Advances in Immunology最新文献

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.

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.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections trigger viral RNA sensors such as TLR7 and RIG-I, thereby leading to production of type I interferon (IFN) and other inflammatory mediators. Expression of viral proteins in the context of this inflammation leads to stereotypical antigen-specific antibody and T cell responses that clear the virus. Immunity is then maintained through long-lived antibody-secreting plasma cells and by memory B and T cells that can initiate anamnestic responses. Each of these steps is consistent with prior knowledge of acute RNA virus infections. Yet there are certain concepts, while not entirely new, that have been resurrected by the biology of severe SARS-CoV-2 infections and deserve further attention. These include production of anti-IFN autoantibodies, early inflammatory processes that slow adaptive humoral immunity, immunodominance of antibody responses, and original antigenic sin. Moreover, multiple different vaccine platforms allow for comparisons of pathways that promote robust and durable adaptive immunity.

Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) with an unknown etiology. Thereby, MS is not a uniform disease but rather represents a spectrum of disorders, where each aspect needs to be modeled with specific requirements-for a systematic overview see our previous issue of this review (Kurschus, Wortge, & Waisman, 2011). However, there is broad consensus about the critical involvement of the immune system in the disease pathogenesis. To better understand how the immune system contributes to CNS autoimmunity, the model of experimental autoimmune encephalomyelitis (EAE) was developed. EAE can be induced in susceptible animals in many different ways, with the most popular protocol involving the activation of self-reactive T cells by a peptide based on the myelin oligodendrocyte glycoprotein sequence. In the last 10 years this model has led to major advances in our understanding of the immune system, especially the nature of IL-17-producing T cells (Th17 cells), host-microbiome interactions, the gut-brain axis and how the immune system can cause damage in different regions of the brain and the spinal cord. This update summarizes some of the main achievements in the field in the last 10 years.

Neuropsychiatric diseases have traditionally been studied from brain, and mind-centric perspectives. However, mounting epidemiological and clinical evidence shows a strong correlation of neuropsychiatric manifestations with immune system activation, suggesting a likely mechanistic interaction between the immune and nervous systems in mediating neuropsychiatric disease. Indeed, immune mediators such as cytokines, antibodies, and complement proteins have been shown to affect various cellular members of the central nervous system in multitudinous ways, such as by modulating neuronal firing rates, inducing cellular apoptosis, or triggering synaptic pruning. These observations have in turn led to the exciting development of clinical therapies aiming to harness this neuro-immune interaction for the treatment of neuropsychiatric disease and symptoms. Besides the clinic, important theoretical fundamentals can be drawn from the immune system and applied to our understanding of the brain and neuropsychiatric disease. These new frameworks could lead to novel insights in the field and further potentiate the development of future therapies to treat neuropsychiatric disease.

The antiviral innate immune and inflammatory responses are critical for host defense against viral infection. How these antiviral responses are initiated and regulated has been intensively investigated. Viral nucleic acids are sensed by pattern-recognition receptors (PRRs), which trigger various signaling pathways by utilizing distinct adaptor proteins, kinases and regulatory proteins. These pathways lead to activation of the transcriptional factors NF-κB and IRF3 and ultimate induction of antiviral effector proteins including type I interferons (IFNs), TNF and IL-1β, which are critical mediators of antiviral innate immune and inflammatory responses. For the past 20 years, our groups at Peking University and Wuhan University have made restless efforts in deciphering the molecular mechanisms of antiviral innate immune and inflammatory responses. Here, we summarize the major discoveries from our groups, including the identifications of the critical adaptors VISA/MAVS and MITA/STING, regulatory mechanisms of these adapter-mediated signaling, and regulation of TNF- and IL1β-triggered inflammatory responses.

Natural killer (NK) cells are important innate effectors for their defense against pathogens and tumors without the need of prior sensitization. Along with the growing understanding of basic NK cell biology, it has been widely accepted that NK cells are a heterogeneous population of innate lymphoid cell (ILC) family. Apart from the conventional NK cell (cNK) subset that circulates throughout the body, some non-lymphoid tissues contain tissue-resident NK (trNK) cell subsets, and the composition of NK cell subsets varies greatly with different locations. Except for cNK cells, other ILCs are known as tissue-resident cells. In this review, we summarize the unique properties of trNK cells, discuss their lineage relationship with other ILCs, and highlight recent advances in our understanding of the functions of trNK cells and other ILCs.

Immune responses are often accompanied by radical changes of cellular metabolism of immune cells. On the other hand, an ever increasing number of metabolic pathways and products have been found to possess immune regulatory functions. The field of immunometabolism that investigates the interplay between metabolism and immunity has developed rapidly during the past decade. In this chapter, we attempt to summarize the recent progresses by scientists in China on metabolic regulation of innate immunity from the following three perspectives: metabolic regulation of myeloid cell functions, metabolic adaptations of tissue resident myeloid cells, and metabolism and immunity at the mucosal surfaces.