Immunology
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The identification of the HVCN1 gene, encoding the only mammalian voltage-gated proton channel, prompted a number of studies on how proton channels affect cellular functions. As their expression is mainly restricted to immune cells, it is not surprising that proton channels regulate different aspects of immune responses. In this review, I will examine the current knowledge of voltage-gated proton channels in both innate and adaptive responses and assess the remaining outstanding questions.
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Glia and microglia in particular elaborate pro-inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other non-neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood-spinal cord and blood-brain barriers when barrier compromise results from CNS pathology. ⋯ N-Palmitoylethanolamine has proven efficacious in mast-cell-mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell-microglia cross-talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.
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Alzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid β-protein (Aβ) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. ⋯ As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Aβ in humans and mice and discusses past, present and future Aβ-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease.
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CD1d-restricted invariant natural killer T (iNKT) cells bear characteristics of innate and adaptive lymphocytes, which allow them to bridge the two halves of the immune response and play roles in many disease settings. Recent work has characterized precisely how their activation is initiated and regulated. Novel antigens from important pathogens have been identified, as has an abundant self-antigen, β-glucopyranosylcaramide, capable of mediating an iNKT-cell response. ⋯ The iNKT-cell activation is further modulated by recent foreign or self-antigen encounter. Activation of dendritic cells through pattern recognition receptors alters their antigen presentation and cytokine production, strongly influencing iNKT-cell activation. In a range of bacterial infections, dendritic cell-dependent innate activation of iNKT cells through interleukin-12 is the dominant influence on their activity.
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'It's high time molecular biology became quantitative, it cries out to a physicist ... for modeling. Modeling isn't a crutch, it's the opposite; it's a way of suggesting experiments to do, to fill gaps in your understanding.' John Maddox, Editor of Nature 1966-73, and 1980-95.