Leukocyte adhesion deficiency type III (LADIII) is an autosomal recessive disorder that presents with a severe leukocyte adhesion defect and a Glanzmann-type thrombocytopathy. Hematopoietic stem cell transplantation (HSCT)-the only definitive treatment for LADIII-appears to have a high rate of complications. In this study, we describe a new group of patients with LADIII, highlighting further clinical and immunologic aspects of this disease, and reevaluating the effectiveness of HSCT for its treatment. The patients had clinical and laboratory findings consistent with LADIII. Molecular analysis confirmed the presence of a mutation in the kindlin-3 gene. HSCT was carried out in 3 patients and was successful in 2. The diagnosis of LADIII should be considered in all patients who present with recurrent infections and a bleeding diathesis, regardless of the leukocyte count. LADIII is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of the disease using appropriate conditioning.
Autosomal dominant Hyper IgE syndrome (AD-HIES) is a rare and complex primary immunodeficiency that affects multiple systems. Mutations in signal transducer and activator of transcription 3 (STAT3) gene cause AD-HIES. These mutations have a dominant-negative effect and the presence of such mutations is associated with a clinical phenotype. We aim to describe genetic and clinical characteristics of patients with AD-HIES in our clinic and to highlight the variability of clinical patterns in the same family.
Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity.
There is a paucity of data on the relationship between demographic characteristics, specific clinical manifestations, and neutrophil dysfunction, guiding physicians to decide which clinical signs and symptoms are a code for an underlying phagocytic disorder.
Chronic granulomatous disease (CGD) is an immune deficiency syndrome caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme that generates reactive oxygen species (ROS) in phagocytizing leukocytes. This study evaluates the NADPH oxidase capacity in two X-linked CGD patients with mutations in gp91(phox) that alter the regions in this membrane-bound NADPH oxidase component involved in docking of the cytosolic component p47(phox).
Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.
Leukocyte adhesion deficiency 1 (LAD1) is an inherited disorder of neutrophil function. Nonsense mutations in the affected CD18 (ITB2) gene have rarely been described. In other genes containing such mutations, treatments with aminoglycoside types of antibiotics (e.g., gentamicin) were reported to partially correct the premature protein termination, by induction of readthrough mechanism.
Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations.
CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-? is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state.
Neutropenia, which may develop as a consequence of chemotherapy, increases the risk of bacterial infection. Similarly, increased risk of bacterial infection appears in disorders of phagocytic functions, such as the genetic disorder chronic granulomatous disease. To elucidate the organizing principles behind these distinct immunodeficiency conditions, we investigated the interaction between in vitro bacteria and human neutrophils by experiments and mathematical modeling. The model and the experiments showed that the in vitro bacterial dynamics exhibit bistability for a certain range of neutrophil concentration and function. Thus, there is a critical bacterial concentration above which infection develops, and below which neutrophils defeat the bacteria. Whereas with normal neutrophil concentration and function, an infection may develop when the initial bacterial concentration is very high, under neutropenic conditions or when there is neutrophil dysfunction, the critical bacterial concentration can be lower, within the clinically relevant range. We conclude that critical bacterial concentration has clinically relevant implications. The individual maximum bearable bacterial concentration depended on neutrophil concentration, phagocytic activity, and patient barrier integrity; thus, the resulting maximal bearable bacterial concentration may vary by orders of magnitude between patients. Understanding the interplay between neutrophils and bacteria may enhance the development of new therapeutic approaches to bacterial infections.
Related JoVE Video
Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.