Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Intramanual and intermanual transfer of the curvature aftereffect

The existence and transfer of a haptic curvature aftereffect was investigated to obtain a greater insight into neural representation of shape. The haptic curvature aftereffect is the phenomenon whereby a flat surface is judged concave if the preceding touched stimulus was convex and vice versa. Single fingers were used to touch the subsequently presented stimuli. A substantial aftereffect was found when the adaptation surface and the test surface were touched by the same finger. Furthermore, a partial, but significant transfer of the aftereffect was demonstrated between fingers of the same hand and between fingers of both the hands. These results provide evidence that curvature information is not only represented at a level that is directly connected to the mechanoreceptors of individual fingers but is also represented at a stage in the somatosensory cortex shared by the fingers of both the hands

Using curvature information in haptic shape perception of 3D objects

Are humans able to perceive the circularity of a cylinder that is grasped by the hand? This study presents the findings of an experiment in which cylinders with a circular cross-section had to be distinguished from cylinders with an elliptical cross-section. For comparison, the ability to distinguish a square cuboid from a rectangular cuboid was also investigated. Both elliptical and rectangular shapes can be characterized by the aspect ratio, but elliptical shapes also contain curvature information. We found that an elliptical shape with an aspect ratio of only 1.03 could be distinguished from a circular shape both in static and dynamic touch. However, for a rectangular shape, the aspect ratio needed to be about 1.11 for dynamic touch and 1.15 for static touch in order to be discernible from a square shape. We conclude that curvature information can be employed in a reliable and efficient manner in the perception of 3D shapes by touch

Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/β, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis

Grasping Objects with Environmentally Induced Position Uncertainty

Due to noisy motor commands and imprecise and ambiguous sensory information, there is often substantial uncertainty about the relative location between our body and objects in the environment. Little is known about how well people manage and compensate for this uncertainty in purposive movement tasks like grasping. Grasping objects requires reach trajectories to generate object-fingers contacts that permit stable lifting. For objects with position uncertainty, some trajectories are more efficient than others in terms of the probability of producing stable grasps. We hypothesize that people attempt to generate efficient grasp trajectories that produce stable grasps at first contact without requiring post-contact adjustments. We tested this hypothesis by comparing human uncertainty compensation in grasping objects against optimal predictions. Participants grasped and lifted a cylindrical object with position uncertainty, introduced by moving the cylinder with a robotic arm over a sequence of 5 positions sampled from a strongly oriented 2D Gaussian distribution. Preceding each reach, vision of the object was removed for the remainder of the trial and the cylinder was moved one additional time. In accord with optimal predictions, we found that people compensate by aligning the approach direction with covariance angle to maintain grasp efficiency. This compensation results in higher probability to achieve stable grasps at first contact than non-compensation strategies in grasping objects with directional position uncertainty, and the results provide the first demonstration that humans compensate for uncertainty in a complex purposive task

Order-Based Representation in Random Networks of Cortical Neurons

The wide range of time scales involved in neural excitability and synaptic transmission might lead to ongoing change in the temporal structure of responses to recurring stimulus presentations on a trial-to-trial basis. This is probably the most severe biophysical constraint on putative time-based primitives of stimulus representation in neuronal networks. Here we show that in spontaneously developing large-scale random networks of cortical neurons in vitro the order in which neurons are recruited following each stimulus is a naturally emerging representation primitive that is invariant to significant temporal changes in spike times. With a relatively small number of randomly sampled neurons, the information about stimulus position is fully retrievable from the recruitment order. The effective connectivity that makes order-based representation invariant to time warping is characterized by the existence of stations through which activity is required to pass in order to propagate further into the network. This study uncovers a simple invariant in a noisy biological network in vitro; its applicability under in vivo constraints remains to be seen

The Grasping Side of Odours

Background: Research on multisensory integration during natural tasks such as reach-to-grasp is still in its infancy. Crossmodal links between vision, proprioception and audition have been identified, but how olfaction contributes to plan and control reach-to-grasp movements has not been decisively shown. We used kinematics to explicitly test the influence of olfactory stimuli on reach-to-grasp movements. Methodology/Principal Findings: Subjects were requested to reach towards and grasp a small or a large visual target (i.e., precision grip, involving the opposition of index finger and thumb for a small size target and a power grip, involving the flexion of all digits around the object for a large target) in the absence or in the presence of an odour evoking either a small or a large object that if grasped would require a precision grip and a whole hand grasp, respectively. When the type of grasp evoked by the odour did not coincide with that for the visual target, interference effects were evident on the kinematics of hand shaping and the level of synergies amongst fingers decreased. When the visual target and the object evoked by the odour required the same type of grasp, facilitation emerged and the intrinsic relations amongst individual fingers were maintained. Conclusions/Significance: This study demonstrates that olfactory information contains highly detailed information able to elicit the planning for a reach-to-grasp movement suited to interact with the evoked object. The findings offer a substantia

Doyne lecture 2016:intraocular health and the many faces of inflammation

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses