Capture, crawl, cross: the T cell code to breach the blood-brain barriers

The central nervous system (CNS) is an immunologically privileged site to which access of circulating immune cells is tightly controlled by the endothelial blood-brain barrier (BBB; see Glossary) localized in CNS microvessels, and the epithelial blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus. As a result of the specialized structure of the CNS barriers, immune cell entry into the CNS parenchyma involves two differently regulated steps: migration of immune cells across the BBB or BCSFB into the cerebrospinal fluid (CSF)-drained spaces of the CNS, followed by progression across the glia limitans into the CNS parenchyma. With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers.

The Semantics and Typology of Yes/No Particles (A Cross-Linguistic Study)

Taking the three basic systems of Yes/No particles the group looked at the relative deep and surface structures, and asked what types of systems are present in the Georgian, Polish and Armenian languages. The choice of languages was of particular interest as the Caucasian and Indo-European languages usually have different question-answering systems, but Georgian (Caucasian) and Polish (Indo-European) in fact share the same system. The Armenian language is Indo-European, but the country is situated in the southern Caucasus, on Georgia's southern border, making it worth analysing Armenian in comparison with Georgian (from the point of view of language interference) and with Polish (as two relative languages). The group identified two different deep structures, tracing the occurrence of these in different languages, and showed that one is more natural in the majority of languages. They found no correspondence between relative languages and their question-answer systems and demonstrated that languages in the same typological class may show different systems, as with Georgian and the North Caucasian languages. It became clear that Georgian, Armenian and Polish all have an agree/disagree question-answering system defined by the same deep structure. From this they conclude that the lingual mentalities of Georgians, Armenians and Poles are more oriented to the communicative act. At the same time the Yes/No system, in which a positive particle stands for a positive answer and a negative particle for a negative answer, also functions in these languages, indicating that the second deep structure identified also functions alongside the first.

Linguistic Stylistics

Marina Katnic-Bakarsic. Linguistic Stylistics The practical, i.e. educational, objective of this research was to produce lectures on linguistic stylistics for the students of Sarajevo University, while the theoretical one was to produce a monograph on the subject. This monograph, which can also be used as a university textbook, includes twenty-nine chapters, an index of topics, a bibliography and a list of sources. The theoretical postulates are followed by examples from texts in various functional styles in Bosnian, Croatian, Serbian, and in some cases Russian or English. Linguo-stylistic problems were investigated from both the structuralist and post-structuralist points of view. Linguistic stylistics is therefore understood as a discipline which studies expressive, stylistically marked language units on all language levels, functional-stylistic language variation and various aspects of intertextuality and metatext. The author introduces a notion of stylistic competence. The stylistic competence of a speaker is directly proportional to his/her knowledge of different varieties of language (i.e. subcodes) and to the successful switching from one subcode to another. Stylistic creativity is a special segment of stylistic competence as a feature of individual style. A new classification of functional styles has also been introduced. This includes six primary styles (scientific, colloquial, administrative, publicistic, journalistic and literary-artistic) and five secondary styles (oratorical, the style of advertisements and commercials, that of comics, that of essays and that of screenplays). A special place is given to the analysis of the style of hypertext and hypermedia, which can be understood only within the post-structuralist theory of text deconstruction and intertextuality. The project also analysed some new topics, including reregistration in literary texts, gender and style of dialogue, and citations as metatextual signals and their role in different types of text. The results therefore offer a new approach to the study of linguistic stylistics both in Bosnia and Herzegovina and in the field in general.

Affective and linguistic processing of speech prosody: DC potential studies

Speech melody or prosody subserves linguistic, emotional, and pragmatic functions in speech communication. Prosodic perception is based on the decoding of acoustic cues with a predominant function of frequency-related information perceived as speaker's pitch. Evaluation of prosodic meaning is a cognitive function implemented in cortical and subcortical networks that generate continuously updated affective or linguistic speaker impressions. Various brain-imaging methods allow delineation of neural structures involved in prosody processing. In contrast to functional magnetic resonance imaging techniques, DC (direct current, slow) components of the EEG directly measure cortical activation without temporal delay. Activation patterns obtained with this method are highly task specific and intraindividually reproducible. Studies presented here investigated the topography of prosodic stimulus processing in dependence on acoustic stimulus structure and linguistic or affective task demands, respectively. Data obtained from measuring DC potentials demonstrated that the right hemisphere has a predominant role in processing emotions from the tone of voice, irrespective of emotional valence. However, right hemisphere involvement is modulated by diverse speech and language-related conditions that are associated with a left hemisphere participation in prosody processing. The degree of left hemisphere involvement depends on several factors such as (i) articulatory demands on the perceiver of prosody (possibly, also the poser), (ii) a relative left hemisphere specialization in processing temporal cues mediating prosodic meaning, and (iii) the propensity of prosody to act on the segment level in order to modulate word or sentence meaning. The specific role of top-down effects in terms of either linguistically or affectively oriented attention on lateralization of stimulus processing is not clear and requires further investigations.

Unattended emotional intonations modulate linguistic prosody processing

Prosody or speech melody subserves linguistic (e.g., question intonation) and emotional functions in speech communication. Findings from lesion studies and imaging experiments suggest that, depending on function or acoustic stimulus structure, prosodic speech components are differentially processed in the right and left hemispheres. This direct current (DC) potential study investigated the linguistic processing of digitally manipulated pitch contours of sentences that carried an emotional or neutral intonation. Discrimination of linguistic prosody was better for neutral stimuli as compared to happily as well as fearfully spoken sentences. Brain activation was increased during the processing of happy sentences as compared to neutral utterances. Neither neutral nor emotional stimuli evoked lateralized processing in the left or right hemisphere, indicating bilateral mechanisms of linguistic processing for pitch direction. Acoustic stimulus analysis suggested that prosodic components related to emotional intonation, such as pitch variability, interfered with linguistic processing of pitch course direction.

The blood-central nervous system barriers actively control immune cell entry into the central nervous system

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Distinct molecular composition of blood and lymphatic vascular endothelial cell junctions establishes specific functional barriers within the peripheral lymph node

Lymph nodes are strategically localized at the interfaces between the blood and lymphatic vascular system, delivering immune cells and antigens to the lymph node. As cellular junctions of endothelial cells actively regulate vascular permeability and cell traffic, we have investigated their molecular composition by performing an extensive immunofluorescence study for adherens and tight junction molecules, including vascular endothelium (VE)-cadherin, the vascular claudins 1, 3, 5 and 12, occludin, members of the junctional adhesion molecule family plus endothelial cell-selective adhesion molecule (ESAM)-1, platelet endothelial cell adhesion molecule-1, ZO-1 and ZO-2. We found that junctions of high endothelial venules (HEV), which serve as entry site for naive lymphocytes, are unique due to their lack of the endothelial cell-specific claudin-5. LYVE-1(+) sinus-lining endothelial cells form a diffusion barrier for soluble molecules that arrive at the afferent lymph and use claudin-5 and ESAM-1 to establish characteristic tight junctions. Analysis of the spatial relationship between the different vascular compartments revealed that HEV extend beyond the paracortex into the medullary sinuses, where they are protected from direct contact with the lymph by sinus-lining endothelial cells. The specific molecular architecture of cellular junctions present in blood and lymphatic vessel endothelium in peripheral lymph nodes establishes distinct barriers controlling the distribution of antigens and immune cells within this tissue.

Strategies to advance translational research into brain barriers

There is a paucity of therapies for most neurological disorders--from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimer's disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier, the blood-CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here.

The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction

The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood-CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood-CNS barriers with focus on CNS autoimmune inflammation.