Altered resting-state functional connectivity in patients with chronic bilateral vestibular failure

AbstractPatients with bilateral vestibular failure (BVF) suffer from gait unsteadiness, oscillopsia and impaired spatial orientation. Brain imaging studies applying caloric irrigation to patients with BVF have shown altered neural activity of cortical visual–vestibular interaction: decreased bilateral neural activity in the posterior insula and parietal operculum and decreased deactivations in the visual cortex. It is unknown how this affects functional connectivity in the resting brain and how changes in connectivity are related to vestibular impairment.We applied a novel data driven approach based on graph theory to investigate altered whole-brain resting-state functional connectivity in BVF patients (n= 22) compared to age- and gender-matched healthy controls (n= 25) using resting-state fMRI. Changes in functional connectivity were related to subjective (vestibular scores) and objective functional parameters of vestibular impairment, specifically, the adaptive changes during active (self-guided) and passive (investigator driven) head impulse test (HIT) which reflects the integrity of the vestibulo-ocular reflex (VOR).BVF patients showed lower bilateral connectivity in the posterior insula and parietal operculum but higher connectivity in the posterior cerebellum compared to controls. Seed-based analysis revealed stronger connectivity from the right posterior insula to the precuneus, anterior insula, anterior cingulate cortex and the middle frontal gyrus. Excitingly, functional connectivity in the supramarginal gyrus (SMG) of the inferior parietal lobe and posterior cerebellum correlated with the increase of VOR gain during active as compared to passive HIT, i.e., the larger the adaptive VOR changes the larger was the increase in regional functional connectivity.Using whole brain resting-state connectivity analysis in BVF patients we show that enduring bilateral deficient or missing vestibular input leads to changes in resting-state connectivity of the brain. These changes in the resting brain are robust and task-independent as they were found in the absence of sensory stimulation and without a region-related a priori hypothesis. Therefore they may indicate a fundamental disease-related change in the resting brain. They may account for the patients' persistent deficits in visuo-spatial attention, spatial orientation and unsteadiness. The relation of increasing connectivity in the inferior parietal lobe, specifically SMG, to improvement of VOR during active head movements reflects cortical plasticity in BVF and may play a clinical role in vestibular rehabilitation

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation

TFT construction of RCFT correlators II: Unoriented world sheets

A full rational CFT, consistent on all orientable world sheets, can be constructed from the underlying chiral CFT, i.e. a vertex algebra, its representation category C, and the system of chiral blocks, once we select a symmetric special Frobenius algebra A in the category C [I]. Here we show that the construction of [I] can be extended to unoriented world sheets by specifying one additional datum: a reversion on A - an isomorphism from the opposed algebra of A to A that squares to the twist. A given full CFT on oriented surfaces can admit inequivalent reversions, which give rise to different amplitudes on unoriented surfaces, in particular to different Klein bottle amplitudes. We study the classification of reversions, work out the construction of the annulus, Moebius strip and Klein bottle partition functions, and discuss properties of defect lines on non-orientable world sheets. As an illustration, the Ising model is treated in detail.Comment: 112 pages, table of contents, several figures. v2: typos corrected, version to be published in Nucl.Phys.

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21: IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.This work was supported by grants from the Diabetes Australia Research Trust and the National Health and Medical Research Council

Correction: Cytokines in the Germinal Center Niche Antibodies 2016, 5(1), 5

The following corrections should be made to the references and bibliography of the published paper [1]:[...

Cytokines in the Germinal Center Niche

Cytokines are small, secreted, glycoproteins that specifically affect the interactions and communications between cells. Cytokines are produced transiently and locally, acting in a paracrine or autocrine manner, and they are extremely potent, ligating high affinity cell surface receptors to elicit changes in gene expression and protein synthesis in the responding cell. Cytokines produced during the differentiation of T follicular helper (Tfh) cells and B cells within the germinal center (GC) niche play an important role in ensuring that the humoral immune response is robust, whilst retaining flexibility, during the generation of affinity matured antibodies. Cytokines produced by B cells, antigen presenting cells and stromal cells are important for the differentiation of Tfh cells and Tfh cell produced cytokines act both in an autocrine fashion to firm Tfh cell differentiation and in a paracrine fashion to support the differentiation of memory B cells and plasma cells. In this review, we discuss the role of cytokines during the GC reaction with a particular focus on the influence of cytokines on Tfh cells

Correction: Cytokines in the Germinal Center Niche Antibodies 2016, 5(1), 5

The following corrections should be made to the references and bibliography of the published paper [1]:[...

Cytokines in the germinal centre reaction to T-dependent antigen

During the germinal centre (GC) response to T-dependent antigen B cells undergo the processes of somatic hypermutation and affinity maturation to become high-affinity antibody producing plasma cells or memory B cells. While the GC B cells undergo these processes they are crucially dependent on help from T cells located within the follicle. These T follicular helper (Tfh) cells provide help in the form of cell-to-cell interaction as well as the secretion of cytokines.Our studies focused on the crucial role cytokines play in the GC reaction, with a special focus on the important but antagonizing roles of the cytokines IL-2 and IL-21. We were able to describe a novel T cell intrinsic mechanism of IL-21 restricting the expansion of regulatory T cells and the follicular regulatory T (Tfr) cell subset via the Bcl-6 mediated inhibition of responsiveness to IL-2. The absence of IL-21 not only led to increased regulatory T cell and Tfr populations in vivo, but also we could also show the increased expression of the alpha subunit of the high-affinity IL-2R (CD25), this was especially apparent on Il21r-/- Tfr cells. Furthermore, we discovered the ability of IL-21 to influence CXCR4 expression on both follicular and extrafollicular T helper cell subsets, as well as GC B cells. With the help of a novel mouse model, with a single point mutation in the cytosolic part of the IL-21R, leading to a STAT1-specific IL-21 signalling defect, we were able to investigate the relative importance of IL-21 mediated STAT1 and STAT3 activation during the GC response to T-dependent antigen. These Il21rEINS mice enabled uncover a regulatory role of IL-21 mediated STAT1 activation on the Tfr cell population. Astonishingly, we also detected a crucial cell intrinsic function of IL-21 dependent activation of STAT1 for the differentiation and function of Tfh cells. This exacerbated Tfh phenotype in Il21rEINS mice in comparison to Il21r-/- mice might be explained by compensatory mechanisms mediated by other cytokines, such as IL-6, at work in the total absence of the IL-21R, but not when a partially functional receptor is still present

Postural Control in Bilateral Vestibular Failure: Its Relation to Visual, Proprioceptive, Vestibular, and Cognitive Input

Patients with bilateral vestibular failure (BVF) suffer from postural and gait unsteadiness with an increased risk of falls. The aim of this study was to elucidate the differential role of otolith, semicircular canal (SSC), visual, proprioceptive, and cognitive influences on the postural stability of BVF patients. Center-of-pressure displacements were recorded by posturography under six conditions: target visibility; tonic head positions in the pitch plane; horizontal head shaking; sensory deprivation; dual task; and tandem stance. Between-group analysis revealed larger postural sway in BVF patients on eye closure; but with the eyes open, BVF did not differ from healthy controls (HCs). Head tilts and horizontal head shaking increased sway but did not differ between groups. In the dual task condition, BVF patients maintained posture indistinguishable from controls. On foam and tandem stance, postural sway was larger in BVF, even with the eyes open. The best predictor for the severity of bilateral vestibulopathy was standing on foam with eyes closed. Postural control of our BVF was indistinguishable from HCs once visual and proprioceptive feedback is provided. This distinguishes them from patients with vestibulo-cerebellar disorders or functional dizziness. It confirms previous reports and explains that postural unsteadiness of BVF patients can be missed easily if not examined by conditions of visual and/or proprioceptive deprivation. In fact, the best predictor for vestibular hypofunction (VOR gain) was examining patients standing on foam with the eyes closed. Postural sway in that condition increased with the severity of vestibular impairment but not with disease duration. In the absence of visual control, impaired otolith input destabilizes BVF with head retroflexion. Stimulating deficient SSC does not distinguish patients from controls possibly reflecting a shift of intersensory weighing toward proprioceptive-guided postural control. Accordingly, proprioceptive deprivation heavily destabilizes BVF, even when visual control is provided