469-z

Copy DOI

Abstract

Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafficking defects. There is a paucity of data describing the intracellular transport of IgG in the context of endosomal-lysosomal alterations linked to trisomy 21. In this study, we analyzed the intracellular traffic of IgG mediated by the human neonatal Fc receptor (FcRn) in fibroblast cell lines with trisomy 21. Intracellular IgG trafficking studies in live cells showed that fibroblasts with trisomy 21 exhibit higher proportion of IgG in lysosomes (~ 10% increase), decreased IgG content in intracellular vesicles (~ 9% decrease), and a trend towards decreased IgG recycling (~ 55% decrease) in comparison to diploid cells. Amyloid-beta precursor protein (APP) overexpression in diploid fibroblasts replicated the increase in IgG sorting to the degradative pathway observed in cells with trisomy 21. The impact of APP on the expression of FCGRT (alpha chain component of FcRn) was investigated by APP knock down and overexpression of the APP protein. APP knock down increased the expression of FCGRT mRNA by ~ 60% in both diploid and trisomic cells. Overexpression of APP in diploid fibroblasts and HepG2 cells resulted in a decrease in FCGRT and FcRn expression. Our results indicate that the intracellular traffic of IgG is altered in cells with trisomy 21. This study lays the foundation for future investigations into the role of FcRn in the context of DS.

Highlights

Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafficking defects
Co-localization analysis revealed that trisomic fibroblasts exhibited a ~ 11% increase in the distribution of immunoglobulin G (IgG) in lysosomes compared to diploid cells (Pearson’s Colocalization Coefficient, Pearson’s correlation coefficient (PCC) DS: 0.42 ± 0.16, PCC NDS: 0.38 ± 0.17) (Fig. 1A,D)
Trisomic fibroblasts showed decreased IgG recycling in comparison to diploid cell lines derived from age- and sex-matched donors (Fig. 2B)

Summary

Introduction

Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafficking defects. We analyzed the intracellular traffic of IgG mediated by the human neonatal Fc receptor (FcRn) in fibroblast cell lines with trisomy 21. Amyloid-beta precursor protein (APP) overexpression in diploid fibroblasts replicated the increase in IgG sorting to the degradative pathway observed in cells with trisomy 21. The human neonatal Fc receptor (FcRn) plays a key role in controlling the traffic and recycling of immunoglobulin G (IgG), mAbs, and a lbumin[19,20,21,22]. This receptor binds to the Fc region of IgG molecules at acidic pH in early endosomes. The goal of this study was to examine the intracellular FcRn-mediated traffic and recycling of IgG in cells with trisomy 21

Objectives

Methods

Results

Conclusion