Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG).

Roberto García-López,Belén Pérez-Dueñas,María Eugenia De La Morena-Barrio,Trinidad Hernández-Caselles,Jaak Jaeken,Mercedes Serrano,Mercedes Casado,Laia Alsina,Francois Trottein

doi:10.1371/journal.pone.0158863

Abstract

BackgroundPMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.ObjectiveTo evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.MethodsWe studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.ResultsWe found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.ConclusionsOur results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.

Highlights

Congenital disorders of glycosylation (CDG) are rare genetic diseases caused by defective glycosylation of glycoproteins and glycolipids
We found an increase of blood natural killer (NK) cells in three patients with a severe phenotype
NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells

Summary

Introduction

Congenital disorders of glycosylation (CDG) are rare genetic diseases caused by defective glycosylation of glycoproteins and glycolipids. These disorders show an extremely broad clinical spectrum that can affect most organs and systems, including immunity, with degrees of severity that range from early death to very mildly affected adults [1, 2]. PMM2-CDG, one of the most prevalent CDG, is an autosomal recessive defect of phosphomannomutase 2 due to mutations in PMM2 [3]. Both cell surface and secreted glycoproteins are affected. PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder

Methods

Results

Conclusion