Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

Abstract

The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.

Newfound features associated with Hennekam Syndrome (Intestinal Lymphangiectasia-Lymphedema-Intellectual-Disability Syndrome) complicated with comorbid Waldmann’s disease resulting in celiac disease

“…6 HS has been associated with absent neck holding and webbed neck. 1,23,24,44,45 Our patient sat sideways in a wheelchair, his face turned downwards and to the left, looking at his mother throughout his clinical encounter. Our patient's asymmetrical cervical muscle tone could be due to the absence of neck holding reported in HS.…”

“…1,5 HS has also been associated with limb deformities. 1,2,22,23,24 Our patient had long-standing established care with a podiatrist prior to his chief complaint clinic visit. He reported that he had been unable to wear shoes for many years because of swelling episodes.…”

“…In addition, central nervous system anomalies, vertebral defects such as scoliosis, pectus excavum, hypersplenism, umbilical hernia, renal or urinary abnormalities, microcephaly, hypoplastic corpus callosum, pachygyria, seizures, hearing defects, and glaucoma have been reported. 1,23,24,21,19 Some patients also presented with food allergies and atopic dermatitis. 17 It should be noted that the presence of both low albumin and iron-deficiency anemia could indicate that lymphangiectasias may cause silent GI bleeding.…”

Collagen as a Biomaterial for Skin and Corneal Wound Healing

“…A key molecule involved in pathogenic corneal neovascularization is VEGF [ 80 ]. Expression of VEGF has been attributed to stimulation by inflammatory cytokines, notably interleukins-1,6 and tumor necrosis factor-alpha (IL-1, IL-6, TNF-α) [ 81 , 82 , 83 ]. Interestingly in some pathologies, corneal neovascularization occurs in parallel with epithelial hyperplasia, disruption of the Bowman layer, disorganized stromal collagen fibers and fibroblast activation [ 4 ].…”

“…This process is accelerated when the injury is superficial such as with most corneal abrasions that heal without any complications [ 4 , 86 ]. Stem cells and, in particular, progenitor cells such as the transient amplifying cells of the limbal epithelium contribute to the rapid healing [ 82 , 86 , 87 , 88 ]. Corneal epithelial wound healing involves several key phases: adhesion of the ingrowing cells to the BM, migration to cover the wound, cell proliferation and differentiation [ 87 , 89 , 90 ].…”