Wessley Immune Ring
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Wessely rings are sterile, corneal intrastromal reactions resulting from immune response to foreign antigens. It can be found in various corneal infections as well as in non-infectious processes.
Wessely rings are corneal intrastromal sterile infiltrates, coined after Wessely who first documented the “Wessely phenomenon”, a reproducible immune reaction in rabbit corneas exposed to cattle or horse serum protein and later challenged with the same antigen in 1911. In 1956, Morawiecki provided insight into the pathophysiology of the disease and the role of immune complex-mediated complement activation.  Later, it was found that other antigens may trigger antibody-independent, properdin-mediated alternative pathway complement activation, including bacterial endotoxins.
The pathogenesis of Wessely rings involves the interaction of foreign antigens with antibodies diffusing from the limbal vasculature into the stroma, resulting in immune complex formation which activate the complement system, leading to polymorphonuclear leukocyte recruitment into the stroma. Both the classical and the alternate pathways of the complement system have been observed to lead to Wessely ring formation, which may explain the variable time courses between symptom onset and Wessely ring observation. Neutrophils are the predominant infiltrative cells in Wessely immune rings.
Corneal immune ring formation can be associated with infectious agents, or they can be sterile corneal infiltrates.
• Infectious agents
o Gram-negative rods (e.g. Pseudomonas)
o Gram-negative diplobacillus (e.g. Moraxella atlantae) 
o Herpes zoster
o Microsporidium keratitis 
o Non-tuberculous Mycobacteria
o Fungal keratitis, including Pythium insidiosum keratitis 
o Antigenic corneal foreign bodies
o Excimer LASER photoablation 
o Topical drugs (e.g. diclofenac) 
o Corneal burns
o Intracorneal insect stings
o Palytoxin (PTX)-producing zoanthids (corals) 
o Behçet’s syndrome 
Since the Wessely immune stromal ring arises in patients with underlying causes for stromal immune reactions, the patient’s symptoms are usually related to the underlying etiology; the Wessely ring is usually not visually significant.
Presenting symptoms may include ocular pain, foreign body sensation, or burning; tearing or purulent discharge; blurred vision, halos around lights; photophobia; and redness.
It is important to identify potential causative agents and/or inciting events, including contact lens wear, ocular trauma by physical (e.g. excimer LASER), thermal or chemical agents (e.g. topical diclofenac, palytoxin), and systemic auto-immune disease.
The typical Wessely phenomenon consists of a corneal stromal ring forming peripherally near the limbus, with centripetal migration ahead of peripheral clouding. The “true” Wessely ring (resulting of immune complex-mediated complement activation) usually appears at 10-14 days from symptom or disease onset, creating a visible ring separated from the central nidus of infection by a clear space.  However, immune rings may appear earlier (within 1 to 5 days of symptom onset) due to activation of the alternate pathway of the complement cascade, as in cases of Pseudomonas keratitis, or in cases of previous exposure to the inciting antigens. In cases of microbial agents with more protacted clinical courses such as Acanthamoeba or Microsporidium keratitis, immune rings may appear after a longer delay.   In cases of herpetic immune stromal keratitis, the Wessely immune ring appears as a mid-stromal of deep ring of stromal haze, usually central or paracentral in location, and may surround a disciform area of endotheliitis,  
The presence of a Wessely immune ring can aid in the differential diagnosis but can also be misleading. When evaluating a corneal ring infiltrate, the most important alternative diagnostic consideration is an infectious ring infiltrate. It is especially important to differentiate infectious ring infiltrates from non-infectious immune rings since both may form in the course of microbial keratitis.
In patients with microbial keratitis, the following signs suggest infectious infiltrate with viable microorganisms invading host tissue rather than a pure immune ring:
• conjunctival injection,
• epithelial defects,
• anterior chamber reaction.
Milder findings of an infiltrate outside the ulcer borders and responsive to topical corticosteroids suggest areas of “pure” immune ring formation in patients with microbial keratitis.
Wessely rings have been reported in patients with herpetic keratitis, Pseudomonas keratitis and other Gram-negative rod keratitis, Moraxella atlantae keratitis, Acanthamoeba keratitis, fungal keratitis, and Microsporidia stromal keratitis. Although the Wessely immune ring of deep stromal haze has been classically described in herpes simplex immune stromal keratitis, immune stromal rings have also been reported in patients with herpes zoster keratitis.
Regarding non-infectious stromal rings, the anamnesis and clinical findings guide the ophthalmologist to the most likely etiology. Notably, these have also been observed in patients with contact lens (CL), hypothesized to be immune responses to bacterial antigens, particularly Gram-negative rods such as Pseudomonas.   In these cases, foreign antigens such as bacterial endotoxin may migrate into the corneal stroma and cause activation of the alternative pathway of the complement cascade. However, in patients with CL-related Wessely ring, a high index of suspicion for infectious keratitis is advised. Finally, storage fluid contamination may also be a cause of Wessely ring in CL wearers.
Excimer LASER photoablation has been reported to cause ring-shaped immune stromal reactions, including both photorefractive keratectomy (PRK) and phototherapeutic keratectomy (PTK).   The mechanisms behind excimer LASER-induced Wessely immune ring formation remains unclear. Although previously thought to result from liberation of trapped antigens (denaturated proteins of DNA at the edge of the ablation zone) could induce a reaction, more recently it has been hypothesized that mammalian heat-shock proteins (HSPs) produced following physical stress (LASER photoablation) may cross-react with circulating antibodies against bacterial HSPs originated from previous contact or infection. Although topical diclofenac has been reported as a cause of sterile corneal infiltrates, pure drug toxicity is unlikely to lead to a ring-shaped infiltrate.
Systemic autoimmune diseases may also be associated with appearance of Wessely immune rings. Inflammation of the limbal vasculature in Behçet’s disease may facilitate the diffusion of immune complexes into the corneal peripheral stroma and stromal ring formation.
Corneal immune infiltration is an uncommon complication of RCE.  Epithelial injury produces a leukocyte chemotactic factor that can lead to sterile infiltrates. These cases should probably always be treated as potentially infected, since clinical distinction between sterile or infected cases is seldom clear in this setting. However, in cases of “truly sterile” infiltrates, resolution is usually rapid and complete, and addition of topical steroids may hasten resolution, especially in severe cases.
PTX-induced toxic keratoconjunctivitis is a rarely reported ocular surface inflammatory disease reported in individuals handling zoanthid (coral) colonies or during cleaning of an aquarium containing these corals.  The receptor for PTX is the plasma membrane that contains the sodium-potassium adenosine triphosphatase (Na-K ATP-ase) pump, and consequently the toxicity of PTX can affect multiple organ systems and can be severe. In the ocular surface, PTX can result in corneal epithelial sloughing and corneal nerve altered sensation, and may trigger Wessely ring formation as well as peripheral corneal thinning due to degradation of keratocytes, collagen, and proteoglycans. The clinical presentation of PTX keratitis may range from mild ocular surface disease to vision-threatening corneal melting and perforation.
Management of Wessely rings depends on etiology. Infectious keratitis should be treated according to the causative agent. Sterile immune rings usually require no therapy, but frequently these patients are frequently managed with topical corticosteroids.
The visual prognosis is largely related to etiology, as “purely” immune stromal infiltrates fade slowly and are usually not visually significant.
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