Herpes simplex virus is responsible for numerous ocular diseases, the most common of which is herpetic stromal keratitis. This is a recurrent infection of the cornea that typically begins with a subclinical infection of the cornea that establishes a latent infection of sensory ganglia, most often the trigeminal ganglia. Recurring infections occur when the virus is reactivated from latency and travels back to the cornea, where it restimulates an inflammatory response. This inflammatory response can lead to decreased corneal sensation, scarring, and blindness. The diagnosis of these lesions as the result of a recurrent herpes simplex virus infection can at times be problematic. Currently, herpetic stromal keratitis is diagnosed by its clinical presentation on the slit-lamp examination, but the literature does not always support the accuracy of these clinical findings. Other diagnostic tests such as polymerase chain reaction assay, enzyme-linked immunosorbent assay, immunofluorescent antibody, and viral cultures have provided more definitive diagnosis, but also have some limitations. That said, accurate diagnosis is necessary for proper treatment, in order to prevent serious consequences. Current treatment reduces the severity of lesions and controls further viral spread, but does not provide a cure.

Purpose To evaluate the utility of Endothelial/Descemet's membrane complex (En/DM) characteristics in diagnosing corneal graft rejection. Design Diagnostic reliability study. Methods 139 eyes (96 corneal grafts post penetrating keratoplasty or Descemet's stripping automated endothelial keratoplasty: 40 clear, 23 actively rejecting, 24 rejected and 9 non-immunological failed grafts, along with 43 age-matched control eyes) were imaged using high-definition optical coherence tomography. Images were used to describe En/DM and measure central corneal thickness (CCT) and central En/DM thickness (DMT). En/DM rejection index (DRI) was computed to detect the relative En/DM thickening to the entire cornea. Results In actively rejecting grafts, DMT and DRI were significantly greater than controls and clear grafts (28, 17 and 17 μm and 1.5, 1 and 1, respectively; P<0.001). Rejected grafts had the highest DMT and DRI compared to all groups (59 μm and 2.1; P<0.001). DMT and DRI showed excellent accuracy, significantly better than that of CCT, in differentiating actively rejecting from clear grafts (100% and 96% sensitivity; 92.5% and 92.5% specificity), actively rejecting from rejected grafts (88% and 83% sensitivity; 91% and 83% specificity) and non-immunological failed from rejected grafts (100% and 100% sensitivity; 88% and 100% specificity). DMT correlated significantly with rejection severity (P<0.001). Conclusions In corneal grafts, in vivo relative thickening of the En/DM is diagnostic of graft rejection as measured by DMT and DRI. These indices have excellent accuracy, sensitivity and specificity in detecting graft immunological status, superior to CCT. DMT is a quantitative index that correlates accurately with the severity of rejection.

Herpetic eye disease, termed herpetic stromal keratitis (HSK), is a potentially blinding infection of the cornea that results in over 300,000 clinical visits each year for treatment. Between 1 and 2 percent of those patients with clinical disease will experience loss of vision of the infected cornea. The vast majority of these cases are the result of reactivation of a latent infection by herpes simplex type I virus and not due to acute disease. Interestingly, the acute infection is the model most often used to study this disease. However, it was felt that a recurrent model of HSK would be more reflective of what occurs during clinical disease. The recurrent animal models for HSK have employed both rabbits and mice. The advantage of rabbits is that they experience reactivation from latency absent any known stimulus. That said, it is difficult to explore the role that many immunological factors play in recurrent HSK because the rabbit model does not have the immunological and genetic resources that the mouse has. We chose to use the mouse model for recurrent HSK because it has the advantage of there being many resources available and also we know when reactivation will occur because reactivation is induced by exposure to UV-B light. Thus far, this model has allowed those laboratories using it to define several immunological factors that are important to this disease. It has also allowed us to test both therapeutic and vaccine efficacy. Video LinkThe video component of this article can be found at

Herpetic stromal keratitis is characterized by an inflammatory response that includes neutrophils, macrophages, NK cells and T cells. The factors that are responsible for this inflammation are pro-inflammatory cytokines and chemokines. Many of these factors have been defined for primary disease, but relatively few have been investigated during recurrent HSK. The present study was designed to determine the role that two of these factors, IL-6 and CXCL1 play during recurrent HSK. Results clearly indicate that unlike primary disease, IL-6 plays no role in recurrent HSK. However, the presence of CXCL1 is required for recurrent HSK as evidenced by the lack of corneal disease in mice treated with anti-CXCL1 antibody. This was confirmed using mice lacking the primary receptor for CXCL1, CXCR2. Corneal disease in this strain was significantly reduced compared to wild-type B6 controls. Unexpectedly, lack of disease occurs even though CXCL1 KO mice display increased viral shedding at the cornea. The primary mechanism that CXCL1 plays during disease is its ability to stimulate neutrophils to infiltrate the cornea following reactivation. This report provides further evidence that primary HSK and recurrent HSK possess overlapping yet distinct disease mechanisms.

Herpes simplex virus-1 (HSV) infection of the cornea leads to a potentially blinding immuno-inflammatory lesion of the cornea that is termed herpetic stromal keratitis (HSK). It has also been demonstrated that one of the factors that limits inflammation of the cornea is the presence of Fas ligand (FasL) on corneal epithelium and endothelium. In this study the role that FasL expression in the cornea plays following acute infection with HSV-1 was determined. HSV-1 infection of both BALB/c and C57BL/6 (B6) mice were compared to their lpr and gld counterparts. Results indicated that mice bearing mutations in the Fas antigen (lpr) displayed most severe disease while the FasL defective gld mouse displayed an intermediate phenotype. It was further demonstrated that increased disease was due to lack of Fas expression on bone-marrow derived cells. Interestingly, while virus persisted slightly longer in the corneas of mice bearing lpr and gld mutations, the persistence of infectious virus in the trigeminal ganglia was the same for all strains infected. Furthermore, B6 mice bearing lpr and gld mutations were also more resistant to virus-induced mortality than wild-type B6 mice. Thus neither disease nor mortality correlated with viral replication in these mice. Collectively, these findings indicate that the presence of FasL on the cornea restricts the entry of Fas+ bone marrow-derived inflammatory cells and thus reduces the severity of HSK.

Herpes simplex keratitis is a disease of the cornea caused by HSV-1. It is a leading cause of corneal blindness in the world. Underlying molecular mechanism is still unknown, but experimental models have helped give a better understanding of the underlying molecular pathology. Cytokines and chemokines are small proteins released by cells that play an important proinflammatory or anti-inflammatory role in modulating the disease process. Cytokines such as IL-17, IL-6, IL-1α, and IFN-γ and chemokines such as MIP-2, MCP-1, MIP-1α, and MIP-1β have proinflammatory role in the destruction caused by HSV including neutrophil infiltration and corneal inflammation, and other chemokines and cytokines such as IL-10 and CCL3 can have a protective role. Most of the damage results from neutrophil infiltration and neovascularization. While many more studies are needed to better understand the role of these molecules in both experimental models and human corneas, current studies indicate that these molecules hold potential to be targets of future therapy.

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