Journal Staff

Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation'' sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons

Net section fracture assessment of steel bolted joints with shear lag effect

Bolted connections are willingly used in steel structures because of their easiness of fabrication and assembly, but often they are the weakest component in the construction. In case of tensile lap connections, fracture of net cross section usually determines a joint capacity. Additionally, possible eccentricities can affect the distribution of stresses in the cross section and hence its load capacity. Analysis of fracture is a completely different issue compared to well-known and established problems of stability or plastic resistance. Paper relates to steel angle tension members connected by one bolt. It starts from the description of experimental investigations which results were used for hierarchical validation of computational models. Choice between two types of material models (elastic-plastic and Gurson–Tvergaard–Needleman) and building of FE models, representing different degrees of complexity, were described. Paper ends with parametric study taking into account influence of the edge distance from the centre of a fastener hole to the adjacent edge of angle. The paper’s aim is to verify and present the methodology for fracture prediction in steel angle tension members, which can be next extended for bolted joints with larger number of bolts and different geometrical configurations

New insights in the use of immunoglobulins for the management of immune deficiency (PID) patients

Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient’s life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient’s compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient’s preference and needs

Chronic granulomatous disease: the European experience.

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

The role of ARNT in liver and myeloid cell function

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor which acts as a general partner for members of the bHLH/PAS family of transcription factors. To investigate the effect of long term ARNT deletion in hepatocyte and myeloid cells, we created 2 lines of mice with ARNT deletion in these cells. Mice lacking hepatocyte ARNT had impaired glucose tolerance, increased gluconeogenesis, decreased ATP and increased post-prandial serum triglycerides. However, in contrast to type 2 diabetes (T2D) hepatic ARNT deletion resulted in decreased liver steatosis. Importantly, these changes became non-significant after high fat diet (HFD). Decreased ARNT in myeloid cells led to decreased cytokine expression, decreased phagocytosis, decreased bactericidal activity, impaired response to infection, and impaired wound healing. Again, the phenotype of impaired wound healing equilibrated in a diabetic milieu. In addition mice lacking ARNT in myeloid cells displayed impaired glucose tolerance on HFD and paradoxically increased liver inflammation. In human monocytes ARNT mRNA correlated negatively with serum cytokine levels of IL-6, IL-8, MCP-1 and TNF-α. This data demonstrates that ARNT has important roles in hepatocyte and myeloid cell function and suggests that modulation of this transcription factor could be used in future therapy for diabetes and disorders of immune function

Chronic granulomatous disease recognised in 42-years-old patient

Przewlekła choroba ziarniniakowa (PChZ) jest heterogenną grupą chorób związanych z defektem enzymu oksydazy NADPH odpowiedzialnej za produkcję nadtlenków przez granulocyty obojętnochłonne, których brak lub niedobór uniemożliwia zabijanie sfagocytowanych przez nie drobnoustrojów. Typowymi objawami PChZ są bakteryjne lub grzybicze nawracające ciężkie, często zagrażające życiu infekcje głównie płuc, skóry, węzłów chłonnych oraz przewodu pokarmowego (wątroby). Rozpoznanie jest ustalane na podstawie wywiadów, objawów oraz testów wykazujących upośledzoną funkcję fagocytozy granulocytów (testy NBT, RDH czy bezpośrednie testy, których wynik wskazuje na deficyt produkcji nadtlenków). Objawy występują zwykle w pierwszych latach życia, prowadzą często do zgonu w 2. lub 3. dekadzie. Poniżej przedstawiono przypadek chorej, u której rozpoznanie PChZ ustalono dopiero w 42. roku życia.Chronic granulomatous disease (CGD) comprises a heterogeneous group of diseases that are caused by defect in the superoxide-producing NADPH oxidase of neutrophils. This defect impairs the intracellular killing of microorganisms. Typical manifestations are recurrent bacterial or mycotic infections affecting the lungs, skin, lymph nodes and gastrointestinal tract (liver). Chronic granulomatous disease could be diagnosed on the basis of the anamnesis, clinical picture and results of granulocyte function tests showing impaired phagocytic activity (NBT tests, RDH test and a deficit of superoxide production). Typically symptoms of disease occur in the first years of live, leading often to death in the 2. or 3. decade. Below we present a patient, in whom diagnosis of the CGD was established at the age of 42

New insights in the use of immunoglobulins for the management of immune deficiency (PID) patients

Immunoglobulin replacement therapy (IRT) is standard treatment for patients with primary immunodeficiency (PID). Because most of the patients with PID will require long life-time immunoglobulin replacement therapy, the quality of the prescribed products is of utmost importance. The IRT is generally administered either intravenously (abbreviated IVIG), or subcutaneously (abbreviated SCIG). Both routes have been demonstrated to be effective. The preferred route may vary at different times during a given patient’s life. Options are therefore not fixed and the choice of route for immunoglobulin therapy will depend on several factors, including patient characteristics, clinical indication, venous access, side effects, rural or remote location, treatment compliance and patient preference. Many years ago, immunoglobulin therapy was associated with side effects which may compromise patient’s compliance and quality of life of the patients. Most of the side effects were related to impurities. Recently, major advances in the manufacturing process have been made and new processes, such as the Quality by design (QbD) approach were added into the manufacturing steps to ensure patients tolerability and safety. Due to the improved purity of the immunoglobulin products obtained by these processes, the incidence of side effects is lower, while the ways of administration of Ig therapy and the choice of the regimen has widened to suit patient’s preference and needs