Advances in Immunology最新文献

Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis. For the vast majority of those who initially respond, relapses will repeatedly occur with increasing refractoriness to available treatments. Addressing the clinical challenges in FL warrants deep understanding of the nature of treatment-resistant FL cells seeding relapses, and of the biological basis of early disease progression. Great progress has been made in the last decade in the description and interrogation of the (epi)genomic landscape of FL cells, of their major dependency to the tumor microenvironment (TME), and of the stepwise lymphomagenesis process, from healthy to subclinical disease and to overt FL. A new picture is emerging, in which an ever-evolving tumor-TME duo sparks a complex and multilayered clonal and functional heterogeneity, blurring the discovery of prognostic biomarkers, patient stratification and reliable designs of risk-adapted treatments. Novel technological approaches allowing to decipher both tumor and TME heterogeneity at the single-cell level are beginning to unravel unsuspected cell dynamics and plasticity of FL cells. The upcoming drawing of a comprehensive functional picture of FL within its ecosystem holds great promise to address the unmet medical needs of this complex lymphoma.

The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.

The complement system was long considered as only a powerful effector arm of the immune system that, while critically protective, could lead to inflammation and cell death if overactivated, even in the central nervous system (CNS). However, in the past decade it has been recognized as playing critical roles in key physiological processes in the CNS, including neurogenesis and synaptic remodeling in the developing and adult brain. Inherent in these processes are the interactions with cells in the brain, and the cascade of interactions and functional consequences that ensue. As a result, investigations of therapeutic approaches for both suppressing excessive complement driven neurotoxicity and aberrant sculpting of neuronal circuits, require broad (and deep) knowledge of the functional activities of multiple components of this highly evolved and regulated system to avoid unintended negative consequences in the clinic. Advances in basic science are beginning to provide a roadmap for translation to therapeutics, with both small molecule and biologics. Here, we present examples of the critical roles of proper complement function in the development and sculpting of the nervous system, and in enabling rapid protection from infection and clearance of dying cells. Microglia are highlighted as important command centers that integrate signals from the complement system and other innate sensors that are programed to provide support and protection, but that direct detrimental responses to aberrant activation and/or regulation of the system. Finally, we present promising research areas that may lead to effective and precision strategies for complement targeted interventions to promote neurological health.

Among the multiple events leading to immunoglobulin (Ig) expression in B cells, stepwise activation of the Ig heavy chain locus (IgH) is of critical importance. Transcription regulation of the complex IgH locus has always been an interesting viewpoint to unravel the multiple and complex events required for IgH expression. First, regulatory germline transcripts (GLT) assist DNA remodeling events such as VDJ recombination, class switch recombination (CSR) and somatic hypermutation (SHM). Second, productive spliced transcripts restrict heavy chain protein expression associated either with the surface receptor of developing B cells or secreted in large amounts in plasma cells. One main transcriptional regulator for IgH lies at its 3' extremity and includes both a set of enhancers grouped in a large 3' regulatory region (3'RR) and a cluster of 3'CTCF-binding elements (3'CBEs). In this focused review, we will preferentially refer to evidence reported for the murine endogenous IgH locus, whether it is wt or carries deletions or insertions within the IgH 3' boundary and associated regulatory region.

In the past, brain function and the onset and progression of neurological diseases have been studied in a neuron-centric manner. However, in recent years the focus of many neuroscientists has shifted to other cell types that promote neurodevelopment and contribute to the functionality of neuronal networks in health and disease. Particularly microglia and astrocytes have been implicated in actively contributing to and controlling neuronal development, neuroinflammation, and neurodegeneration. Here, we summarize the development of brain-resident macrophages and astrocytes and their core functions in the developing brain. We discuss their contribution and intercellular crosstalk during tissue homeostasis and pathophysiology. We argue that in-depth knowledge of non-neuronal cells in the brain could provide novel therapeutic targets to reverse or contain neurological diseases.

Transforming Growth Factor-β is a potent regulator of the immune system, acting at every stage from thymic differentiation, population of the periphery, control of responsiveness, tissue repair and generation of memory. It is therefore a central player in the immune response to infectious pathogens, but its contribution is often clouded by multiple roles acting on different cells in time and space. Hence, context is all-important in understanding when TGF-β is beneficial or detrimental to the outcome of infection. In this review, a full range of infectious agents from viruses to helminth parasites are explored within this framework, drawing contrasts and general conclusions about the importance of TGF-β in these diseases.