X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability

Marciano, Beatriz E.; Zerbe, Christa S.; Falcone, Emilia Liana; Ding, Li; Ravin, Suk See De; Daub, Janine; Kreuzburg, Samantha; Yockey, Lynne; Hunsberger, Sally; Foruraghi, Ladan; Barnhart, Lisa A.; Matharu, Kabir; Anderson, Victoria; Darnell, Dirk; Frein, Cathleen; Fink, Danielle; Lau, Karen; Priel, Debra A. Long; Gallin, John I.; Malech, Harry L.; Uzel, Gülbû; Freeman, Alexandra F.; Kuhns, Douglas B.; Rosenzweig, Sergio D.; Holland, Steven M.

doi:10.1016/j.jaci.2017.04.035

Cited by 150 publications

(108 citation statements)

References 30 publications

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“…The clinical manifestations reported in this cohort were all present, regardless of whether they had previously been associated with XL-CGD carriers [1][2][3][4][5]. As in other series, dermatological symptoms were reported in almost half of the participants.…”

mentioning

confidence: 64%

Clinical Manifestations in Carriers of X-Linked Chronic Granulomatous Disease in Mexico

López-Hernández¹,

Mn²,

Medina‐Vera³

et al. 2019

J Investig Allergol Clin Immunol

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Chronic granulomatous disease (CGD) is characterized by defects in NADPH oxidase, causing phagocytes to improperly clear invading pathogens. Owing to lyonization, X-linked CGD carriers (XL-CGD) have a dual phagocyte population, with 20% to 80% functioning phagocytes. Neutrophils with inactivation of the mutated X chromosome in the CYBB gene have a normal respiratory burst, whereas neutrophils with inactivation of the normal X chromosome have a CGD phenotype [1-3]. XL-CGD carriers exhibit a variety of autoimmune manifestations, mainly lupus-like signs and symptoms [3-5]. Skin diseases include recurrent photosensitive rash, folliculitis, postadolescent acne, eczema, and oral aphthous ulcers [1]. Gastrointestinal manifestations include abdominal pain, intermittent diarrhea, rectal bleeding, and chronic inflammatory bowel disease [6]. Recurrent infections characteristic of CGD include recurrent skin abscesses, pneumonia, hidradenitis suppurativa, and liver abscesses [2,5]. Other symptoms are chorioretinitis and fatigue [7]. All of these symptoms have an impact on quality of life. No studies have documented the symptoms presented by XL-CGD carriers in Latin America. The aims of this study were to describe the main signs and symptoms of Mexican XL-CGD carriers and to correlate the percentage of neutrophils with normal production of hydrogen peroxide (H 2 O 2 +) and various clinical variables. Sixty-five XL-CGD carriers diagnosed from 2011 to 2018 were invited to participate, although not all accepted the invitation.

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mentioning

confidence: 64%

Clinical Manifestations in Carriers of X-Linked Chronic Granulomatous Disease in Mexico

López-Hernández¹,

Mn²,

Medina‐Vera³

et al. 2019

J Investig Allergol Clin Immunol

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“…An FV vector carrying the gp91phox gene under the control of a PGK or a MSCV-LTR promoter was tested for its ability to restore superoxide levels in transplanted animals. With an average of 41.5% chimerism, the transplanted animals displayed phagoburst activity that reached 40% of the wt animals, clearly indicating a robust therapeutic effect in the preclinical model [55,56]. Overall, superoxide production reached 70% of normal with low vector copy numbers per cell (<2), a finding that argues for copy number dependent expression and minimal cytotoxic effects.…”

Section: Therapeutic Gene Transfer In Murine Preclinical Modelsmentioning

confidence: 93%

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

Simantirakis

Tsironis

Vassilopoulos

2020

Viruses

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Hematopoietic Stem Cells (HSCs) are a unique population of cells, capable of reconstituting the blood system of an organism through orchestrated self-renewal and differentiation. They play a pivotal role in stem cell therapies, both autologous and allogeneic. In the field of gene and cell therapy, HSCs, genetically modified or otherwise, are used to alleviate or correct a genetic defect. In this concise review, we discuss the use of SFVpsc_huHSRV.13, formerly known as Prototype Foamy Viral (PFV or FV) vectors, as vehicles for gene delivery in HSCs. We present the properties of the FV vectors that make them ideal for HSC delivery vehicles, we review their record in HSC gene marking studies and their potential as therapeutic vectors for monogenic disorders in preclinical animal models. FVs are a safe and efficient tool for delivering genes in HSCs compared to other retroviral gene delivery systems. Novel technological advancements in their production and purification in closed systems, have allowed their production under cGMP compliant conditions. It may only be a matter of time before they find their way into the clinic.

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“…Interestingly, autoimmune disorders seem to be even more prevalent in X-linked female carriers. Skin manifestations such as photosensitivity, discoid/malar rash, and Raynaud phenomenon are the most common [24, 25]. …”

Section: Clinical Presentationsmentioning

confidence: 99%

“…The DHR assay can usually differentiate between X-linked CGD, AR CGD, and X-linked carrier status (in females) (Figure 1) [43]. It also can assess the degree of lyonization in X-linked carriers, which has been shown to correlate with infection risk in females who have a normal neutrophil population of less than 20% [25]. …”

Section: Diagnostic Testingmentioning

confidence: 99%

Considerations in the Diagnosis of Chronic Granulomatous Disease

Azar

Chong

et al. 2018

Journal of the Pediatric Infectious Diseases Society

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Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.

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X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability

Abstract: A low %DHR value strongly predicts infection risk in X-linked CGD carriers, and the carrier state itself is associated with autoimmunity.

Cited by 150 publications

References 30 publications

Clinical Manifestations in Carriers of X-Linked Chronic Granulomatous Disease in Mexico

Clinical Manifestations in Carriers of X-Linked Chronic Granulomatous Disease in Mexico

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

Considerations in the Diagnosis of Chronic Granulomatous Disease

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