Treating the Ocular Component of Allergic Rhinoconjunctivitis and Related Eye Disorders

Leonard Bielory, MD; C. H. Katelaris, MD; Susan Lightman, FRCP, FRCOphth, PhD; Robert M. Naclerio, MD

In This Article


Allergic eye disease represents a spectrum of disorders, comprising SAC, PAC, AKC, VKC, and GPC. GPC is not always included in this grouping as it is caused by physical trauma and is typically associated with use of 'extended wear' soft contact lenses, although patients with a history of allergy may be at greater risk.[27] Of these ocular allergy types, SAC and PAC are the most common, although the proportion of the more severe forms of ocular allergic disease (AKC, VKC, and GPC) increase in countries in the southern hemisphere.[28] This could be due to increasing levels of industrialization and pollution or, alternatively, may be an anomaly arising from under-reporting of milder conditions.[28]

Common ocular clinical features of SAC, PAC, AKC, and VKC include redness, itching, and tearing.[29,30] The most striking difference within this group of ocular diseases is that SAC and PAC remain self-limited without ocular surface damage, while AKC and VKC can compromise the cornea, causing ulcers and scarring, and can ultimately lead to vision loss.[29,31] A study of 6 VKC and 13 AKC patients demonstrated that the severity of corneal damage was related to conjunctival injection and edema, which are signs of inflammation,[32] while other studies have shown some correlation with cellular infiltrates and mucous discharge on the upper tarsal conjunctiva.[33,34] The differing involvement of right and left eyes in patients also indicates that local inflammatory factors are controlling the severity of these diseases. Due to the severity of AKC and VKC, it is important to identify the responsible inflammatory mediators and differentiate them from those responsible for SAC and PAC.

SAC and PAC are well defined by their initiation by an immunoglobulin E (IgE)-mediated mast-cell response (Figure 3), which leads to the production of mediators including histamine, leukotriene C4 (LTC4), and prostaglandin D2 (PGD2).[35] This early phase response peaks at approximately 20 minutes post-allergen exposure, and is followed by a late-phase response that peaks at approximately 6 hours, and is characterized by upregulation of adhesion molecules and increased mast cells, neutrophils, eosinophils, macrophages, and basophils in conjunctival biopsies.[36]

The immediate-phase reaction of seasonal and perennial allergic conjunctivitis is initiated by antigen binding to IgE on ocular mast cells, leading to degranulation and the release of histamine and other factors into the conjunctiva. The late-phase response involves mast cells, T cells and eosinophils, and peaks at approximately 6 hours post-allergen exposure. Ag, antigen; MBP, major basic protein; ECP, eosinophilic cationic protein; PAF, platelet-activating factor; LTC4, leukotriene C4; TNF-alpha, tumor necrosis factor-alpha; IL-4, interleukin-4; IL-5, interleukin-5; Th2, T-helper 2.

SAC is thought to be primarily mast-cell driven[37]; however, in addition to the mast-cell response, output of cytokines by conjunctival epithelium T cells leads to multiple cytokine appearance in tears in SAC. T cells also release cytokines in VKC and AKC.[38] Cytokine profiles have been shown to vary between diseases, and indicate a role for Th2 cells in VKC and a greater involvement of Th1 cells in AKC. T cells isolated from GPC-patient conjunctival biopsies, however, produced low amounts of cytokines.[39] Conversely, other studies have shown that cytokine profiles in tears of AKC,[40] and SAC, AKC, and VKC[38] patients support the involvement of mixed helper T cell populations in each disease type. The more prominent role of T cells in the pathogenesis of VKC and AKC is supported by the finding that greater numbers of these cells infiltrate the conjunctiva than in cases of SAC/PAC.[41]

A role for other conjunctival cells, such as epithelial cells and fibroblasts, has been suggested in many forms of conjunctival disorders but particularly in VKC since these cells produce elevated amounts of eotaxin-1 (an eosinophil chemoattractant) in VKC patients. Tear eotaxin-1 levels correlate with the involvement of the cornea in the disease process,[42] and infiltration of eosinophils into the conjunctiva is thought to lead to corneal lesions seen in VKC.[43] Although conjunctival eosinophil numbers have been shown to be raised above normal levels in a study of VKC, AKC, and GPC patients, GPC (which does not lead to corneal involvement) displayed the highest eosinophil infiltration, indicating that eosinophil numbers in the conjunctiva per se are not related to corneal involvement, but rather their state of activation.[44] However, a more recent study has found no eosinophil infiltration into the tarsal conjunctiva (the site at which the characteristic papillary reaction of GPC occurs) in GPC patients.[45] VKC and AKC, but not GPC, are associated with raised expression of several surface antigens of eosinophils in the conjunctiva,[44] which suggests that the level and type of activation of these cells are indicative of disease progression. Furthermore, conjunctival eosinophil granule major basic protein (MBP) has been shown to be raised in AKC patients, while both neutrophil elastase and MBP were raised in conjunctiva of VKC patients, which also indicates a role for neutrophils in this disease.[46] MBP, and also eosinophil cationic protein, have been shown to both reduce viability and affect the morphology of human corneal epithelial cells in vitro.[43] In combination, these data show that although there is still some debate about the pathogenesis of each disease type, steps have been taken toward identifying the cellular mediators that lead to disease progression in the severe forms of ocular allergy. These mediators may provide targets for new treatments aimed at preventing the associated severe discomfort and blindness experienced by a subset of patients.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.