Journal of internal medicine
-
Review
The mother-offspring dyad: microbial transmission, immune interactions and allergy development.
The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. ⋯ Here, the influence of microbial and immune interactions within the mother-offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic.
-
Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma. ⋯ In CLL, both ibrutinib and idelalisib have an established role as first-line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy. Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully. In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders.
-
Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. ⋯ We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.
-
The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. ⋯ Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic β-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.
-
Infectious diseases remain a major health problem, and sepsis and other severe infectious diseases are common causes of morbidity and mortality. There is a need for clinical and laboratory tools to identify patients with severe infections early and to distinguish between bacterial and nonbacterial conditions. Heparin-binding protein (HBP), also known as azurocidin or cationic antimicrobial protein of 37 KDa, is a promising biomarker to distinguish between patients with these conditions. ⋯ The dysregulation of vascular barrier function and cellular inflammatory responses can then lead to organ dysfunction. Indeed, it has been shown that patients with sepsis express elevated levels of HBP in plasma several hours before they develop hypotension or organ dysfunction. HBP has a major role in the pathophysiology of severe bacterial infections and thus represents a potential diagnostic marker and a target for the treatment of sepsis.