Common Mechanisms and Uncommon Questions: Atopic Dermatitis and Ocular Allergy

In this feature video, Dr Debajyoti Ghosh discusses the common etiologic components of atopic dermatitis and ocular allergy, aka allergic eye disease, following his study, “Atopic Dermatitis and Ocular Allergy: Common Mechanisms and Uncommon Questions.”

Debajyoti Ghosh, PhD, is a research instructor and biomedical research scientist of internal medicine at University of Cincinnati in Cincinnati, OH.

Transcript:
What common etiologic components such Th2 immune signaling have been suggested for atopic dermatitis (AD) and ocular allergy aka allergic eye disease (AED)?

There is a lot common going on between two different conditions. So for example, like you just mentioned, the Th2 pathways and there are additional pathways are in common like Th17, Th31, Th32 for signaling pathways. But obviously, like you said, Th2 pathways are most obvious commonality between two different conditions.

So, one very dominant allergic eye disease can be seasonal conjunctivitis. Those are manifestations of common allergic diseases induced by exposure of conjunctival exposure to pollen, for example. So they induce pollen contents, allergens and our conjunctiva associated lymphoid system, which is exposed to allergens present in Pollen. And so those allergens, they augment the production of IgE and IgE and Th2 switching, producing like IL-4 mediated pathways, IL-4 and IL-13 mediated pathways, which induce Ig production eosinophilia and eventually eosinophils mast cells. Those and other lymphocytes, activated lymphocytes, they migrate to our conjunctiva and they contribute to manifestation of symptoms.

And I just wanted to mention another thing which is not pretty much allergen dependent, which is protease dependent and like oxidative stress. So pollen contains, a lot of pollen contains several proteases. Many proteases are strong inducer of Th2 responses. So the proper Th2 responses and then they actually degrade tight junction proteins. So those cementing things present in between cells, conjunctival cells, so the increasing bioavailability of allergen molecules. So yeah, so the proteases are great like adjuvant to induce allergy, eye immune responses. So those are pretty much common pathways mechanisms, path of mechanisms between ad and allergic eye diseases.

Can you describe the differentially regulated genes and pathways relevant for AD disease manifestations?

This actually, this question is very central to a lot of allergic diseases and very close to my heart. So that's what I have been doing for several years. So we started, but it's an era of big data and a lot of big data, genomic data or transcriptomic data are available in the public domain for secondary analysis to obtain powerful insights, mechanistic insights. So we actually pulled such data, transcriptomic data sets from five independent studies on atopic dermatitis skin transcriptome. Surprisingly we found that for example, the genes that are up regulated and down regulated, they've had between studies, they've had a lot. So that how I got interested to look deep into the problem and I found that, well these five studies, each study reported different genes but different up regulated and down regulated genes. But they are actually the members of same different pathways. So we captured the members of different pathways.

Imagine the elephant, the story of the elephant, someone grasp the tail, some the trunk, some the legs. But actually that is come if you capture, if you have a holistic approach, this kind of the same elephant. So that's how we ended up in finding from the big data. We found that different groups reported different market genes, biomarkers, but they belong to same pathways, same different pathways functionally in functional terms, we found they're barrier function proteins, skin barrier function, proteins, those are normally down regulated in a.d. Then we have acute protease and protease inhibitor homeostasis genes. We have lipid metabolic genes in the skin because usually ad skin is very dry and leading to a high transepidermal water loss. So proteases are active there. And then the lipid pathway, so lipid synthesis is down-regulated, particularly ceramides. And then there is a dysregulated Th2 and inflammatory cytokines, chemokines. So those are major functional clusters of genes involved in an ad scheme.

How can emerging noninvasive ocular sampling techniques be used to understand similar information for AED?

Actually, this is the need of the hour. So emerging non-invasive techniques might include cytologic brushing and using cytologic brushes. We can collect samples, Ocular samples which can be analyzed by flow cytometry to find out the cellular populations present there like lymphocyte, activated lymphocytes, CD four, CD eight cells, and other cells. And then we have tear proteomics, tear sample proteomics and lipidomics. And then we can use swabs to get samples. So this is a very important area and growing very fast because our proteomics facilities all over the world is actually becoming more and more powerful nowadays. So in other words, we can use very minute microgram amount of samples to capture lots of genes, proteins, and pathways and networks. So that's fantastic. And simple, small amount of samples, big data, small amount of samples from small amount of samples to big data. And that's what we need because that is also very important to find out disease mechanisms and endo types.

So, disease endo types. Disease endo types are like disease subtypes and with minor variations in underlying mechanisms. And capturing endo types is very important for personalized medicine because these are all very complex diseases involving a lot of genes and proteins. So endo typing is very important. And to get disease endo types, we have to actually collect a lot of patient samples to get optimal statistical power. So the sample sizes should be high and like invasive techniques, usually patients are not very, it's not suitable for a lot of patients, particularly pediatric population. So that's why we need to develop non-invasive techniques for ad, there's a lot going on in this area. For example, the skin stripping, skin taping, tape strips. Which can collect samples for transcriptomic studies and lipidomic studies and very useful for pediatric population and collecting samples from larger patient populations, different patient populations and in small-time, non-invasively. So this area is fast-growing.

Can you describe the emerging evidence that indicated a reduction in goblet cell number and mucin production in a subpopulation of patients with AD leading to adverse ocular outcomes?

This is the age of biologics, so humanized monoclonal antibodies, pathway blockers and so on. So with the use of these biologics, we can specifically block certain pathways. For example, dupilumab, which blocks I L four I L 13 signaling pathways. But a significant number of patients can develop treatment associated eye problems, eye diseases. So there is a need to find why it happens. So there are several hypothesis. So we have right now very convincing data that I L 13 pathways pathway blocking can down regulate mucin production. And so actually I think in 2015, so quite a few years ago, quite a while ago, US group used cultured conjunctival cells and treated them with i L 13 blockers blocking treatment. And they found that I L 13 is very important. I L four I L 13 signaling is very important for proliferation of cultured conjunctival cells. If you block that pathway, so this proliferation goes down, so mucin production goes down and goblet cell intercarpalia cellular goblet cells proliferation goes down. So that was one of the very early and kind of convincing evidence. So in 2019, another Dutch group, a Dutch group actually reported they collected ocular samples and did histologic analysis. They found significant downregulation in ocular goblet cell numbers in dupilumab treated patients versus untreated normal controls. So that was a very great another evidence. And there are more recent accumulating evidences showing that dupilumab treatment actually down regulates mucin production and goblet cell proliferation in patients.

Are there any tips or insights you’d like to share with your dermatologist colleagues regarding atopic dermatitis and ocular allergy?

Yeah, like I said, it's an age of big data. It's also in age of biologics. So at this point biologics will be, and we can foresee that biologics will be more and more used down the line. So three different conditions. So we have seen in case of dupilumab, which blocks I L four I L 13 signaling, there are other biologics like lupikizuma, which also blocks I L 13 signaling and is associated with similar eye problems, eye disorders. So this is kind of a pacing problem right now. And this investigation, this field of investigation, we can see that it will continue to increase and more and more pharmaceutical industries and also academia will be investing more efforts and funds in this area.

And one of this, I would say it's important to find out some kind of biomarker which can predict early on to who is going to develop a treatment associated eye problems. Usually most of these problems are self-limiting, but does not require association of the treatment. But, it can. There are evidences that it can happen at some time. So although it's rare, but we have to stop the treatment and resume to the eye problem and resume other treatment so that it can happen. So we need a good biomarker, OMIC's best biomarker to find out who is susceptible to this, to predict early on and which personalized treatment is the best for that patient endotype or the disease endo type. So it's a great area, field of research where dermatologists can join hands with ophthalmologists and with basic scientists who works on OMIC's based data and data analysis to find out perfect gene signatures and personalized, better personalized treatment for these conditions.

Reference
Ghosh D, Mersha TB. Atopic dermatitis and ocular allergy: common mechanisms and uncommon questions. Curr Opin Allergy Clin Immunol. 2023;23(5):383-389. doi:10.1097/ACI.0000000000000931