Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease.

Adriana S Albuquerque,Rita Tendeiro,Rui M M Victorino,Ana E Sousa,Rémi Cheynier,Susana L Silva,Margarida Lucas,Susana M Fernandes

doi:10.3389/fimmu.2017.00543

Abstract

Chronic granulomatous disease (CGD) results from primary defects in phagocytic reactive oxygen species (ROS) production. T-cell evaluation is usually neglected during patients’ follow-up, although T-cell depletion has been reported in CGD through unknown mechanisms. We describe here a 36-year-old patient with X-linked CGD with severe CD4 T-cell depletion <200 CD4 T-cells/μl, providing insights into the mechanisms that underlie T-cell loss in the context of oxidative burst defects. In addition to the typical infections, the patient featured a progressive T-cell loss associated with persistent lymphocyte activation, expansion of interleukin (IL)-17-producing CD4 T-cells, and impaired thymic activity, leading to a reduced replenishment of the T-cell pool. A relative CD4 depletion was also found at the gut mucosal level, although no bias to IL-17-production was documented. This immunological pattern of exhaustion of immune resources favors prompt, potentially curative, therapeutic interventions in CGD patients, namely, stem-cell transplantation or gene therapy. Moreover, this clinical case raises new research questions on the interplay of ROS production and T-cell homeostasis and immune senescence.

Highlights

Chronic granulomatous disease (CGD) is the most common primary immunodeficiency affecting phagocytes
We report here long-lasting severe CD4 lymphopenia in a 36-year-old patient with CGD that allowed us to investigate the pathways involved in T-cell production and peripheral homeostasis in the context of markedly impaired reactive oxygen species (ROS) production
We found evidence of compromised thymopoiesis via the quantification of by-products of T-cell receptor (TCR) rearrangement that are generated during thymic T-cell development [signal joint and DβJβ TCR rearrangement circles, T-cell receptor rearrangement excision circle (TREC)] and progressively decline during ageassociated thymus involution

Summary

Introduction

Chronic granulomatous disease (CGD) is the most common primary immunodeficiency affecting phagocytes. It is due to genetic defects in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [1, 2], leading to impaired reactive oxygen species (ROS) production by monocytes and neutrophils, defective microorganism clearance, and chronic inflammation [1,2,3,4]. The defective ROS production by myeloid cells indirectly contributes to the T-cell loss through the promotion of inflammation [1, 2]. T-cells have been shown to harbor NADPH [6], and T-cell intrinsic defects in ROS production are associated with disturbances in T-cell effector differentiation and regulatory function [6,7,8,9,10,11]. T-cell alterations in susceptibility to apoptosis have been described [13], as well as impairments in autophagy [14], which may impact on T-cell development and function

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Conclusion