Autoimmune and autoinflammatory mechanisms in uvei

Authors: Richard W Lee Lindsay B Nicholson H Nida Sen ChiChao Chan Lai Wei Robert B Nussenblatt Andrew D Dick

Publish Date: 2014/05/24

Volume: 36, Issue: 5, Pages: 581-594

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Abstract

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 immunemediated insult clinically inflammation following such an insult is termed uveitis The intraocular inflammation in uveitis may be clinically obvious as a result of infection eg 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 eg CD200R and soluble inhibitory factors eg alphaMSH 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 disordersSurvival depends on the pivotal sense of vision Many pathologies affect vision and the eye and almost all involve the immune response at some level The function of the immune system in the eye is critical correspondingly there are active mechanisms in place to preserve immune homeostasis When these are disrupted frank inflammation ensues which is clinically manifest as uveitisUveitis is defined as inflammation of the vascular uveal tract of the eye including the iris ciliary body and choroid however adjacent structures such as the retina optic nerve vitreous and sclera may also be affected Therefore in practice any intraocular inflammation involving compromise of the blood ocular barrier is considered to be in the same group of disorders Clinically uveitis is classified anatomically as anterior intermediate posterior or panuveitis depending on which anatomical structures of the eye are involved 1 All these forms are characterised by an inflammatory cellular infiltrate which ophthalmologists visualize directly in an office setting using a biomicroscope The anterior chamber of the eye is filled with optically clear aqueous fluid allowing the practitioner to clearly see infiltrating leukocytes that are counted and scored in accordance with standardized grading systems 1 This also applies to vitreous gel which occupies the posterior segment of the eyeDiagnostic imaging depicting manifestations of uveitis a Vitreous haze seen in the right eye of a 39yearold African American female with sarcoidosis associated panuveitis i left panel clears following treatment ii right panel Please note that the borders of optic nerve and details of retinal vasculature are not clearly visible due to vitreous haze b Peripheral fundus photographs of an African American male with neurosarcoidosis and panuveitis show significant perivascular exudates and chorioretinal granulomas c Fluorescein angiogram of the same patient in b shows no staining in the very early phase but diffuse involvement of the entire retinal vasculature with staining of the exudates in earlymid phase upper right and lower left panels and leakage in late phase lower right panel is evident d Spectral domain optical coherence tomography SD OCT of a 28yearold Hispanic male with noninfectious uveitis and cystoid macular edema shows intra retinal cysts as well as subretinal fluid arrows Please note the detailed visibility of different retinal layers and the disruption of outer segment ellipsoid layer in the area of subretinal fluid arrow e Fundus photograph of the left eye of a 58yearold Caucasian female with Birdshot chorioretinopathy shows multiple deep yellowish choroidal lesions scattered in the posterior pole particularly nasal to the optic nerveIn 2010 WHO estimated that 285 million people were visually impaired of these 39 million were blind and approximately 10  was due to uveitis 2 In the USA and Europe uveitis accounts for 10–20  of severe visual handicaps and up to 10  of blindness in working age adults 3 4 5 6 7 Uveitis may be caused by infections and/or autoimmunity The relative proportion of causation is highlighted by geography uveitis related to autoimmune disease is more common in developed countries whilst overt infectious disease causes are more frequent in the developing world Approximately 70–90  of sightthreatening uveitis in developed countries is reported to be noninfectious 4 8Noninfectious uveitis comprises a heterogeneous group of disorders diagnosed based on their clinical characteristics which may be either confined to the eye or present together with systemic symptoms Salient examples include birdshot chorioretinopathy BCR characterised by multiple small inflammatory lesions distributed throughout the retina and choroid Fig 1e BCR’s association with the retinal protein Santigen is well established 3 9 Although recent reports have demonstrated a systemic immune deviation in BCR 10 11 clinically BCR is an isolated ocular pathology In contrast sarcoidosis and Behcet’sassociated uveitis and ankylosing spondylitis have clear systemic manifestationsThe clinical phenotype of noninfectious intraocular inflammation is replicated in experimental animal models that are driven by immune responses to selfantigen 12 The animal models support a role for autoimmunity albeit experimentally inflammation is often shaped by the presence of mycobacterial protein However unlike other classical systemic autoimmune disorders there are no clearly defined serological markers to assist diagnosis eg autoantibodies within majority of uveitis entities except high HLA association HLAA29 and Birdshot chorioretinopathy Nor are there markers in clinical use predictive of either severity or prognosis Nonetheless 25 to 30  of uveitis is associated with systemic autoimmune or autoinflammatory disease 4 5 as described above

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