scholarly journals Granuloma Formation in a Cyba-Deficient Model of Chronic Granulomatous Disease Is Associated with Myeloid Hyperplasia and the Exhaustion of B-Cell Lineage

2021 ◽  
Vol 22 (16) ◽  
pp. 8701
Author(s):  
Rodrigo Prieto-Bermejo ◽  
Marta Romo-González ◽  
Alejandro Pérez-Fernández ◽  
María Carmen García-Macías ◽  
Carmen Sánchez-Bernal ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Blood Cells ◽  
Cell Lineage ◽  
Significant Loss ◽  
Innate Immune ◽  
Granulomatous Disease ◽  
Inflammatory Lesions ◽  
Loss Of Weight ◽  
Phagocyte Oxidase ◽  
Inactivating Mutations

Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba−/− mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb−/− and Ncf1−/− models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba−/− mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.

Dysregulation of innate immune receptors on neutrophils in chronic granulomatous disease

2008 ◽  
Vol 121 (2) ◽  
pp. 375-382.e9 ◽  
Author(s):  
Dominik Hartl ◽  
Natalie Lehmann ◽  
Florian Hoffmann ◽  
Annette Jansson ◽  
Andreas Hector ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Innate Immune ◽  
Granulomatous Disease ◽  
Immune Receptors

NORMAL GRANULOCYTE INFUSION THERAPY FOR ASPERGILLOSIS IN CHRONIC GRANULOMATOUS DISEASE

PEDIATRICS ◽  
1973 ◽  
Vol 51 (2) ◽  
pp. 230-233
Author(s):  
Andrew A. Raubitschek ◽  
Alan S. Levin ◽  
Daniel P. Stites ◽  
Edward B. Shaw ◽  
H. Hugh Fudenberg
Keyword(s):  
Adverse Effects ◽  
Chronic Granulomatous Disease ◽  
Blood Cells ◽  
White Blood Cells ◽  
Infusion Therapy ◽  
Granulomatous Disease ◽  
Transient Improvement ◽  
Life Threatening ◽  
Granulocyte Function

An 8-year-old boy with chronic granulomatous disease (CGD) was admitted in moribund condition with aspergillus pneumonia. Because of the gravity of the situation, normal granulocyte infusions were used as adjuncts to the more conventional antimicrobial therapy. White blood cells, derived from a total of 58 units of whole blood obtained by leukophoresis of the father, were given in two separate doses. The first dose, totaling 2.8 x 1010 granulocytes, was coincident with significant improvement, and the second, totaling 3.0 x 1010 granulocytes, was coincident with the onset of clinical improvement and interim recovery. Transient improvement in in vitro granulocyte function was noted in cells taken from the patient's blood immediately after infusion. No adverse effects of the infusions were noted in either the patient or the donor. Although it is impossible to divorce the therapeutic effect of the granulocyte infusions from the more conventional therapy, we conclude that normal granulocyte infusions can be considered a valid adjunct in children with CGD who are suffering from a life-threatening infection.

scholarly journals Protein phosphorylation in neutrophils from patients with p67-phox- deficient chronic granulomatous disease

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4404-4410 ◽  
Author(s):  
PG Heyworth ◽  
J Ding ◽  
RW Erickson ◽  
DJ Lu ◽  
JT Curnutte ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Protein Phosphorylation ◽  
Inorganic Phosphate ◽  
Granulomatous Disease ◽  
Cell Stimulation ◽  
Phagocyte Oxidase ◽  
Stimulation Of

Neutrophils are known to contain a major 67-kD protein that undergoes enhanced phosphorylation and translocation to the membrane during cell stimulation. Recent studies have assumed that this 67-kD phosphoprotein is the 67-kD subunit of the phagocyte oxidase (p67-phox). We compare here the protein phosphorylation patterns in lysates of normal neutrophils and neutrophils from patients with chronic granulomatous disease (CGD) that are completely deficient in p67-phox. The phosphoproteins were labeled by incubation of the cells with radioactive inorganic phosphate (32Pi) or by the addition of [gamma- 32P]ATP to electropermeabilized neutrophils. With either method, stimulation of the normal or CGD cells always resulted in an enhanced incorporation of 32p into two proteins in the 67-kD area. The extent of phosphorylation of these two proteins was very similar in the normal and CGD cells when permeabilized neutrophils loaded with [gamma - 32P]ATP were compared. Moreover, no overall differences in the protein phosphorylation patterns were observed between the normal and CGD cells. Our data indicate that the major 67-kD phosphoproteins observed in stimulated neutrophils are clearly different from p67-phox.

scholarly journals Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1570-1573 ◽  
Author(s):  
Felix Meissner ◽  
Reinhard A. Seger ◽  
Despina Moshous ◽  
Alain Fischer ◽  
Janine Reichenbach ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Mononuclear Phagocytes ◽  
Biologically Active ◽  
Inflammasome Activation ◽  
Granulomatous Disease ◽  
Caspase 1 ◽  
Inflammatory Conditions ◽  
Asymptomatic Patients ◽  
Phagocyte Oxidase

Abstract Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox. We report that mononuclear phagocytes from CGD patients activated caspase-1 and produced biologically active interleukin-1β (IL-1β) in response to danger signals. Notably, caspase-1 activation and IL-1β secretion from CGD monocytes was elevated in asymptomatic patients and strongly increased in patients with noninfectious inflammatory conditions. Treatment with IL-1 receptor antagonist reduced IL-1 production in monocytes ex vivo and during medical therapy. Our results identify phagocyte oxidase defective monocytes as a source of elevated IL-1 and provide a potential therapeutic option to ameliorate inflammatory conditions associated with CGD.

scholarly journals NADPH-binding component of the superoxide-generating oxidase in unstimulated neutrophils and the neutrophils from the patients with chronic granulomatous disease

1987 ◽  
Vol 243 (2) ◽  
pp. 467-472 ◽  
Author(s):  
T Umei ◽  
K Takeshige ◽  
S Minakami
Keyword(s):  
Red Blood Cells ◽  
Chronic Granulomatous Disease ◽  
Molecular Mass ◽  
Blood Cells ◽  
Binding Domain ◽  
Human Neutrophils ◽  
Activation Process ◽  
Granulomatous Disease ◽  
Neutrophil Superoxide ◽  
Binding Component

The NADPH-binding component of the neutrophil superoxide-generating oxidase was studied in the particulate oxidase fractions obtained from the neutrophils of normal and chronic-granulomatous-disease (CGD) patients. The molecular mass of the NADPH-binding component of the stimulated human neutrophils, which was labelled with the 2′,3′-dialdehyde derivative of NADPH and sodium cyanoboro[3H]hydride, was 66 kDa. The 66 kDa component was also labelled in monocytes, but not in red blood cells, platelets and lymphocytes. The particulate oxidase fractions obtained from the patients with CGD had a diminished amount of FAD, whether they contained cytochrome b558 or not. The fractions labelled with the NADPH analogue showed that CGD patients had the NADPH-binding component in the neutrophils. The molecular mass of the component was identical with that of the normal neutrophils. The patients are thought to have an intact NADPH-binding domain of the oxidase in the neutrophils in spite of a diminished amount of FAD in the particulate fractions. The component of the oxidase in the resting neutrophils was also labelled with the analogue. The molecular mass of the component in the resting neutrophils was identical with that of the stimulated neutrophils, and the component was not phosphorylated during the activation process. These results indicate that the NADPH-binding component of the oxidase, which is specific to phagocytes, is present in the resting neutrophils and that the component does not change with respect to molecular mass during the activation process.

scholarly journals Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor

Gut ◽  
1998 ◽  
Vol 42 (1) ◽  
pp. 127-130 ◽  
Author(s):  
B Myrup ◽  
N H Valerius ◽  
P B Mortensen
Keyword(s):  
Chronic Granulomatous Disease ◽  
Storage Disease ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Neutrophil Granulocytes ◽  
Granulomatous Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Inflammatory Lesions ◽  
Stimulating Factor

Background—In several diseases there is a relation between deficiency of neutrophil granulocytes and granulomatous lesions. Recently, in glycogen storage disease type Ib, this relation has been supported by the beneficial effect of treatment of enteritis with granulocyte-macrophage colony stimulating factor.Aim—To investigate whether chronic granulomatous disease could be treated according to the same principle.Patients and methods—Inflammatory lesions were monitored in two brothers with chronic granulomatous disease demonstrated by very low superoxide production in neutrophil granulocytes. The two patients were treated with recombinant human granulocyte colony stimulating factor on three occasions when the disease was active.Results—In one patient, remission of an inflamed stenosis of the colon sigmoideum was shown by granulocyte scintigraphy after one month of treatment with granulocyte colony stimulating factor. In the other patient, remission of colon disease and later of a non-malignant tumour in the right lung hilum was shown by colonoscopy and computed tomography scans respectively.Conclusion—Remission of inflammatory lesions in two brothers with chronic granulomatous disease was induced by granulocyte colony stimulating factor on three occasions. The mechanism for this effect is not known. The result is similar to the response found in patients with leucocyte deficiency due to glycogen storage disease type Ib.

scholarly journals Chronic Granulomatous Disease and Myelodysplastic Syndrome in a Patient with a Novel Mutation in CYBB

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1476
Author(s):  
Bárbara C. S. Reis ◽  
Daniela P. Cunha ◽  
Ana Paula S. Bueno ◽  
Flavia A. A. Carvalho ◽  
Juliana Dutra ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Myelodysplastic Syndrome ◽  
Chronic Granulomatous Disease ◽  
Bacterial Infections ◽  
Novel Mutation ◽  
Cell Lineage ◽  
Erythroid Cell ◽  
Granulomatous Disease ◽  
Acute Leukemias ◽  
Nadph Oxidase Complex

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterized by impaired phagocyte function, recurrent fungal and bacterial infections and granuloma formation in multiple organs. Pediatric myelodysplastic Syndrome (MDS) is a rare hematological stem cell disease that leads to an ineffective hematopoiesis with variable risk of evolution to acute leukemias. Both disorders are rare and have distinct pathophysiologic mechanisms, with no known association. A 7-month-old boy presenting with recurrent infections and anemia at age 2 months underwent immunological, hematological and genetic investigation that culminated in the diagnosis of both CGD and MDS. Next generation sequencing was performed and identified a silent variant predicted as of Uncertain Significance, located in the splicing site at the end of exon 5 in CYBB. CYBB variants account for at least two thirds of CGD cases, but no previous descriptions of this variant were found in ClinVar or The Human Gene Mutation Database (HGMD) databases. We were able to demonstrate an exon 5 skipping on the proband’s cDNA, which strongly suggests the disruption of the NADPH oxidase complex, abrogating the formation of reactive oxygen species from neutrophils. Moreover, erythroid cell lineage could be also affected by NADPH oxidase complex damages. Further investigation is needed to evaluate the potential effect of CYBB gene alterations in hematopoiesis, as well as in MDS and CGD association.

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