Eosinophilic Esophagitis - Scientific Excitement - Part 1 of 2

The allergy world was abuzz this past week that a major research breakthrough for Eosinophilic Esophagitis (EoE) was published in Nature Genetics (1), spear-headed by Dr. Marc Rothenberg’s lab at Cincinnati Children’s Hospital (follow the lab on FaceBook). For anyone dealing with this devastating allergic disorder, the news was welcome, but what does it all mean? And what could the future hold for people dealing with EoE or allergic disorders more generally?

My hope is to distill some pretty intense science in this two part series – the paper is scientifically very cool, yet very dense! Tackling this paper is not for the faint of heart (myself included)!

PART 1 – BACKGROUND TO UNDERSTAND EoE AND THE RESEARCH FINDINGS.

What is EoE?

The esophagus is the thin muscular tube that propels food/drink between the mouth and the stomach. In medical terms, any part of the body followed by the suffux, -itis, means inflammation of that body part. Thus, esophagitis is inflammation of the esophagus. When eosinophilic is added in front of esophagitis, it means that the inflammation is stemming from eosinophils, a type of white blood associated with the allergic response. Under normal conditions, the lining (mucosa) of the esophagus has very few if any eosinophils. However, if biopsies of the esophagus are taken, stained, and viewed under the microscope, the accumulation of eosinophils in the mucosa is quite striking. (In fact, this is one of the essential diagnostic tests to differentiate EoE from the inflammation caused by gastroesophageal reflux disease, GERD).

Microscope image of a biopsy from an EoE esophagus. Circled in purple is a single epithelial cell (cells that make the mucosa) that lines the esophagus. Circled in red is an eosinophil. Notice the large number of eosinophils (red color) in this microscope field. 

When triggered by allergens, these eosinophils unleash packets of inflammatory chemicals, thus inflaming and potentially damaging any nearby tissue. Normally, this type of response would be reserved for ridding the body of an invading parasite! If untreated, it may cause pain, problems with swallowing, food impaction, sometimes vomiting, and narrowing of the esophagus. Treating the inflammation and identifying/avoiding the triggers, which is often an offending food, is key to reversing the damage.     
                  

I don’t deal with EoE, so what does this paper mean for me?

EoE is medically a growing concern with increasing prevalence. Just as individuals with traditional IgE-mediated food allergies tend to have other allergic disorders – i.e. atopic dermatitis (eczema), allergic rhinitis (nasal allergies), and asthma – the same applies to EoE. An estimated 50-80% of individuals with EoE have another atopic disorder (2).

A recent study suggest that individuals who have outgrown traditional IgE-mediated food allergies may later go on to develop EoE (3). Furthermore, some individuals undergoing oral immunotherapy (OIT)(4) or sublingual immunotherapy (SLIT)(5) may develop EoE. OIT involves consuming increasing doses of allergen over a long period of time (months to years), whereas SLIT involves increasing doses of allergen-containing drops under the tongue. Understanding EoE and identifying who is at risk, will help not only those who currently have EoE, but it could very well help prevent EoE in susceptible individuals.

After I distill the complex science, I will explain why understanding where EoE shares mechanisms with other allergic disorders and where it fundamentally differs from all the others provides important clues for not only EoE, but ALL allergic disorders.  Are you ready to dig deep into the science? Here we go…

Background biology (if you understand DNA & epigenetic regulation, feel free to skip ahead!)

The instruction set for building and maintaining a human being from the beginning (when egg meets sperm) and continuing for an entire lifetime is found in the DNA in each and every bodily cell (with a few exceptions). Our genome is considered the totality of information contained in our DNA – occurring in a specific sequence using only 4 letters – A, T, C, or G. (You can think of it as composing “words” out of an alphabet containing 4 “letters!”).  An entire human genome contains roughly 3 billion “letters,” yet only a very small portion of our DNA may be active at any given time, and it is this precise control over what DNA is active when and where and to what degree that allows our body to use the same exact DNA blue print contained in all of our bodily cells to differentiate our heart muscle cells from our brain cells from our specific immune cells, etc.

DNA is housed in the nuclei of most bodily cells in 23 pairs of chromosomes. The information in the DNA code is contained as a long string of A's, T's, C's, and G's - over 3 billion "letters" for the human genome! Image source: http://www.genome.gov/dmd/img.cfm?node=Photos/Graphics&id=85148

What’s more, our environment (or even our parents or grandparents environment!) can influence how our DNA code gets expressed – epigenetic regulation. Epigenetic regulation of our DNA code does not change the DNA “letters,” but it does influence which sets of letters – i.e. -  genes (“words in the DNA dictionary”) - get turned on/off, and if turned “on” to what degree - much like a light switch with dimming capabilities.

The positive of epigenetic regulation is that it allows an individual to adapt to a rapidly changing environment (remember, an individual’s DNA blueprint of A’s, T’s, C’s, and G’s is primarily fixed for a lifetime). The blessing of epigenetic regulation can also be a curse because it can lead to misregulated gene expression and therefore disease. Misregulation of epigenetics is thought to play a significant role in allergic diseases – i.e., currently unknown environmental culprits underlying increased prevalence of allergic disorders.  Scientists are only just beginning to understand epigenetic regulation. (Epigenetic regulation will be important in Part 2)

The scientists’ approach – Genome-Wide Association Study (GWAS)

Remember that genome refers to the entire instruction set contained in our DNA? A GWAS allows scientists to look at targeted sites across the genome of many individuals. In this case, individuals diagnosed with EoE (n = 736 individuals) had portions of their genome (over 1.5 million sites!) compared to individuals without EoE (controls, n= 9,246 individuals).

Once scientists have all of that DNA data (and it’s a LOT of data), they can begin to extract the meaningful bits, answering the question - which portions of DNA significantly differ between those with EoE and those who don’t have EoE (controls).  This process is a bit like picking out individual flute melodies within the cacophony of the warming up orchestra. As you can expect, there is relatively very little difference in DNA from one human to the next and most differences may end up being useless “noise.” But every now and again, certain regions of DNA differences will stand out consistently between those with EoE and controls.

Of over 1.5 million regions analyzed, only 4 regions definitively passed the “noise test” – e.g. pulling out those flute melodies from the cacophony. On top of this, there may only be one difference in a DNA letter between those with EoE and control (single nucleotide polymorphism – aka – SNPs, pronounced “snips”). Differences in SNPs is like pulling out all of the flute melodies and discovering that one of the flutes plays the note “G” in individuals with EoE and the others play the note “A” in controls. These regions or “SNPs” are said to be associated with EoE – e.g. the “association” in genome-wide association study!

Association vs. causation (i.e. – correlation vs. causation)

While the results of the GWAS alone are exciting, the scientists’ work is far from done. These are regions of DNA that are “associated (or correlated) with” EoE – it does not mean that these DNA differences are the “cause” of EoE. It is entirely plausible that these differences could mean nothing to EoE! This is like observing that that prevalence of food allergy has increased at the same time that prevalence of cell phone use has increased or the prevalence of antibiotic use has increased – these are “associated” with food allergy. In this example, one association seems like a more plausible “cause” of food allergy (i.e. antibiotic use) than the other (cell phone use).

In the next step of this study, the scientists begin addressing which of these “associated” DNA regions may actually be meaningful to EoE biologically.

STAY TUNED FOR PART2!

References (Freely available references are chosen when possible)

1.           Kottyan LC, Davis BP, Sherrill JD,Liu K, Rochman M, Kaufman K, et al. Genome-wide association analysis ofeosinophilic esophagitis provides insight into the tissue specificity of thisallergic disease. Nat Genet. 2014. Epub 2014/07/16. doi: 10.1038/ng.3033.PubMed PMID: 25017104.

2.           Dellon ES. Diagnosis and management of eosinophilicesophagitis. Clinical gastroenterology and hepatology : the official clinicalpractice journal of the American Gastroenterological Association.2012;10(10):1066-78. Epub 2012/06/26. doi: 10.1016/j.cgh.2012.06.003. PubMed PMID:22728382; PubMed Central PMCID: PMCPMC3458791.

3.           Maggadottir SM, Hill DA, Ruymann K, Brown-Whitehorn TF,Cianferoni A, Shuker M, et al. Resolution of acute IgE-mediated allergy withdevelopment of eosinophilic esophagitis triggered by the same food. The Journalof allergy and clinical immunology. 2014;133(5):1487-9, 9 e1. Epub 2014/03/19.doi: 10.1016/j.jaci.2014.02.004. PubMed PMID: 24636092.

4.           Sanchez-Garcia S, Rodriguez Del Rio P, Escudero C,Martinez-Gomez MJ, Ibanez MD. Possible eosinophilic esophagitis induced by milkoral immunotherapy. The Journal of allergy and clinical immunology.2012;129(4):1155-7. Epub 2012/01/13. doi: 10.1016/j.jaci.2011.11.042. PubMedPMID: 22236725.

5.           Miehlke S, Alpan O,Schroder S, Straumann A. Induction of eosinophilic esophagitis by sublingualpollen immunotherapy. Case reports in gastroenterology. 2013;7(3):363-8. Epub2013/10/29. doi: 10.1159/000355161. PubMed PMID: 24163646; PubMed CentralPMCID: PMCPMC3806675.