The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.

INTRODUCTION

Immunobiology

The immune system is essential for protection again infectious agents and, consequently, the survival of complex organisms. However, immunity is a double-edged sword: although immune deficiency may lead to life-threatening infection, uncontrolled activation of immune cells can cause tissue damage. Therefore immunity needs to be tightly controlled in time and space. This regulation is achieved by complex regulatory networks which include cell–cell interaction and action of various cytokines. The immune system has two major arms: innate and adaptive immunity.

Innate immunity is composed of granulocytes, macrophages, dendritic cells (DCs) and natural killer (NK) cells. Those cells represent the first defence against pathogens. Recognition by innate immune cells occurs via pattern recognition receptors (PRRs) [e.g. recognition of fungal β-glucans through dectin-1 receptor or of lipopolysaccharide (LPS) through toll-like receptor 4 (TLR4)]. Cells of the innate immune system possess powerful killing mechanisms, e.g. the phagocyte NADPH oxidase in granulocytes and macrophages.

Adaptive immunity (also referred to as specific immunity) is composed of T- and B-lymphocytes. Those cells differ from innate immune cells as they can generate antigen-specific receptors by gene rearrangement. T-lymphocytes can be broadly divided into two main subtypes: helper and cytotoxic T-cells. The main role of helper T-cells is to produce cytokines that regulate the immune response. As indicated by its name, cytotoxic T-cells kill target cells in an antigen-specific fashion. Finally, B-lymphocytes are responsible for the development of the humoral response by producing antigen-specific antibodies.

Antigen-presenting cells (APCs) (in particular DCs) act as a bridge between innate and adaptive immunity after stimulation through PRRs. Their function is to activate adaptive immunity by presenting antigens to T-lymphocytes.

NADPH oxidases

NADPH oxidases are a family of reactive oxygen species (ROS)-generating enzymes that in mammals includes seven distinct members {NOX1–NOX5, dual oxidase 1 (DUOX1) and DUOX2; reviewed in [1]}. The role of these enzymes is to transfer electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen. This reaction results in the formation of superoxide, which will be further metabolized into hydrogen peroxide (H2O2) and other ROS. In the present review we will focus on the phagocyte NADPH oxidase 2 (NOX2).

The phagocyte NADPH oxidase is composed of five subunits (Figure 1). Two membrane proteins (for NOX2, gp91phox and p22phox) compose the core of the enzyme. NOX2 contains the catalytic site and the NADPH-binding site. The second, smaller membrane subunit p22phox is responsible for NOX2 stability, as well as for the docking of the cytosolic subunit p47phox. Other cytosolic subunits include p40phox and p67phox, which dock to p47phox. Also, small G-proteins of the Rac family, in particular Rac1 and Rac2, play an important role in NOX2 function. Activation mechanisms are complex; however, a key step is the phosphorylation of p47phox, leading to its binding to p22phox where it brings together the different subunits, thereby initiating enzyme activity.

Schematic representation of the NOX2 enzyme complex

Figure 1
Schematic representation of the NOX2 enzyme complex

Electrons are transferred through the catalytic subunit Gp91phox/NOX2 from cytoplasmic NADPH to extracellular oxygen leading to the formation of superoxide anion (O2). The second membrane subunit, p22phox, stabilizes NOX2 at the membrane. Cytosolic subunits (Rac, p67phox, p47phox and p40phox) are regulatory subunits. The charge build-up due to electron transfer is compensated by a flux of protons through the Hv1 proton channel to the extracellular space. Superoxide anion readily dismutates into H2O2, which freely diffuses through lipid membranes and therefore may back-diffuse into the cytoplasm. NOX2 can be located in the plasma membrane or within the membrane of intracellular organelles. The enzyme orientation is conserved as follows: the NADPH-binding site is in the cytosol; the superoxide-producing site is extracellular or within the lumen of the organelle.

Figure 1
Schematic representation of the NOX2 enzyme complex

Electrons are transferred through the catalytic subunit Gp91phox/NOX2 from cytoplasmic NADPH to extracellular oxygen leading to the formation of superoxide anion (O2). The second membrane subunit, p22phox, stabilizes NOX2 at the membrane. Cytosolic subunits (Rac, p67phox, p47phox and p40phox) are regulatory subunits. The charge build-up due to electron transfer is compensated by a flux of protons through the Hv1 proton channel to the extracellular space. Superoxide anion readily dismutates into H2O2, which freely diffuses through lipid membranes and therefore may back-diffuse into the cytoplasm. NOX2 can be located in the plasma membrane or within the membrane of intracellular organelles. The enzyme orientation is conserved as follows: the NADPH-binding site is in the cytosol; the superoxide-producing site is extracellular or within the lumen of the organelle.

NOX2 is predominantly expressed in professional phagocytes (neutrophils and macrophages) and related cells (e.g. eosinophils, DCs and B-lymphocytes). Note that expression of NOX2 in T-lymphocytes is still a matter of debate. NOX2 has also been described in cells unrelated to the immune system; however, this topic is beyond the scope of the present review.

Reactive oxygen species

ROS refer to a variety of oxygen derivatives characterized by their high reactivity with other molecules. ROS can be either oxygen radicals (e.g. O2) or non-radical derivates (e.g. H2O2), and need to be distinguished from reactive nitrogen species (RNS). A notable exception to this distinction is peroxynitrite, which is the product of the reaction of superoxide (a ROS) and nitrogen oxide (a RNS) and which therefore has an intermediate status.

NOX2-derived ROS play two main biological roles: they exhibit microbicidal effects when produced in large amounts in phagosomes within neutrophils or macrophages. In this context, they can lead to inflammatory tissue damage. However, they can also exert a role of second messenger by acting on a redox-sensitive cellular signalling system and thereby influencing many cellular pathways [2]. H2O2, which can diffuse across the cellular membrane, is an important ROS involved in cell signalling. The role of NOX2 in specific immunity is for most parts explained by its signalling function.

Phagocyte NADPH oxidase deficiency: chronic granulomatous disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency (incidence 1:200000–1:500000) that is due to a defect in NOX2 complex. Genetic mutation of all genes coding for NOX2 subunits (NOX2/gp91phox, p22phox, p47phox, p67phox and p40phox) have been reported and all lead to a relatively similar phenotype. However, the disease severity varies from one patient to another, the more severe forms being often linked to a defect in gp91phox. Those differences in severity are linked to residual ROS production: patients with residual ROS have a higher survival rate [3]. It is not clear whether the increased survival is explained by an increased microbicidal effect of residual ROS production by neutrophils. However, it is likely that those residual ROS also play a protective role as signalling molecule.

CGD mutations result in a strongly impaired ROS generation in phagocytic cells. Of importance, the gene coding for NOX2 is located on the X chromosome, thus half of the male offspring of carrier mothers will develop the disease.

Typical clinical history of CGD patients is the development of recurrent infections toward certain fungi (Aspergillus) and catalase-positive bacteria (Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens and Nocardia). First manifestations of CGD occur typically during infancy; however, cases of later onset of the symptoms have been also observed. Insufficient bactericidal effect due to lack of ROS production in phagocytes is probably the main cause of recurrent infections. CGD diagnosis relies on testing the capacity of neutrophils to generate ROS in response to a stimulus and subsequently on sequencing of the mutation.

It is important not to overlook the diagnosis of the disease for several reasons: (i) risk of CGD patients for certain medical interventions [e.g. Bacille Calmette–Guérin (BCG vaccination, treatment with tumour necrosis factor (TNF) inhibitors]; and (ii) improved management of diagnosed patients through prophylactic antibiotics and interferon-γ (IFNγ) therapy. However, cure of CGD can only be achieved by bone marrow transplantation and/or gene therapy.

Given the improved treatment of infections and survival in CGD patients nowadays, a second aspect of disease consequences is taking centre stage in patient medical care, namely the increased susceptibility to inflammatory and autoimmune diseases. Establishment of a clear distinction between infection, autoimmunity and aseptic inflammatory lesion is a difficult task. Chronic infection can lead to the development of chronic inflammation which potentially could lead to the development of autoimmunity. However, most of the CGD-typical inflammatory syndromes are aseptic and seem to be due to a problem of immune regulation rather than to latent and chronic infection [4].

Although CGD is undoubtedly a genetic disease of the innate immune system, there is increasing evidence that CGD patients have marked alterations of their specific immunity. Relevant clinical observation in CGD patients and rodents as well as current knowledge of the role of NOX2 in the regulation of innate and specific immunity will be discussed in the present review.

INNATE IMMUNITY

The function of the phagocyte NADPH oxidase NOX2 has been most extensively studied in neutrophils and macrophages. Its most relevant role in neutrophils is bactericidal function, whereas in macrophages the enzyme seems to also play an important role in the regulation of cellular signalling and cell activation. In particular, macrophages appear to play a key role in the phenomenon of hyperinflammation, observed in CGD patients and CGD mice [5]. As the role of NOX2 in neutrophils and macrophages has been reviewed extensively [6,7], it will not be covered in detail in the present review.

CGD: typical inflammatory syndromes

1. Granulomas

An important inflammatory lesion (from which the disease takes its name), the formation of large granulomas, which can develop virtually everywhere and cause complications linked to their location (bowel or urethra obstruction): in some cases, surgery is needed to remove granulomas. In most cases, no pathogen could be detected in CGD granulomas, and patients respond better to immunosuppression rather than to antibiotic treatment. Thus it is most likely that CGD granulomas are not caused by infection, but rather due to an inflammatory process [8].

2. Colitis

CGD colitis is an inflammatory bowel disease exhibiting certain similarities with Crohn's disease [9]. In some cases, CGD colitis can be the initial presentation of CGD, which may lead to misdiagnosis as Crohn's disease. This is clinically important because anti-TNF treatments are widely used in Crohn's disease; however, this may lead to overwhelming sepsis in CGD patients [10].

3. Cystitis

Inflammatory bladder lesions observed in CGD patients are similar to a syndrome described in children called eosinophilic cystitis [1113]. In contrast with normal individuals in whom eosinophilic cystitis is usually transient, it is recurrent and long-lasting in CGD patients and requires a different therapeutic approach. One study reported successful treatment of eosinophilic cystitis in CGD patients using intravesical corticosteroids combined with oral antihistamine, underlining the inflammatory nature of this CGD complication [14].

4. Chorioretinitis

Retinitis is frequently missed by normal examination, but specific ocular examination of CGD patients highlights scars of chorioretinal lesion [15]. It appears that from 23.7% [16] up to 44% [17] of CGD patients present chorioretinal lesion, which is also present in some CGD carriers [16]. Importantly, in some cases, chorioretinitis can lead to vision loss [18]. Although specific staining of the scars for fungi and bacteria are usually negative [19], new studies have detected signs of bacterial infection in the lesion by specific PCR [20,21]. To conclude, chorioretinitis in CGD patients is common, but easily missed by regular examination. As lesions could be dramatic and give rise to vision loss, a follow up by an ophthalmologist is recommended.

5. Periodontitis

Whether periodontitis in the context of CGD should be classified as a typical syndrome of CGD is still a matter of debate, given the high frequency of periodontitis in the general population [22].

Treatment of typical inflammatory syndromes of CGD is complicated by the context of immunodeficiency. To illustrate this complexity, treatment of a CGD patient with TNF blockers will be discussed. Inflammatory syndromes in CGD patients are often associated with high levels of TNF and treatment of CGD-typical inflammatory syndromes with TNF blockers has been suggested and off-label use in CGD patients has been described. However, the recent literature does not provide any convincing evidence for disease amelioration in response to such a treatment, but instead reports higher frequencies of infections in anti-TNF-treated CGD patients [10]. Note also that a previous study suggests that hyperinflammation observed in CGD mice is TNF-independent. Indeed, CGD mice crossed with TNF-knockout mice display the same hyperinflammatory phenotype as regular CGD mice [10]. Thus there is currently no convincing rationale for using anti-TNF compounds as a treatment for CGD inflammatory complications (e.g. colitis)

Role of NOX2 in innate cell function

I. NOX2 in the phagosome

Globally speaking, most phagocytes activate NOX2 during phagocytosis. The most obvious function for NOX2-derived ROS during phagocytosis is bactericidal activity. However, the situation is most likely more complex. For example, superoxide, the primary product of NOX2 released into the phagosome, is a weak base. Thus NOX2 activity influences intraphagosomal pH (Figure 2). In macrophages, in general the phagosomal pH remains acidic, despite the potential of superoxide to alkalinize. In contrast, in neutrophils, the phagosomal pH rather becomes neutral. This is probably explained by the high activity of NOX2 in neutrophils. It also makes sense in terms of physiology, because neutrophil phagosomes contain mostly neutral proteases that are probably poorly active at acidic pH. Interestingly, neutrophils from CGD patients exhibit more acidic phagosomes, and it has been suggested that this leads to a decreased activity of neutral proteases in phagosomes of CGD neutrophils [6]. Surprisingly, it appears that the situation in DCs is more comparable with neutrophils than with macrophages [23]: in that study, the phagosomal pH was found to be neutral and even slightly alkaline in wild-type DCs, but acidic in CGD DCs.

Impact of NOX2 on phagosomal pH in different cell types
Figure 2
Impact of NOX2 on phagosomal pH in different cell types

Three types of phagocytes are well known to contain NOX2 within the membrane of their phagosomes: macrophages, neutrophils and DCs. In the presence of functional NOX2 enzymes, macrophages exhibit acidic phagosomes in contrast with the neutral or even slightly alkaline pH of phagosomes formed within neutrophils or DCs. Phagosomes are more acidic in CGD cells, which might be particularly relevant with respect to cross-presentation by APCs. Note, however, that the phagosomal environment of NOX2-deficient cells (NOX2KO) is also more reducing, which might also impact antigen presentation. The colour scale shows the approximate pH. WT, wild-type.

Figure 2
Impact of NOX2 on phagosomal pH in different cell types

Three types of phagocytes are well known to contain NOX2 within the membrane of their phagosomes: macrophages, neutrophils and DCs. In the presence of functional NOX2 enzymes, macrophages exhibit acidic phagosomes in contrast with the neutral or even slightly alkaline pH of phagosomes formed within neutrophils or DCs. Phagosomes are more acidic in CGD cells, which might be particularly relevant with respect to cross-presentation by APCs. Note, however, that the phagosomal environment of NOX2-deficient cells (NOX2KO) is also more reducing, which might also impact antigen presentation. The colour scale shows the approximate pH. WT, wild-type.

ROS generated during phagocytosis may also influence the activity of redox-sensitive proteins, including kinases and phosphatases, ion channels and transcription factors. Interestingly, there is also evidence that proteases, which play an important role in antigen processing by DCs, might also be redox sensitive (see below).

II. Dendritic cells

DCs are professional APCs. They present antigens to naïve T-cells, activating them and thereby playing a pivotal role in the regulation of adaptive immunity. By the nature of their biological function, DCs are phagocytes, yet their role in antigen presentation places them at the interface of innate and adaptive immunity. DCs can present antigens to T-lymphocytes either through MHC I or MHC II molecules. Intracellular pathogens are presented by MHC I to CD8+ T-lymphocytes. This leads to activation and expansion of antigen-specific cytotoxic CD8+ T-lymphocytes destined to kill infected cells. Extracellular pathogens are phagocytosed by DCs, digested inside phagosomes and mainly presented by MHC II to CD4+ T-lymphocytes. This leads to the activation and expansion of antigen-specific helper CD4+ T-lymphocytes, which for example activate macrophages through IFNγ production. Beside this classical antigen-processing route, some phagocytosed antigens are presented to CD8+ T-lymphocytes through loading on to MHC I rather than MHC II by a mechanism called cross-presentation. Similarly, some intracellular antigens can be presented by the MHC II molecule rather than MHC I by a mechanism called autophagy.

In addition to the interaction of their T-cell receptor (TCR) with the peptide–MHCs expressed by DCs, naïve T-lymphocytes need a second signal to efficiently differentiate into effector cells. This second signal is provided by co-stimulatory molecules, such as B7.1/CD80 and B7.2/CD86, which are up-regulated by mature DCs having encountered a pathogen. This second signal ensures that T-lymphocytes are activated only in the context of infections. Beside this cellular interaction between T-lymphocytes and DCs, DCs also produce cytokines that strongly influence T-cell phenotype: mature DCs produce interleukin 12 (IL-12), TNFα, IL-23, IL-6 or IL-1β. In non-infectious conditions, steady-state DCs express a low amount of co-stimulatory molecules and mainly present self-antigens to naïve T-lymphocytes, the subsequent T-cell fate being Treg induction, T-cell anergy or T-cell clonal deletion.

Role of NOX2 in dendritic cell function

DCs are able to produce ROS through NOX2 activity [24]. ROS production by DCs can be triggered by numerous mechanisms, including phagocytosis of micro-organisms, as well as exposure of cells to lipopolysaccharide (LPS), contact allergens [25] or cationic liposome adjuvants [26]. Signalling pathways between cell activation and ROS production have been only partially studied: it appears that the phosphoinositide 3-kinase pathway is important for DC-derived ROS production after LPS stimulus [27].

There is some evidence that molecules inhibiting NOX2 function may interfere with cytokine release and co-stimulatory molecule expression by DCs. For example, ebselen, which among multiple pharmacological activities is thought to inhibit NOX, induces a dose-dependent decrease in IL-1β, IL-6, IL-12p40 and TNFα secretion and abrogates CD86 up-regulation after LPS treatment of the DC line XS52 [28]. Extracellular superoxide dismutase (SOD3) also diminishes MHC II, CD80 and CD86 expression in a mouse model of skin inflammation [29]. In human monocyte-derived DCs, treatment with free radical scavengers supresses inflammatory cytokine production, without affecting co-stimulatory molecule expression [30]. However, data based on genetically altered APCs did not corroborate findings obtained after pharmacological exposure: DCs isolated from p47phox−/− [31] and NOX2−/− [32] mice produce more IL12p70 after activation by IFNγ/LPS or attenuated bacteria.

As mentioned above, antigen presentation is critical for T-cell activation. For optimal antigen processing, phagosomal proteases need to be tightly controlled. Whereas proteolytic activity is necessary to generate peptides that can be presented, an excessive proteolytic activity can nevertheless lead to the degradation of antigen. ROS seem to be important for the control of protease expression and activity, but their precise role seems, however, to vary depending on proteases: for instance, although ROS might inhibit the activity of some phagosomal proteases [33], they might in contrast activate some metalloproteinases, in particular at the level of gene expression [34]. NOX2-deficient DCs displayed higher degradation of antigen [35], resulting in an inefficient MHC I-dependent antigen cross-presentation in mice [23] and humans [36]. However, the mechanism underlying the effect of NOX2 deficiency is still debated: both phagosomal pH and redox status have been implicated in that mechanism through impact on protease activity. Similar evidence for a role of NOX2 in antigen processing was obtained with macrophages [37,38]. A recent study has also suggested that NOX2 plays a role in proteolytic processing of MHC II-dependent antigens. Indeed NOX2-deficient DCs generate different antigenic peptides. Therefore, through control of antigen processing, NOX2 could not only modulate MHC I- but also MHC II-restricted epitopic repertoires [39]. The same difference in MHC II-dependent antigens repertoire has been found with B-lymphocytes [40].

Although the literature is not unanimous concerning the effect of NOX2 on DC biology, it seems that ROS have an impact on DC activation and antigen processing. Those effects may influence the cross-talk between DCs and T-cells. However, it is difficult to determine at this stage the importance of the effect of ROS-derived DC phenotype on T-cell behaviour.

ADAPTIVE IMMUNITY

CGD-associated autoimmune diseases

There is abundant evidence that CGD patients have an increased risk of developing autoimmune diseases. Lupus erythematosus, including cutaneous or systemic presentations, is the most prevalent autoimmune disorder of CGD patients. Note that in several instances, heterozygous carriers (i.e. mothers and sisters of males with X-linked CGD) may also exhibit increased incidence of a lupus-like phenotype despite the fact that they do not appear to be at increased risk of infection [41]. The second most reported autoimmune disease in CGD patients is idiopathic (immune) thrombocytopenic purpura (ITP), followed by arthritis. Case reports and cohort studies of autoimmune diseases in CGD patients are reported in Table 1.

Table 1
Summary of autoimmune diseases in CGD patients

Autoimmune diseases described in CGD patients are listed in the Table with the overall number of cases found in the literature.

Autoimmune and/or inflammatory diseaseNumber of cases publishedReference(s)
Discoid lupus erythematosus (cutaneous presentation) 33 [114118
Idiopathic thrombolytic purpura 10 [114,115,117,119121
Juvenile rheumatoid arthritis [115,118,119,122
Systemic lupus erythematosus [114117,123,124
Kawasaki disease [125127
IgA nephropathy [118
Recurrent pericardial effusion [118
Antiphospholipid syndrome [118
Autoimmune pulmonary disease [118
Myasthenia gravis [114
Autoimmune and/or inflammatory diseaseNumber of cases publishedReference(s)
Discoid lupus erythematosus (cutaneous presentation) 33 [114118
Idiopathic thrombolytic purpura 10 [114,115,117,119121
Juvenile rheumatoid arthritis [115,118,119,122
Systemic lupus erythematosus [114117,123,124
Kawasaki disease [125127
IgA nephropathy [118
Recurrent pericardial effusion [118
Antiphospholipid syndrome [118
Autoimmune pulmonary disease [118
Myasthenia gravis [114

The picture found in humans is recapitulated, at least in part, in animal study. CGD mice and rats are described to be more susceptible to autoimmune arthritis. Using reverse genetics, Holmdahl's group demonstrated a correlation between a mutated p47phox allele and the arthritis severity in mice [42] and rats [43]. This genetic correlation has been confirmed in animal experiments [4448]. At least for some arthritic murine models, breakdown of tolerance seems to be T-cell dependent: transfer of T-cells isolated from arthritic CGD mice into wild-type mice is sufficient to induce arthritis [43]. Levels of reduced cell surface thiols, which is increased on T-cells from p47phox-mutated mice, seem to be important for the ability of T-cells to induce arthritis [49]. Different mechanisms have been implicated for the increased self-tolerance disruption in an autoimmune arthritis model of CGD mice. First, although macrophages are relatively poor APCs to activate naïve T-lymphocytes, this capacity seems greatly enhanced in the context of NOX2 deficiency [50]. Secondly, NOX2 deficiency might induce changes in DC maturation state, which could impact T-cell responses [45].

NOX2-deficient mice crossed on to the lupus-prone MRL.Faslpr genetic background developed more severe lupus and higher autoantibody titer compared with wild-type MRL.Faslpr mice [51]. Interestingly, this might not be exclusively due to enhanced immune responses in CGD mice, but also possibly to abnormal neutrophil apoptosis in the absence of NOX2. Immunization with apoptotic NOX2-deficient neutrophils induces autoantibodies not only in CGD mice, but also in wild-type mice. In agreement, apoptotic NOX2-deficient neutrophils have impaired surface exposure of phosphatidylserine, which has been suggested as a mechanism of increased autoantibody production [52].

However, the role of NOX2-derived ROS in autoimmunity is not clearly known. Historically, ROS have been considered as deleterious with respect to end-organ damage in immune-mediated disease. Indeed, autoimmunity leads to chronic inflammation and subsequently to the accumulation of ROS that might damage organs. Accordingly, signs of oxidative stress have been reported in patients suffering from rheumatoid arthritis [5355] and neutrophils from those patients produced more ROS [56,57]. A similar pathological role for ROS has been suggested for multiple sclerosis [58] and for autoimmune thyroiditis [59]. This deleterious role of NOX2 in autoimmune disease is also found, at least to some extent, in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In this model, animals are immunized with myelin oligodendrocyte glycoprotein (MOG), either with the full-length protein or with MOG peptidic fragment. Observations on EAE development in CGD mice are very interesting, even though they highlight a puzzling complexity. Results obtained with MOG immunization depend on the background and/or on the gene mutation of CGD mice used for the experiments, as well as on the sequence of MOG peptide used for the immunization. Depending on the mouse genetic background, discrepancy between the ability of full-length MOG protein and different MOG peptides to induce EAE pathogenesis has been reported (Table 2). In summary, most available data suggest that EAE development is attenuated in CGD mice [37,60]. However, at least one study suggests that under certain circumstances EAE development may also be enhanced in CGD mice [61]. Thus the situation is reminiscent of the situation in autoimmune arthritis, where NOX2-derived ROS can be a double-edged sword (Figure 3). This chronic oxidative stress probably helps to cause tissue damage and sustain chronic inflammation.

Table 2
Immunogenicity of MOG protein and MOG peptide in different CGD mice

The results of three different studies that investigate EAE development in CGD mice are summarized in the Table. Results differ depending on the genetic background and the antigen used. n.d., not determined; ↑, increase; ↓, decrease.

Impact of mutation on EAE development
ReferenceMouse backgroundMHCII haplotypeGenetic mutationAntigenOnsetSeverityIncidenceConclusion
[37C57BL/6 I-Ab Ncf1*/* NOX2−/− MOG protein Delayed (NOX2) Unchanged (Ncf1) ↑ ↓ NOX2 knockout and Ncf1 mutations protective in EAE 
    MOG35–55 peptide Delayed ↓ ↓  
[60C57BL/6 I-Ab p47phox−/− MOG35–55 peptide n.d. Virtually abolished No EAE detected Ncf1 knockout abolishes disease phenotype 
[61B10.Q H2q Ncf1*/MOG protein n.d. ↑ n.d. Increased EAE severity with whole-length MOG protein, but decreased severity with MOG peptide in Ncf1 mutant mice 
    MOG79–96 peptide n.d. ↓ n.d.  
Impact of mutation on EAE development
ReferenceMouse backgroundMHCII haplotypeGenetic mutationAntigenOnsetSeverityIncidenceConclusion
[37C57BL/6 I-Ab Ncf1*/* NOX2−/− MOG protein Delayed (NOX2) Unchanged (Ncf1) ↑ ↓ NOX2 knockout and Ncf1 mutations protective in EAE 
    MOG35–55 peptide Delayed ↓ ↓  
[60C57BL/6 I-Ab p47phox−/− MOG35–55 peptide n.d. Virtually abolished No EAE detected Ncf1 knockout abolishes disease phenotype 
[61B10.Q H2q Ncf1*/MOG protein n.d. ↑ n.d. Increased EAE severity with whole-length MOG protein, but decreased severity with MOG peptide in Ncf1 mutant mice 
    MOG79–96 peptide n.d. ↓ n.d.  

Schematic illustration of the Janus-face role of ROS in rheumatoid arthritis

Figure 3
Schematic illustration of the Janus-face role of ROS in rheumatoid arthritis

Upper panel: during disease onset, absence of ROS seems to facilitate the development of auto-reactive T- or B-lymphocytes, leading to autoimmune disorder. Lower panel: once chronic inflammation is established, high levels of ROS are produced at the inflammatory site and might be involved in cartilage damage. Auto-B, auto-reactive B-cell; Auto-T, auto-reactive T-cell.

Figure 3
Schematic illustration of the Janus-face role of ROS in rheumatoid arthritis

Upper panel: during disease onset, absence of ROS seems to facilitate the development of auto-reactive T- or B-lymphocytes, leading to autoimmune disorder. Lower panel: once chronic inflammation is established, high levels of ROS are produced at the inflammatory site and might be involved in cartilage damage. Auto-B, auto-reactive B-cell; Auto-T, auto-reactive T-cell.

Therefore low ROS generation is involved in cell signalling and in the regulation of adaptive immunity, and consequently in protection from autoimmune disease. However, once autoimmunity is established, it appears that high-level production of ROS can also be deleterious. This Janus-face role of NOX2-derived ROS in autoimmune pathology is illustrated in Figure 3.

An important common feature of the autoimmune diseases described in CGD patients (in particular lupus, ITP and arthritis) is the presence of autoantibodies, which are consequently considered as diagnostic criteria. Screening for a panel of well-established autoantibodies in CGD carriers and patients revealed a high prevalence of autoantibodies even in the absence of autoimmune disease [62,63]. In contrast, when anti-nuclear antibodies were investigated in CGD carriers with lupus erythematous, 73% of carriers were found to be negative [41]. Thus lupus erythematosus in the context of CGD might possibly involve autoantibodies different from those observed in the commonly encountered lupus erythematosus.

Alterations of specific immunity in CGD patients

CGD patients typically present hypergammaglobulinaemia [64,65]. Indeed, when CGD was first described [66], this was a clear contrast with other immunodeficiencies, which often were characterized by hypo- or a-gammaglobulinaemia. Note, however, that in some instances hypogammaglobulinaemia has been reported in CGD patients [67]. Therefore, it is still worth looking for CGD diagnosis in cases of hypogammaglobulinaemia when other causes of immunodeficiency have been excluded. Accordingly, most immunization studies suggest an enhanced immune response in CGD mice. Indeed, immunization with DNP-Ficoll [68], collagen [47] or bacteria [69] led to increased specific immunoglobulin production in mice lacking a functional phagocyte NADPH oxidase. Thus it appears that NOX2 diminishes antibody production. However, the mechanisms underlying this phenotype are not yet fully understood. The enhanced antibody production in response to the T-cell-independent antigen DNP-Ficoll (see bellow), but the absence of an enhanced antibody production in response to the T-cell-dependent antigen DNP-KHP [68], might suggest a cell autonomous mechanism within B-cells, rather than a phenomenon of intercellular communication.

Differences in B-cell repartition in CGD patients have also been reported: numbers of memory B-cells are decreased in the peripheral blood of CGD patients [70,71]. However, despite this skewed B-cell repartition with diminished memory B-cells, the response of influenza-specific memory B-cells remains unchanged [71], suggesting unaltered memory B-cell response. Interestingly, circulating levels of B-cell activating factor (BAFF), an important factor for B-cell survival, are typically increased in CGD patients [72].

Mechanistic studies on NOX2 in cellular and humoral immunity

I. Humoral immunity

Humoral immunity is a complex system of extracellular proteins which are involved in the recognition and elimination of pathogens. Two main different humoral components ensure host defence: the complement, which belongs to innate immunity; and the immunoglobulin from adaptive immunity. There is so far no evidence for a direct role of ROS in the complement system, and the present review will therefore mostly focus on specific humoral immunity, e.g. antibody production and B-cell function. Antibodies are able to provide protection against pathogens at various stages and sites of infection. In the present review, we will focus on IgG antibodies, which are highly antigen specific and are crucial for long-lasting protection. Beside their role in the clearance of pathogens, antibodies have also been implicated in the pathogenesis of some autoimmune diseases. For example, auto-antibodies are thought to be particularly important for the development of lupus erythematosus [73].

Antibodies are generated by B-lymphocytes and their highly differentiated derivatives referred to as plasma cells. B-lymphocyte activation is distinct from the mechanisms described above for T-lymphocyte activation. Indeed, naïve B-lymphocytes capture antigens through their (randomly generated) B-cell receptor (BCR). Capturing of a ‘fitting’ native antigen leads to BCR internalization and trimming of the antigen by proteases within endosomes. Typically, ‘trimmed’ peptides will then be presented to helper T-lymphocytes through MHC II molecules expressed by B-lymphocytes, this step being crucial in the induction of terminal B-cell differentiation (immunoglobulin class-switch, high-affinity antibody production and differentiation of B-cell memory). Note that T-cell-independent pathways of B-cell activation also exist, driven by specific antigens (repetitive molecules or polyclonal B-cell activator).

Impact of ROS on B-lymphocyte signalling and function

NOX2-derived ROS production by B-lymphocytes has been convincingly demonstrated. Measurement of ROS in B-lymphocytes was performed for the first time in Epstein–Barr virus (EBV)-transformed B-cell lines [74] and was confirmed soon after in tonsillar B-lymphocytes [75]. Despite relatively high NOX2 mRNA levels, ROS generation is markedly lower in B-lymphocytes than in neutrophils, possibly due to a post-transcriptional inhibition of gp91 mRNA [76]. In vitro, ROS production in B-lymphocytes is detected after various stimuli such as the TI-2 antigen SAC [77], anti-CD40 antibody [7880], anti-IgM F(ab′)2 antibody (BCR crosslinking) [68] and LPS [81].

The literature provides contradictory results with respect to the role of ROS and NOX2 in B-lymphocyte proliferation. Although one study suggested increased B-lymphocyte proliferation in NOX2-deficient mice [68], another study shows no impact of p47phox deficiency on this parameter [82]. Similarly, addition of exogenous antioxidants leads to increased B-cell proliferation in one study [77], but to diminished B-cell proliferation in another [82]. The reason for these discrepancies is not yet clear and will require further studies.

It has also been shown that ROS influence signalling pathways downstream of CD40: antioxidants block nuclear factor κB (NF-κβ), c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) signalling and IL6 production after CD40 activation [78,79]. As ROS production is undetectable in NOX2-deficient B-cells, the activation of these signalling molecules is probably NOX2-dependent.

NOX2 in EBV-immortalized B-cell lines (lymphoblastoid cell lines)

NOX2 is not only expressed in circulating and tissue B-lymphocytes, but also in EBV-immortalized B-cell lines, often referred to as lymphoblastoid cell lines. Immortalized B-cell lines can be readily generated from isolated human B-lymphocytes and have provided important tools in the past to better understand activation of the NADPH oxidase complex. For instance, the importance of Rac for the regulation of the NOX complex was first demonstrated by using antisense oligonucleotide in EBV-transformed B-cell lines [83]. This system was also helpful to identify phosphorylated sites of p47phox and p67phox required for NOX activation [84,85]. In addition, EBV-immortalized B-cells were used to study NOX2 rescue and provided proof of concept for gene therapy in CGD patients. For instance, transfection of the gene coding for p47phox in the EBV-transformed B-cell line from CGD patients with a p47phox-mutation restores protein expression and ROS production [86].

Furthermore, immortalized B-cells give access to a cell line reflecting the capacity of the individual from which the line was established, to generate NOX2-derived ROS. Using such B-cell lines from cohorts spanning several generations of related individuals, it was possible to determine that ~50% of NOX2-dependent ROS generation was inherited [87]. Using immortalized B-cells from unrelated individuals, it also became clear that CYBA/p22phox haplotypes influence 30% NOX2-dependent ROS generation [88]. In the future, this approach might also be a tool for translational medicine to investigate the relationship between genetic propensity for NOX2-dependent ROS generation and disease phenotypes.

II. Cellular immunity

Sources of ROS that might modulate T-cell activation and their impact on T-cell activation

Whether T-lymphocytes produce ROS upon activation is controversial [27,8992]. Three main possible sources of ROS during T-lymphocyte activation have been reported. First, mitochondria have been implicated in ROS generation by T-lymphocytes based on the use of exogenous mitochondrial-specific SOD or knockdown of proteins of the mitochondrial respiratory chain complex III [89]. Secondly, using inhibitors of different potential sources of ROS, the enzyme 5-lipo-oxygenase has been suggested as another source of ROS during T-lymphocyte activation [90]. Finally, NADPH oxidase has been reported to be involved in ROS generation by activated T-lymphocytes in a series of studies. Indeed, activation of T-lymphocytes using cross-linking anti-CD3 antibodies leads to oxidation of redox-sensitive probes {dichlorofluorescein diacetate (DCFDA) and dihydroethidium (DHE) [91,92]}. However, many of these experiments were performed with T-lymphocytes activated with anti-CD3, which might be irrelevant in the context of physiological antigen-specific T-lymphocyte activation. Only one study looked at ROS production during DC and T-cell lymphocyte co-culture [28] and observed a signal of a redox-sensitive probe in both DCs and T-lymphocytes. It is therefore difficult to exclude H2O2 diffusion from DCs to T-lymphocytes. In contrast, some groups were unable to detect any ROS production by T-lymphocytes following TCR activation [93]. Interestingly, an elegant study has demonstrated that the DCFDA signal detected in activated T-lymphocytes could come from contaminating phagocytic cells [94].

Many studies have implicated ROS in T-lymphocyte signalling (reviewed in [95,96]). Briefly, ROS have an impact on several crucial signalling pathways, including redox-sensitive proteins such as protein kinases and tyrosine phosphatases [97,98], transcription factors [99] and Ca2+ channels [100].

Basically, three strategies have been used to study the role of ROS in T-lymphocyte activation. First, addition of exogenous ROS. These results have shown that several T-lymphocyte signalling pathways are sensitive to ROS. Among others, H2O2 has an important effect on Ca2+ channels: it inhibits ORAI1, but not ORAI3, Ca2+ channels and has an effect on T-lymphocyte viability and IL2 production [100]. Secondly, effect of antioxidants on T-lymphocyte activation. It has been described that antioxidants could affect MAPK signalling by increasing ERK activation in a model of TCR-activated T-lymphocytes [101]. In another model using concanavalin A-activated T-cells, antioxidants have been reported to decrease linker for activation T-cells (LAT) phosphorylation and to consequently diminish T-cell proliferation [102]. Thirdly, activation of NOX2-deficient T-lymphocytes. The question of whether T-lymphocytes express NOX2 remains debatable (see above). However, some studies have indicated that in the absence of NOX2, ERK phosphorylation is increased [103]. However, a recent study showed no difference in proliferation and activation between NOX2-deficient and wild-type T-lymphocytes following TCR activation [91].

In summary, it is likely that ROS influence T-lymphocyte signalling. However, it is not clear whether T-lymphocytes produce ROS themselves or whether ROS, in particular H2O2, diffuse from APCs to T-lymphocytes (Figure 4).

Possible sources of ROS at the immunological synapse
Figure 4
Possible sources of ROS at the immunological synapse

(1) Indirect effect: ROS are generated by phagocytic cells/APCs after recognition by PRRs and indirectly act on T-cells through cytokine production or co-stimulatory molecule expression/up-regulation. (2) Paracrine effect: ROS are released during antigen presentation by APC into the immune synapse and have a direct impact on T-cell activity. (3) Autocrine effect: ROS are produced by T-cell itself after TCR engagement resulting in altered T-cell signalling pathways.

Figure 4
Possible sources of ROS at the immunological synapse

(1) Indirect effect: ROS are generated by phagocytic cells/APCs after recognition by PRRs and indirectly act on T-cells through cytokine production or co-stimulatory molecule expression/up-regulation. (2) Paracrine effect: ROS are released during antigen presentation by APC into the immune synapse and have a direct impact on T-cell activity. (3) Autocrine effect: ROS are produced by T-cell itself after TCR engagement resulting in altered T-cell signalling pathways.

Concerning T-lymphocyte differentiation, the effect of ROS on the development of a specific Th phenotype (Th1/Th2/Th17) is not clear. However, several reports point out that the pro-inflammatory phenotypes Th1/Th17 seem to be favoured. Ex vivo activation of murine CGD T-cells by TCR engagement [103] or by co-culture with DCs [31,45], leads to the expansion of Th1 T-cells with higher IFNγ production. As far as Th17 is concerned, apparently contradictory results have been obtained in studies with human peripheral blood mononuclear cells (PBMCs). A report suggests a more Th17-biased phenotype of PBMCs from CGD patients after activation with PMA/ionomycin and moreover the Th17 subtype is normalized after bone marrow transplant [104]. In contrast, activation of PBMCs from CGD patients with fungi displays a reduced Th17 phenotype compared with healthy control [105]. This discrepancy might be explained by the different triggers used. A biased IL17 phenotype was also reported in mice where the γδ T-lymphocyte subtypes seem to be an important source of IL17 production [106,107]. Tryptophan catabolism and in particular the indoleamine 2,3-dioxygenase (IDO) enzyme has been suggested to be involved in this dysregulation of Th17 production [106], but the decreased activity of IDO has not been confirmed by subsequent studies [105,108,109].

To summarize, the importance of NOX2 in T-lymphocyte activation remains to be clarified, however, it seems that the pro-inflammatory Th1/Th17 subsets are favoured in the CGD condition. The mechanism that leads to this biased Th phenotype needs to be investigated, but probably involves cross-talk between innate and adaptive immunity.

CONCLUDING REMARKS: NOX2 AT THE INTERSECTION OF INNATE AND ADAPTIVE IMMUNITY

The phagocyte NADPH oxidase NOX2 provides ROS for microbial killing. However, it becomes increasingly clear that NOX2 is also an important modulator of the specific immune system. NOX2 deficiency is characterized by altered immune responses and increased susceptibility to autoimmune diseases. However, attempts to unravel the mechanisms of NOX2-dependent modulation of adaptive immunity are still in progress. Increased immunoglobulin levels in CGD patients and CGD mice point towards a role of NOX2 in the regulation of humoral immunity. B-lymphocytes accordingly express NOX2, although a precise understanding of the role of NOX2 in B-lymphocyte biology is still missing. Cellular immunity has not been systematically studied in CGD patients. However, adaptive T-lymphocyte transfer experiments in mice suggest a (direct or indirect) role of NOX2 in limiting autoreactive T-lymphocyte activation in vivo [43]. Convincing in vitro data that would account for the phenotype observed in vivo are, however, still missing.

Thus, although the CGD phenotype concerning specific immunity is increasingly clear, challenges for future research will be to understand the underlying mechanisms. Most in vitro studies have focused on T-lymphocytes, B-lymphocytes or APCs independently. It is, however, likely that an in vitro model that takes into account the complexity of cell–cell interactions and the cross-talk between innate and adaptive immunity will be required to provide a significant advance in mechanistic understanding. So far, evidence points to a dysregulation of the cross-talk between macrophages and T-lymphocytes [110]. Also, although the literature does not always go in the same direction, DC function (cytokine production, expression of co-stimulatory molecule and antigen presentation) is altered in the absence of NOX2, but the effect of those alterations on T-cell activation is unclear. Finally, some T-cell subsets such as γδ Tcell or iNKT cells are other important cell types for the study of cross-talk between innate and adaptive immunity and might be important for the role of NOX2 in the regulation of immune response [106,107,111]. Such studies could give interesting novel information on the role of NOX2 as a regulator of immune response.

Mechanistic studies of the role of NOX2 in adaptive immune response are not only of interest for the comprehension of CGD pathology, but are likely to provide insights into fundamental mechanisms involved in autoimmune disease development and might provide novel hitherto unexpected drug targets. It should also be noted that large variations of NOX2-dependent ROS generation are observed in the general population [87]. Thus the increased propensity to develop autoimmune diseases might not be limited to CGD patients, but potentially also to a part of the population that display a low ROS-generating phenotype.

Although this review concerns the lack of NOX2-dependent ROS generation, there is also abundant evidence that overshooting NOX2-dependent ROS generation is an important mechanism of disease, for example in neurodegeneration [112] and in different types of ischaemia/reperfusion injury [113]. Thus efforts to develop NOX2 inhibitors as new types of drugs are underway. On the basis of the results reviewed in the present article, there is obviously a concern that NOX2 inhibitors might not only increase the risk of infection, but also the risk of autoimmune disease. And clearly, such possible side effects of NOX2 inhibitors should be carefully searched for in the future. However, we still think that the risk of induction of autoimmune disease by NOX2 inhibitors will be rather weak: pharmacological inhibitors typically do not lead to a complete block of the activity of their target and, for pharmacokinetic reasons, target inhibition decreases as a function of time from compound intake. Thus, in our opinion, there is no absolute red flag for the development of NOX2 inhibitors.

Abbreviations

     
  • APC

    antigen-presenting cell

  •  
  • BCR

    B-cell receptor

  •  
  • CGD

    chronic granulomatous disease

  •  
  • DC

    dendritic cell

  •  
  • DCFDA

    dichlorofluorescein diacetate

  •  
  • DUOX

    dual oxidase

  •  
  • EAE

    experimental autoimmune encephalomyelitis

  •  
  • EBV

    Epstein–Barr virus

  •  
  • IDO

    indoleamine 2,3-dioxygenase

  •  
  • IFNγ

    interferon-γ

  •  
  • IL

    interleukin

  •  
  • ITP

    idiopathic (immune) thrombocytopenic purpura

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MOG

    myelin oligodendrocyte glycoprotein

  •  
  • NOX

    NADPH oxidase

  •  
  • PBMC

    peripheral blood mononuclear cell

  •  
  • PRR

    pattern recognition receptor

  •  
  • RNS

    reactive nitrogen species

  •  
  • ROS

    reactive oxygen species

  •  
  • SOD

    superoxide dismutase

  •  
  • TCR

    T-cell receptor

  •  
  • TNF

    tumour necrosis factor

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