Cellular Incursion into Bowman's Membrane in the Peripheral Cone of the Keratoconic Cornea

Keratoconus: an inflammatory disorder?

“…19,20,106,[108][109][110]144 An important decrease in the level of protease inhibitors such as cystatins (inhibitors of cysteine proteases) and TIMP-1 (inhibitor of MMPs) have also been reported. 95,96,101,[129][130][131] The increased activity of several proteolytic enzymes results in higher concentrations of ROS, RNS, cytotoxic aldehydes (CAs) and peroxynitrates (Ps) (which decreases the activity of TIMP-1 and increase MMP-2), 63,143,144,146,149 and given the lower production of SOD 143 possibly related to IL-1α, 158 an environment with high oxidative stress and low pH is formed, causing an increase in the activation of the caspases (caspase-9 and -12), mitochondrial dysfunction (MD), and DNA damage, 156 which eventually lead to increased apoptosis. All of these could probably be the result of a complex interaction of both genetic predisposition and environmental triggering factors, such as eye rubbing and contact lenses wear (the 'two-hit hypothesis') in keratoconus.…”

“…99,100 The decreased levels of cystatins found in tears from eyes with keratoconus could be a sign of an increase in the degradation of tear proteins, which would be correlated with the decrease in the concentration of total protein in tears from keratoconus patients found by Acera et al 96 In concordance with findings by Balasubramanian et al 95 in tears, lysosomal cathepsin B and cathepsin G have been found to be elevated in keratocytes of keratoconic corneas, localized beneath compromised regions of Bowman's layer and the stroma of morphologically compromised regions, compared with normal tissue. 101 Jun et al 103 evaluated Type-1 helper T cell cytokines (IL-12, IFN-γ, and TNF-α), Type-2 helper T cell cytokines (IL-4, IL-10, and IL-13), and T-helper 17 cell cytokines (IL-17) in serum and tears of patients with keratoconus, to determine whether an altered inflammatory response can contribute to the keratoconus etiology or not. There were low levels of cytokines in blood, with no significant differences between the groups, thus suggesting a dissociation between the condition and systemic inflammation.…”

The pathogenesis of keratoconus

“…Stromal thinning, a hallmark of KC, is caused by a reduction in the number of lamellae within the affected region 28 rather than compaction of collagen fibrils within individual lamellae, 29 but the mechanism by which the thinning occurs is uncertain. Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes 30,31 or decreased levels of proteinase inhibitors, 32 it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. 33 This latter mechanism is supported by the observation of reduced inter-lamellar adhesion, 34 lamellar interlacing in the apex of KC corneas 35,36 and a reduced number of lamellar insertions into Bowman's layer.…”

“…19,39,40 These later studies also presented evidence of a redistribution of lamellae away from the apex of the cone and highlight a variability of collagen distribution patterns between individual cases. 19,39 On the basis of these findings, Meek et al proposed that the loss of structural integrity in the KC cornea was caused by the presence of abnormal keratocytes and matrix proteins 15,31 and upregulated proteolysis triggered an unravelling of lamellae along their length and from their anchors at the limbus, with an opening of the lamellar bifurcations. This theory is supported by observations following riboflavin/UVA collagen cross-linking, where the proposed cross-linkage of the tissue increases both the resistance of the stroma to enzymatic digestion and the cohesiveness between collagen fibrils and the non-collagenous matrix.…”

Keratoconus Layer by Layer - Pathology and Matrix Metalloproteinases

“…Studies of the peripheral keratoconic cornea also show discrete incursions of fine keratocytic processes into Bowman's membrane 10 . These processes were often observed in conjunction with posterior collapse of epithelial cells into the Bowman's layer 10 .…”