NADPH Oxidase Deficiency: A Multisystem Approach

Abstract

The immune system is a complex system able to recognize a wide variety of host agents, through different biological processes. For example, controlled changes in the redox state are able to start different pathways in immune cells and are involved in the killing of microbes. The generation and release of ROS in the form of an "oxidative burst" represent the pivotal mechanism by which phagocytic cells are able to destroy pathogens. On the other hand, impaired oxidative balance is also implicated in the pathogenesis of inflammatory complications, which may affect the function of many body systems. NADPH oxidase (NOX) plays a pivotal role in the production of ROS, and the defect of its different subunits leads to the development of chronic granulomatous disease (CGD). The defect of the different NOX subunits in CGD affects different organs. In this context, this review will be focused on the description of the effect of NOX2 deficiency in different body systems. Moreover, we will also focus our attention on the novel insight in the pathogenesis of immunodeficiency and inflammation-related manifestations and on the protective role of NOX2 deficiency against the development of atherosclerosis.

Figure 1

Schematic representation of the inactive and active forms of the NADPH oxidase complex. The complex consists of six subunits. NOX2 and p22phox are associated to form a heterodimer bound to the plasma membrane in both the inactive and the active forms. In resting conditions, p47phox, p67phox, p40phox, and the G-protein Rac are located in the cytosol. In the active form, the cytosolic subunits associate with the membrane-bound NOX2/p22phox heterodimer. The active NADPH oxidase generates superoxide (O₂ ⁻) by transferring electrons from NADPH inside the cell across the membrane and coupling them to molecular oxygen.

Figure 2

Invasive fungal infections in patients with CGD. (a, b) Cerebral invasion (arrows) in a patient with invasive pulmonary aspergillosis. (c) Cerebellar aspergillosis (arrow). (d) Invasive pulmonary aspergillosis. (e) Spinal cord invasion (arrow) in a patient with pulmonary aspergillosis.

Figure 3

Spectrum of clinical manifestations associated with marked reduction (dihydrorhodamine (DHR) < 10%), slight reduction, and increase of the NOX2 activity. The complete absence of NOX2 activity leads to the development of infectious, inflammatory and autoimmune complications observed in CGD. A partial reduction of the NOX2 activity, observed in female carriers, may lead to the development of autoimmune complications. Upregulation of NOX2 has been observed in different cardiovascular and neurodegenerative disorders and in neoplasms.

Figure 4

CT scan of a possible invasive fungal infection in a 5-month-old XCGD patient (a) pre-HSCT and (b) after HSCT. A progressive improvement of the areas of consolidation in the left and right lungs, especially for the right lobes, is observed. Residual pulmonary lesions are visible in the left and right inferior lobe.