Immune mechanisms in allergic eye disease

Reviewed by Dr Andrea Leonardi

Ocular allergy affects millions of people worldwide. It is generally intermittent but sufferers’ quality of life is affected by the resulting ocular discomfort and inflammation: in severe cases they may experience vision disturbance and find that daily activities are hindered.

Common causes of ocular allergy include mites, animal allergens and moulds, which are found indoors; grass, tree and weed pollens, and mould spores, found outdoors; food allergens such as fruits, vegetables, nuts, milk, eggs, shellfish or fish; and injected allergens including insect venoms and therapeutic proteins.

Changes to our environment from the combined effects of warming and more CO₂ mean that the allergy season is becoming longer from year to year, with pollen seasons starting earlier, lengthier peak-pollen periods and even some pollen presence in the winter.

Rising temperatures are changing the botanical landscape, increasing the geographic distribution of allergenic plants, and the amount of pollen in the air will continue to increase as climate change worsens.

As an example of the direct link the environment can have with our health, the number and severity of ocular allergies was observed to increase dramatically in spring 2012 when air pressure, temperature, pollen count and PM10 levels were unusually high. These phenomena seem to increase every year: 2017 was the second-hottest year on record according to NASA data, and was the hottest year that did not have the short-term warming influence of an El Niño event.¹

Allergy-like symtoms

Air pollution constitutes one of the main threats to public health in Europe. Significant impacts on morbidity and mortality have been observed, even in cases of low exposure and when pollutant levels are within limits set by the European Union.²

Focusing on ocular surface diseases, patients commonly present with a type of conjunctivitis that is not strictly of allergic, infectious or dry-eye origin. Clinical studies and experience have shown a cause-and-effect relationship between these allergy-like symptoms and environmental factors, including outdoor air pollutants and poor indoor air quality.³

People with this ‘urban eye allergy syndrome’ experience ocular symptoms that are increased by chemical triggers and pollution in the atmosphere rather than by true allergens.

Proposed mechanisms for the syndrome include free-radical generation and oxidative stress; increased expression of pro-inflammatory cytokines; modification of key intracellular proteins or the innate immune response; stimulation of autonomic nervous system receptors; adjuvant effects on the immune system; and suppression of normal defence mechanisms.

It seems likely these all play roles at different stages of the developing syndrome. These individuals certainly appear not to be allergic to pollutants but rather to be experiencing an allergic-type response to pollutants stimulating the mucosal immune system.

In a recent large survey performed at a national level, focused specifically on ocular allergy, only 40% of subjects diagnosed as affected by allergic conjunctivitis had an associated allergic condition such as rhinitis, asthma or eczema.⁴ Therefore, it is quite common for patients with eye symptoms to request an ophthalmological evaluation before the allergy consultancy.

In this survey, pollens were indicated as the most frequent triggers; however, nonspecific environmental conditions, pollutants, cigarette smoke and particular weather conditions were also reported as common factors in inducing ocular symptoms.

Types of ocular allergy

True ocular allergy involves both IgE- and non-IgE-mediated mechanisms. Seasonal and perennial allergic conjunctivitis are primarily IgE-mediated and can be treated using topical and oral antihistamines and topical mast cell stabilisers, whereas non-IgE-mediated disorders such as contact blepharoconjunctivitis require anti-allergic drugs and topical corticosteroids to treat.

Atopic and vernal keratoconjunctivitis (VKC) have a mixture of IgE-mediated and non-IgE-mediated components and require intense and prolonged anti-allergic drugs, frequently in combination with corticosteroids or topical immunomodulators such as cyclosporine.⁵

The diagnosis of ocular allergy is relatively simple, being based mostly on clinical history, signs and symptoms, and being confirmed by the results of allergy tests. In general, asking the right questions to patients should reveal not only signs and symptoms but also their frequency, duration and severity.⁶

VKC is a severe ocular disease that occurs predominantly in children living in warm climates. It is frequently complicated by corneal involvement that manifests in a variety of forms including Tranta’s dots; superficial punctuate keratitis; shield ulcer; corneal plaque; corneal neovascularisation; lipid infiltration; bacterial or fungal keratitis; keratoconus; pseudogerontoxon; and corneal opacification.

Even though it is relatively easily diagnosed because of its distinct clinical history and ocular manifestations, VKC requires particular attention and is not easy to manage.

Warm climates and sun exposure probably explain the characteristic north-south gradient prevalence of this form of ocular allergy. VKC is associated with other allergic manifestations in approximately half of patients and often arises in response to exposure to specific allergenic triggers: these observations suggest it does indeed have an allergic component.

Tear levels of IgE and mast cell mediators are high, which supports this conclusion. However, this does not explain the length of the disease, its typical regression after puberty or the fact that it most often manifests in response to non-allergenic triggers such as sunlight, heat and wind. Antigen-specific Th2 cells have not been demonstrated infiltrating the conjunctiva, and several non-IgE-mediated mechanisms are believed to also be involved.

Mechanisms at play

Some of the aforementioned mechanisms may involve the integrity of the epithelial barrier. Whereas the junctional complexes are intact in the normal conjunctival epithelium, denying allergens entry, epithelial barrier dysfunction may be induced by endogenous proteases (e.g., metalloproteases) and environmental assailants including some viruses; components of air pollution; cigarette smoke; house dust mites; and pollens, which have intrinsic protease activity.

Initially, epithelial cells were considered to be a passive barrier impeding allergen penetrance, but we know now that they may recognise allergens and mount an innate immune response with multiple factors such as cytokines, alarmins and endogenous danger signals that activate the dendritic cell (DC) network and other innate immune cells.⁷ As a consequence, local immune responses may be initiated, beginning the transition from innate to adaptive immunity.

In particular, allergens induce the production of reactive oxygen species, which activate DC and epithelial cells through NF-kB activation. The innate immunity of epithelial cells not only recognises microbial invasion but may also respond to pollen components from plants, triggering inflammation.⁷

In fact, in response to allergen recognition, epithelial cells promote Th2 immunity through activation of DCs, by activating innate immune cells such as ILC2s, which can help DCs to polarise Th2 responses in naive T cells.⁸

Increased expression of heat-shock proteins (HSPs) in VKC patients was recently described by Leonardi et al.⁹ The HSP-chaperones are highly conserved during evolution and play essential roles in cell survival; however, they are also implicated in the pathogenesis of various diseases such as some types of cancer and inflammatory and autoimmune disorders.

Expression of HSPs is induced by environmental and oxidative stress and forms a link between adaptive and innate immunity. Increased HSP levels induced by agents known to initiate or aggravate VKC, such as histamine, cytokines and UV-B, indicate an active interaction between the chaperoning and the immune systems, with perhaps a mutual modulatory role between the two systems.

HSP27, HSP40, HSP70 and HSP90 seem to be actively involved in VKC, where they may initiate and perpetuate inflammation.

New mass spectrometric techniques to analyse peptide profiles in human tears may elucidate differences between healthy subjects and patients affected by different phenotypes of ocular allergy and possibly identify target proteins that might be of use in the diagnosis, prognosis and management of VKC and other inflammatory ocular surface conditions.

For example, hemopexin, transferrin, mammaglobin-B and secretoglobin 1D were found to be significantly overexpressed in VKC samples and dramatically reduced after treatment with topical cyclosporine.¹⁰

Genetics of ocular allergy

Recently, collecting and optimally processing sufficient RNA from conjunctival surface cells allowed Dr Leonardi’s group to perform a successful transcriptome-wide expression analysis. Factors involved in both innate and adaptive arms of the immune system, including several Toll-like receptors and other pattern-recognition receptors, were found to be overexpressed in VKC samples.¹¹

In addition, they highlighted the increased expression of multiple chemotactic factors for eosinophils and T cells and multiple co-stimulatory signals required for T-cell activation and survival, confirming that VKC is mostly a cell-mediated pathology.

Larger studies including different types and severities of ocular allergy should reveal significant gene expression trends that can be targeted to improve the treatments available for ocular allergy.

Understanding of the role of these different possible mechanisms involved in ocular allergy will open new therapeutic scenarios leading, for example, to the use of specific topical inducers or inhibitors of key proteins in order to prevent the induction of allergic inflammation on the ocular surface and prevent potential severe complications.

References

1.     World Meteorological Organization. https://public.wmo.int/en.

2.     Annesi-Maesano I. Eur Respir Rev. 2017;26:170024.

3.     Leonardi A, Lanier B. Curr Med Res Opin. 2008;24:2295-2302.

4.     Leonardi A, et al. Clin Exp Allergy. 2015;45:1118-1125.

5.     Leonardi A, et al. Allergy 2012;67:1327-1337.

6.     Leonardi A, et al. Allergy 2017;72:1485-1498.

7.     Lambrecht BN, Hammad H. J Allergy Clin Immunol. 2014;134:499-507.

8.     Li J, et al. Sci Rep. 2016;6:36150.

9.     Leonardi A, et al. Allergy 2016;71:403-411.

10.  Leonardi A, et al. Allergy 2014;69:254-260.

11.  Leonardi A, et al. Presented at ARVO Seattle, 4-9 May 2016; www.arvo.org.

Dr Andrea Leonardi

E: andrea.leonardi@unipd.it.

This article was adapted from a presentation given by Dr Andrea Leonardi at the 2017 EuCornea Congress. Dr Leonardi is an associate professor at the Department of Neuroscience, Ophthalmology Unit, University of Padua, Italy, and a board-certified specialist in ophthalmology and in allergy and clinical immunology. Dr Leonardi consulted for Santen; Thea; Novartis; Dompè; Shire (no fee received); Baush & Lomb; and Faes Farma in 2016-17.