Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil.

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI). METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing. RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01). CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.

Granulomatous Diseases of the Central Nervous System.

PURPOSE OF REVIEW: To discuss the pathophysiology, key clinical features, necessary diagnostic evaluation, and current treatment regimens for granulomatous diseases of the central nervous system. RECENT FINDINGS: The diagnosis and management of granulomatous disease of the central nervous system has been revolutionized by advances in diagnostic imaging. Nevertheless, tissue and/or cerebrospinal fluid (CSF) sampling remains necessary to establish the diagnosis in most cases. Establishing a specific diagnosis is critical because treatment selection needs to focus on the granulomatous process centering on either antibiotic or immunosuppressive agents. Particular for non-infectious granulomatous disease more aggressive immunotherapies may help in clinical outcome. There are multiple non-infectious and infectious etiologies for granulomatous disease of the central nervous system. Clinical manifestations result from local structural invasion of granulomas or granulomatous inflammation of the blood vessels and meninges. Rapid diagnosis and specific treatment is essential.

Outcome of chronic granulomatous disease - Conventional treatment vs stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) can cure chronic granulomatous disease (CGD), but it remains debated whether all conventionally treated CGD patients benefit from HSCT. METHODS: We retrospectively analyzed 104 conventionally treated CGD patients, of whom 50 patients underwent HSCT. RESULTS: On conventional treatment, seven patients (13%) died after a median time of 16.2 years (interquartile range [IQR] 7.0-18.0). Survival without severe complications was 10 ± 3% (mean ± SD) at the age of 20 years; 85% of patients developed at least one infection, 76% one non-infectious inflammation. After HSCT, 44 patients (88%) were alive at a median follow-up of 2.3 years (IQR 0.8-4.9): Six patients (12%) died from infections. Survival after HSCT was significantly better for patients transplanted ≤8 years (96 ± 4%) or for patients without active complications at HSCT (100%). Eight patients suffered from graft failure (16%); six (12%) developed acute graft-vs-host disease requiring systemic treatment. Conventionally treated patients developed events that required medical attention at a median frequency of 1.7 (IQR 0.8-3.2) events per year vs 0 (IQR 0.0-0.5) in patients beyond the first year post-HSCT. While most conventionally treated CGD patients failed to thrive, catch-up growth after HSCT in surviving patients reached the individual percentiles at the age of diagnosis of CGD. CONCLUSION: Chronic granulomatous disease patients undergoing HSCT until 8 years of age show excellent survival, but young children need more intense conditioning to avoid graft rejection. Risks and benefits of HSCT for adolescents and adults must still be weighed carefully.

Oxidants in Physiological Processes.

A number of diseases and conditions have been associated with prolonged or persistent exposure to non-physiological levels of reactive oxygen species (ROS). Similarly, ROS underproduction due to loss-of-function mutations in superoxide or hydrogen peroxide (H2O2)-generating enzymes is a risk factor or causative for certain diseases. However, ROS are required for basic cell functions; in particular the diffusible second messenger H2O2 that serves as signaling molecule in redox processes. This activity sets H2O2 apart from highly reactive oxygen radicals and influences the approach to drug discovery, clinical utility, and therapeutic intervention. Here we review the chemical and biological fundamentals of ROS with emphasis on H2O2 as a signaling conduit and initiator of redox relays and propose an integrated view of physiological versus non-physiological reactive species. Therapeutic interventions that target persistently altered ROS levels should include both selective inhibition of a specific source of primary ROS and careful consideration of a targeted pro-oxidant approach, an avenue that is still underdeveloped. Both strategies require attention to redox dynamics in complex cellular systems, integration of the overall spatiotemporal cellular environment, and target validation to yield effective and safe therapeutics. The only professional primary ROS producers are NADPH oxidases (NOX1-5, DUOX1-2). Many other enzymes, e.g., xanthine oxidase (XO), monoamine oxidases (MAO), lysyl oxidases (LO), lipoxygenase (LOX), and cyclooxygenase (COX), produce superoxide and H2O2 secondary to their primary metabolic function. Superoxide is too reactive to disseminate, but H2O2 is diffusible, only limited by adjacent PRDXs or GPXs, and can be apically secreted and imported into cells through aquaporin (AQP) channels. H2O2 redox signaling includes oxidation of the active site thiol in protein tyrosine phosphatases, which will inhibit their activity and thereby increase tyrosine phosphorylation on target proteins. Essential functions include the oxidative burst by NOX2 as antimicrobial innate immune response; gastrointestinal NOX1 and DUOX2 generating low H2O2 concentrations sufficient to trigger antivirulence mechanisms; and thyroidal DUOX2 essential for providing H2O2 reduced by TPO to oxidize iodide to an iodinating form which is then attached to tyrosyls in TG. Loss-of-function (LoF) variants in TPO or DUOX2 cause congenital hypothyroidism and LoF variants in the NOX2 complex chronic granulomatous disease.

Early Identification of Lung Fungal Infections in Chronic Granulomatous Disease (CGD) Using Multidetector Computer Tomography.

PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD.

Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD).

Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative.

TNFα: TNFR1 signaling inhibits maturation and maintains the pro-inflammatory programming of monocyte-derived macrophages in murine chronic granulomatous disease.

Introduction: Loss of NADPH oxidase activity results in proinflammatory macrophages that contribute to hyperinflammation in Chronic Granulomatous Disease (CGD). Previously, it was shown in a zymosan-induced peritonitis model that gp91phox-/- (CGD) monocyte-derived macrophages (MoMacs) fail to phenotypically mature into pro-resolving MoMacs characteristic of wild type (WT) but retain the ability to do so when placed in the WT milieu. Accordingly, it was hypothesized that soluble factor(s) in the CGD milieu thwart appropriate programming. Methods: We sought to identify key constituents using ex vivo culture of peritoneal inflammatory leukocytes and their conditioned media. MoMac phenotyping was performed via flow cytometry, measurement of efferocytic capacity and multiplex analysis of secreted cytokines. Addition of exogenous TNFα, TNFα neutralizing antibody and TNFR1-/- MoMacs were used to study the role of TNFα: TNFR1 signaling in MoMac maturation. Results: More extensive phenotyping defined normal MoMac maturation and demonstrated failure of maturation of CGD MoMacs both ex vivo and in vivo. Protein components, and specifically TNFα, produced and released by CGD neutrophils and MoMacs into conditioned media was identified as critical to preventing maturation. Exogenous addition of TNFα inhibited WT MoMac maturation, and its neutralization allowed maturation of cultured CGD MoMacs. TNFα neutralization also reduced production of IL-1ß, IL-6 and CXCL1 by CGD cells though these cytokines played no role in MoMac programming. MoMacs lacking TNFR1 matured more normally in the CGD milieu both ex vivo and following adoptive transfer in vivo. Discussion: These data lend mechanistic insights into the utility of TNFα blockade in CGD and to other diseases where such therapy has been shown to be beneficial.

Inborn errors of immunity with susceptibility to S. aureus infections.

Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Robust T cell responses to aspergillosis in chronic granulomatous disease: implications for immunotherapy.

Chronic granulomatous disease (CGD) patients are highly susceptible to invasive aspergillosis and might benefit from aspergillus-specific T cell immunotherapy, which has shown promise in treating those with known T cell defects such as haematopoietic stem cell transplant (HSCT) recipients. But whether such T cell defects contribute to increased risks for aspergillus infection in CGD is unclear. Hence, we set out to characterize the aspergillus-specific T cell response in CGD. In murine CGD models and in patients with CGD we showed that the CD4(+) T cell responses to aspergillus were unimpaired: aspergillus-specific T cell frequencies were even elevated in CGD mice (P < 0·01) and humans (P = 0·02), compared to their healthy counterparts. CD4-depleted murine models suggested that the role of T cells might be redundant because resistance to aspergillus infection was conserved in CD4(+) T cell-depleted mice, similar to wild-type animals. In contrast, mice depleted of neutrophils alone or neutrophils and CD4(+) T cells developed clinical and pathological evidence of pulmonary aspergillosis and increased mortality (P < 0·05 compared to non-depleted animals). Our findings that T cells in CGD have a robust aspergillus CD4(+) T cell response suggest that CD4(+) T cell-based immunotherapy for this disease is unlikely to be beneficial.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Fine definition of the epitopes on the human gp91phox/NOX2 for the monoclonal antibodies CL-5 and 48.

Superoxide-producing NADPH oxidase, gp91phox/NOX2, in phagocytes plays a critical role in the host defenses against pathogens. Moreover, gp91phox/NOX2 contributes to the oxidative stress in endothelial cells. Therefore, investigating the level of gp91phox/NOX2 with immunoblotting is important for estimating the amount of superoxide produced. Here, we showed that the epitopes in human gp91phox/NOX2 recognized by monoclonal antibodies (mAbs) CL-5 and 48 were in amino acids 132-147 and 136-144, respectively. Although the epitopes were close to the N-glycosylation sites, N-glycan maturation did not affect mAbs recognition. When Pro-136 was substituted with Arg, the corresponding mouse residue, human gp91phox/NOX2 was not recognized by mAbs CL-5 and 48; however, the substitution did not affect gp91phox/NOX2-based oxidase activity. This finding explains why these mAbs specifically recognize the human but not mouse gp91phox/NOX2. Hence, these mAbs are useful for investigating the level of gp91phox/NOX2 without amino acid substitutions in the epitopes.

De novo mutation of CYBB gene in a boy presenting as intra-abdominal infection of Burkholderia contaminans: a case report.

BACKGROUND: Chronic granulomatous disease (CGD) is an inborn error of immunity. It is characterized by recurrent bacterial or fungal infections, including infections by Burkholderia species. This is due to respiratory burst dysfunction of phagocytes. Currently, there is no report on Burkholderia contaminans (B. Contaminans) infection in children with CGD. CASE PRESENTATION: We present a previously healthy, 17-month-old Chinese boy infected with B. Contaminans in the intra-abdominal regions. Immunological screening, including assessment of cellular immunity and humoral immunity did not yield conclusive results. The level of nicotinamide adenine dinucleotide phosphatase (NADPH) activity was decreased and whole-exome sequencing identified a de novo mutation in the CYBB gene. CONCLUSIONS: For specific pathogens such as B. Contaminans, immune assessment should be carried out even if there is no positive medical history or specificity in basic immunity screening.

Defects of the Innate Immune System and Related Immune Deficiencies.

The innate immune system is the host's first line of defense against pathogens. Toll-like receptors (TLRs) are pattern recognition receptors that mediate recognition of pathogen-associated molecular patterns. TLRs also activate signaling transduction pathways involved in host defense, inflammation, development, and the production of inflammatory cytokines. Innate immunodeficiencies associated with defective TLR signaling include mutations in NEMO, IKBA, MyD88, and IRAK4. Other innate immune defects have been associated with susceptibility to herpes simplex encephalitis, viral infections, and mycobacterial disease, as well as chronic mucocutaneous candidiasis and epidermodysplasia verruciformis. Phagocytes and natural killer cells are essential members of the innate immune system and defects in number and/or function of these cells can lead to recurrent infections. Complement is another important part of the innate immune system. Complement deficiencies can lead to increased susceptibility to infections, autoimmunity, or impaired immune complex clearance. The innate immune system must work to quickly recognize and eliminate pathogens as well as coordinate an immune response and engage the adaptive immune system. Defects of the innate immune system can lead to failure to quickly identify pathogens and activate the immune response, resulting in susceptibility to severe or recurrent infections.

Rapidly progressive IgA vasculitis-associated nephritis successfully treated with immunosuppressive therapy in an adolescent with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder with genetic defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to recurrent severe infections and granuloma formation. Genitourinary involvement, including obstructive granulomas, infections, nephrotoxicity of anti-infective agents, and amyloidosis, is frequently observed in patients with CGD, whereas the clinical and pathological details of the less commonly reported glomerular disease remain obscure. Here, we report the case of a patient with CGD who developed rapidly progressive IgA vasculitis-associated nephritis (IgAVN) and review the literature on biopsy-proven glomerular diseases in patients with CGD. A 22-year-old male patient with CGD developed rapidly progressive glomerulonephritis (RPGN) following peripheral purpura and was diagnosed with crescentic IgAVN based on the renal biopsy evaluation. There was no evidence of active infections, and he received pulse intravenous methylprednisolone followed by oral prednisolone. His renal function returned to normal within 4 weeks, and his proteinuria and microhematuria finally resolved. The present case and literature review indicate that IgAVN and IgA nephropathy with RPGN are the most common causes of glomerular disease in patients with CGD. Clinicians should be aware of the possibility of these diseases as causes of RPGN in CGD, because delays in diagnosis and appropriate treatment may affect renal outcomes.

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

Candida Glabrata Lymphadenitis Following Infliximab Therapy for Inflammatory Bowel Disease in a Patient With Chronic Granulomatous Disease: Case Report and Literature Review.

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by inactivating genetic mutations in any one of the components of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Phagocytic cell reactive oxygen species generation is impaired in the absence of a functional NADPH oxidase complex. As a result, patients with CGD are at high risk of developing deep-seated infections with certain bacteria and fungi. Additionally, aberrant inflammation and granuloma formation may occur in multiple organs including the bowels, with inflammatory bowel disease seen as a common inflammatory complication of CGD. Traditionally, TNF-α inhibitors are considered effective biological therapies for moderate-to-severe inflammatory bowel disease. While limited case series and reports of patients with CGD have shown improvement in fistula healing with use of TNF-α inhibitors, several patients have developed severe, even fatal, infections with CGD-related pathogens while on TNF-inhibitor therapy. In this case report, we describe an adolescent male with X-linked CGD and steroid-refractory colitis with perirectal fistula and abscesses, who was initiated on treatment with infliximab, a TNF-α inhibitor. Following his first two infliximab doses, the patient developed a Candida glabrata lymphadenitis and associated ulcerating oropharyngeal lesions, requiring hospitalization and therapy with amphotericin B for resolution. We compare our patient's case to prior reports of infliximab use in CGD-related inflammatory bowel disease.

Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing.

Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment.

Immunological Aspects of X-Linked Chronic Granulomatous Disease Female Carriers.

X-linked Granulomatous Disease (XL-CGD) carriers were previously thought to be clinically healthy because random X-chromosome inactivation (XCI) allows approximately half of their phagocytes/monocytes to express functional gp91phox protein. This supports the NADPH oxidase activity necessary for the killing of engulfed pathogens. Some XL-CGD carriers suffer from inflammatory and autoimmune manifestations as well as infections, although the skewed-XCI of a mutated allele is reported to be exclusively determinant for infection susceptibility. Indeed, immune dysregulation could be determined by dysfunctional non-phagocytic leukocytes rather than the percentage of functioning neutrophils. Here we investigated in a cohort of 12 X-CGD female carriers at a particular time of their life the gp91phox protein expression/function and how this affects immune cell function. We showed that 50% of carriers have an age-independent skewed-XCI and 65% of them have a misrepresented expression of the wild-type gene. The majority of carriers manifested immune dysregulation and GI manifestations regardless of age and XCI. Immunological investigations revealed an increase in CD19+ B cells, CD56bright-NK cell percentage, a slightly altered CD107a upregulation on CD4+ T cells, and reduced INFγ-production by CD4+ and CD8+ cells. Notably, we demonstrated that the residual level of ROS robustly correlates with INFγ-expressing T cells, suggesting a role in promoting immune dysregulation in carriers.

Immune-Based Anti-Staphylococcal Therapeutic Approaches.

Widespread methicillin-resistant Staphylococcus aureus (S. aureus) infections within community and healthcare settings are responsible for accelerated development of antibiotic resistance. As the antibiotic pipeline began drying up, alternative strategies were sought for future treatment of S. aureus infections. Here, we review immune-based anti-staphylococcal strategies that, unlike conventional antibiotics, target non-essential gene products elaborated by the pathogen. These strategies stimulate narrow or broad host immune mechanisms that are critical for anti-staphylococcal defenses. Alternative approaches aim to disrupt bacterial virulence mechanisms that enhance pathogen survival or induce immunopathology. Although immune-based therapeutics are unlikely to replace antibiotics in patient treatment in the near term, they have the potential to significantly improve upon the performance of antibiotics for treatment of invasive staphylococcal diseases.