Orbital autoimmune inflammatory disorders - Protein regional variability might explain specific lesion location.

In ophthalmology, inflammatory diseases target different highly specific regions within the small confine of the orbit. Some entities even prefer a particular location or depth within the same tissue (ex. anterior, intermediate or posterior uveitides, chorioretinitides with unique topographic presentations). Though the location of a lesion strongly influences and helps us in our differential diagnosis, we still don't understand why specific anatomic sites are susceptible to a disease while other areas are spared. We postulate that regional variability in tissue protein expression can sway the immune system's capacity to trigger an autoimmune response. In addition to this site-specific quantitative and qualitative variability in potential antigen expression, we believe that other proteins implicated in the immune cascade, as well as geographic areas of relative resistance, tolerance and susceptibility, may be unequally distributed within the orbit. To illustrate our hypotheses, we review three major types of ocular myositis and describe how the extraocular muscles different embryologic origins and protein disparities might explain the fundamental clinical differences between these orbital inflammatory diseases. We hope that future differential genomics, proteinomics, epigenomics and analysis of RNA species of affected tissues, compared to their non-affected, yet microscopically similar, counterparts, will help us understand why diseases occur where they do. Hopefully, understanding these immune triggers will pave the way to new treatment options for ocular inflammatory diseases and for other auto-inflammatory conditions with a marked predilection for any given site.

The asymmetric protein expression hypothesis - Explaining the unilaterality of HLA-B27-positive acute anterior uveitides.

For reasons still unclear, most HLA-B27-positive acute anterior uveitides occur unilaterally. Building upon the growing literature showing that left-right asymmetry exist at the biomolecular and at the cellular levels, we propose a new hypothesis to explain why HLA-B27-positive acute anterior uveitides tend to affect one eye selectively. We postulate that left and right uveal tissue may present quantitatively and qualitatively different proteins to the immune system, capable to trigger an autoimmune response, and that other variables, including anatomical, cellular and molecular barriers, as well as our own eye-derived immunological tolerance and immune suppressive intraocular microenvironment may also be unequally distributed, and impact differently the immune privileges of the left and right eye. These same quantitative and qualitative differences might also explain why HLA-B27-positive acute anterior uveitides can flip-flop between the left and the right eye, after the first attack. By trying to figure out why one eye is targeted by an autoimmune reaction while the other is clinically unaffected, we might be able to better understand how and why an autoimmune reaction starts. Hopefully, this will help us devise better treatments for ocular autoimmune diseases, and contribute to the management of autoinflammatory conditions with a marked asymmetric clinical presentation in other fields.

Regional pathology in glaucoma--an overlooked link to neuroprotective strategies.

Primary open-angle glaucoma (POAG) is the second commonest cause of blindness in the world. It is a neurodegenerative disease characterized by retinal ganglion cell loss. The molecular mechanism leading to glaucoma damage is unclear. Understanding the pathways that favor neuronal survival plus those that predispose to neuronal demise in POAG may have direct implications for other neurodegenerative diseases. POAG is a heterogeneous disease. A small subset of POAG patients develop damage in a highly focal form with a discrete sector of the optic nerve manifesting well delineated neuronal loss. It is hypothesized that this pattern of nerve loss indicates the optic nerve is not molecularly homogeneous. Genetic analysis of patients with isolated focal forms of POAG may enable new genes to be identified in glaucoma. Finding the responsible genes in POAG is a critical first step. The potential implications are earlier disease detection with resultant optimized visual preservation. Future treatment options could develop that include altered gene regulation, gene silencing or introducing repair genes. Determining the molecular causes for regional neuronal susceptibility could lead to identification of pathways underlying disease and ultimately effective patient-specific neuroprotective strategies.