Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes

Journal of Clinical Immunology - Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various...     

Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency

Journal of Clinical Immunology - NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are...     

Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder associated with microthrombocytopenia, autoinnmunity and susceptibility to malignant lymphoma. At the molecular level, this rare disorder is caused by mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASP). WASP is a cytosolic adaptor protein mediating the rearrangement of the actin cytoskeleton upon surface receptor signaling. Allogenic hematopoietic stem cell (HSC) transplantation represents a curative approach but remains problematic in light of severe risks and side effects. Recently, HSC gene therapy has emerged as an alternative treatment option. Cumulative preclinical data obtained from WASP-deficient murine models and human cells indicate a marked improvement of the impaired cellular and immunological phenotypes associated with WASP deficiency. The first clinical trial is currently being conducted to assess the feasibility, toxicity, and potential therapeutic benefit of transplanting autologous WASP-reconstituted hematopoietic stem cells.     

Differenzialdiagnose der Anämien

Pädiatrie & Pädologie - Anämien sind definiert als eine Verminderung der altersabhängigen Menge an zirkulierenden Erythrozyten. Weltweit gesehen sind Anämien eine...     

Protein Kinase C δ: a Gatekeeper of Immune Homeostasis

Human autoimmune disorders present in various forms and are associated with a life-long burden of high morbidity and mortality. Many different circumstances lead to the loss of immune tolerance and often the origin is suspected to be multifactorial. Recently, patients with autosomal recessive mutations in PRKCD encoding protein kinase c delta (PKCδ) have been identified, representing a monogenic prototype for one of the most prominent forms of humoral systemic autoimmune diseases, systemic lupus erythematosus (SLE). PKCδ is a signaling kinase with multiple downstream target proteins and with functions in various signaling pathways. Interestingly, mouse models have indicated a special role of the ubiquitously expressed protein in the control of B-cell tolerance revealed by the severe autoimmunity in Prkcd ^?/? knockout mice as the major phenotype. As such, the study of PKCδ deficiency in humans has tremendous potential in enhancing our knowledge on the mechanisms of B-cell tolerance.     

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.     

Quantitative und qualitative Defekte neutrophiler Granulozyten

Neutrophilic granulocytes constitute the body’s first line of defence against bacterial and fungal pathogens and orchestrate the inflammatory response. The analysis of monogenic defects of neutrophilic granulocytes has yielded important insights into mechanisms of the innate immune system. Severe congenital neutropenia is defined by decreased numbers of absolute neutrophil counts and may be caused by mutations in ELANE/ELA2, HAX1, GFI1, WASP or G6PC3. Qualitative defects of neutrophilic granulocytes affect migration, activation and bacterial killing capacity which are manifested clinically as leukocyte adhesion deficiencies I-III andchronic granulomatous disease.