抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.

http://science.sciencemag.org/content/sci/308/5726/1314.full.pdf

Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo

In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.

/pdf/biogenesis-secretion-and-intercellular-interactions-of-4pskmvujl3.pdf

Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

/pdf/neuroinflammation-in-alzheimer-s-disease-36czdowiut.pdf

Neuroinflammation in Alzheimer's disease

Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated—in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.10161

Microglia as a source and target of cytokines.

Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

The transfer of antigens from oligodendrocytes to immune cells has been implicated in the pathogenesis of autoimmune diseases. Here, we show that oligodendrocytes secrete small membrane vesicles called exosomes, which are specifically and efficiently taken up by microglia both in vitro and in vivo. Internalisation of exosomes occurs by a macropinocytotic mechanism without inducing a concomitant inflammatory response. After stimulation of microglia with interferon-γ, we observe an upregulation of MHC class II in a subpopulation of microglia. However, exosomes are preferentially internalised in microglia that do not seem to have antigen-presenting capacity. We propose that the constitutive macropinocytotic clearance of exosomes by a subset of microglia represents an important mechanism through which microglia participate in the degradation of oligodendroglial membrane in an immunologically ‘silent’ manner. By designating the capacity for macropinocytosis and antigen presentation to distinct cells, degradation and immune function might be assigned to different subtypes of microglia.

/pdf/selective-transfer-of-exosomes-from-oligodendrocytes-to-4lkyt9b03h.pdf

Uwe-Karsten Hanisch

Papers

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Physiology of Microglia

Microglia as a source and target of cytokines.

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis