Uveitis: Molecular Pathogenesis and Emerging Therapies

Abstract

The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

“…The IRBP constitutes most of the extracellular matrix present between the photoreceptors and the retinal pigment epithelium [ 77 ]. Thus, in this EAU model, the infiltration of pathogenic CD4+ T cells that mediate an autoimmune response against IRBP, combined with the accumulation of subretinal fluid caused by BRB breakdown, results in the destruction of photoreceptors [ 28 , 29 , 77 , 78 , 79 ]. However, although the EAU-induced disruption of the retinal ONL structure, reflecting photoreceptor loss, was extensive in Gnat1 rd17 mice, the retinal DA levels were higher in EAU Gnat1 rd17 mice compared to age-matched Gnat1 rd17 mice without EAU and signs of photoreceptor degeneration.…”

“…Specifically, DA pretreatment dose-dependently inhibited nuclear translocation of the NF-κΒ p-p65 subunit and p-STAT3, which was accompanied by decreased expression of NF-κΒ and STAT3 target genes encoding IL-6 and chemokines involved in T-cell recruitment. Since the recruitment of autoreactive CD4 + T cells into the retina is a critical hallmark of EAU pathogenesis [ 78 , 79 ], L-DOPA-/DA-mediated reduced activity of NF-κΒ and STAT3 in retinal vascular endothelial cells represents an important mechanism inhibiting BRB permeability to autoreactive CD4 + T cells that initiate the development of EAU. The DA-induced suppression of NF-κΒ and STAT3 activity is not specific only to endothelial cells, as it has also been demonstrated in other cells, including chondrocytes, glioma cells, and hepatocytes [ 96 , 97 , 98 ].…”

Photoreceptor Cells Constitutively Express IL-35 and Promote Ocular Immune Privilege

“…EAU is characterized by the recruitment of proinflammatory lymphocytes of the Th1 and/or Th17 subsets into the retina, and the intraocular inflammation or uveitis is generally manifested between post-immunization (p.i.) day 14 and day 22 [ 11 , 24 , 25 ]. We monitored progression and severity of uveitis during this time period by fundoscopy, a non-invasive procedure that allows visualization of the fundus of the eye (retina, macula, optic disc, fovea and blood vessels) using an ophthalmoscope or fundoscopy.…”

“…The neuroretina is a functional unit of the central nervous system (CNS) that converts photons to electrical signals, which are then transduced to the brain to create visual perception [ 24 ]. It is comprised of photosensitive photoreceptors (rods and cones), retina interneurons (horizontal cells, bipolar cells, amacrine cells) and output neurons (ganglion cells), as well as glial cells (astrocytes, Müller and microglia cells) [ 24 ].…”

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

“…Pathologically, this intraocular inflammation is mediated via antigen-specific CD4 + T cells becoming activated, which then proliferate centrally and migrate into the eye. As a result of this, inflammatory myeloid cells are recruited and contribute to the retinal structural damage and final vision disturbance [ 5 ].…”