Major Shift in Understanding How Eczema Develops (God Bless these Scientists!)

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Now this is some very interesting news. I remembered when someone on the LEF board told me that there probably is a connection between eczema, leaky gut as well as a permeable BBB. The malfunctioning in all these conditions seems to be based on a similar mechanism and as that person told me is connected to each other. In all three conditions the tight junctions seem to malfunction. Here we have a new study that at least confirms that eczema is a disease where permeability of the skin (tight junctions) is the cause.

Manipulating permeability could be a key factor to many diseases as well as their treatment.

http://www.sciencedaily.com/releases/2010/12/101217145920.htm

ScienceDaily (Dec. 18, 2010) — Like a fence or barricade intended to stop unwanted intruders, the skin serves as a barrier protecting the body from the hundreds of allergens, irritants, pollutants and microbes people come in contact with every day. In patients with eczema, or atopic dermatitis, the most common inflammatory human skin disease, the skin barrier is leaky, allowing intruders -- pollen, mold, pet dander, dust mites and others -- to be sensed by the skin and subsequently wreak havoc on the immune system.

While the upper-most layer of the skin -- the stratum corneum -- has been pinned as the culprit in previous research, a new study published in the Journal of Allergy and Clinical Immunology found that a second skin barrier structure, consisting of cell-to-cell connections known as tight junctions [edit: implicated in leaky gut as well], is also faulty in eczema patients and likely plays a role in the development of the disease. Tightening both leaky barriers may be an effective treatment strategy for eczema patients, who often have limited options to temper the disease.


"Over the past five years, disruption of the skin barrier has become a central hypothesis to explain the development of eczema," said Lisa Beck, M.D., lead study author and associate professor in the Department of Dermatology at the University of Rochester Medical Center. "Our findings challenge the belief that the top layer of the skin or stratum corneum is the sole barrier structure: It suggests that both the stratum corneum and tight junctions need to be defective to jumpstart the disease."

Currently, there are no treatments that target skin barrier dysfunction in eczema. To treat eczema, which causes dry, red, itchy skin, physicians typically prescribe anti-inflammatory drugs, like prednisone, and a variety of topical anti-inflammatory creams and ointments. But, modest benefit, negative side effects and cost concerns associated with these therapies leave patients and doctors eagerly awaiting new alternatives.

"We want to figure out what current eczema therapies do to both barrier structures and start thinking about new treatments to close the breaks that let irritants in and water out and subsequently drive the inflammation and dryness that is characteristic of the disease," noted Beck, who treats eczema patients in addition to conducting research on the condition.

To better understand the role of tight junctions in eczema, Beck and her team studied skin samples from eczema patients and healthy individuals. Using resistance and permeability tests, they discovered that tight junctions, which act like a gate controlling the passage of water and particles, were strong and tight in healthy skin samples, yet loose and porous in the skin of eczema patients.

On further investigation, they found that a particular tight junction protein, claudin-1, which determines the strength and permeability of tight junctions in skin, is significantly reduced in the skin of eczema patients, but not in healthy individuals or individuals with psoriasis, another common chronic skin disease. They demonstrated that reducing claudin-1 expression in skin cells from healthy donors made the tight junctions leaky and more permeable, a finding in line with results of other research groups.

"Since claudin-1 was only reduced in eczema patients, and not the other controls, it may prove to be a new susceptibility gene in this disease," said Anna De Benedetto, M.D., postdoctoral-fellow at the Medical Center and first author of the new study. "Our hypothesis is that reduced claudin-1 may enhance the reactivity to environmental antigens and lead to greater allergen sensitization and susceptibility in people with eczema."

If the team's hypothesis stands up in future research, increasing claudin-1 to combat eczema could be a new treatment approach worth exploring. The University of Rochester has applied for patent protection for increasing claudin-1 with drug compounds to treat eczema.

Barrier problems, and in particular tight junction defects, are recognized as a common feature in many other inflammatory diseases, such as inflammatory bowel disease and asthma, where the lining of the intestine and the airways is weakened, which is why Beck and her team decided to focus on the role of this barrier structure in eczema.

Eczema affects up to 17 percent of children and about six percent of adults in the United States -- close to 15 million Americans. While there are varying severities of eczema, all have an itch that can make it difficult to focus on daily activities and to sleep. People with eczema are often counseled to minimize their exposure to allergens, but that is a difficult task given the hundreds of allergens people are exposed to each day.

Beck, who began the research while at Johns Hopkins University, plans to build on these findings by investigating the immunologic consequences of tight junction disruption in the skin and whether there is a relationship between barrier disruption and subjects' intractable itch. In addition, as part of a contract with the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, called the Atopic Dermatitis Research Network, Beck, in collaboration with Kathleen Barnes, Ph.D., at Johns Hopkins, will perform gene mapping of claudin-1 to try to identify mutations in patients with eczema.

The current research was funded by the Atopic Dermatitis and Vaccinia Network at NIAID, the National Eczema Association and the Mary Beryl Patch Turnbull Scholar Program. Along with Beck and De Benedetto, Andrei I. Ivanov, Ph.D., Steve N. Georas, M.D., Kunzhong Zhang, Ph.D., Sadasivan Vidyasagar, M.D., Ph.D., and Takeshi Yoshida, Ph.D., from the University of Rochester Medical Center participated in the research. Scientists from Johns Hopkins University School of Medicine, National Jewish Health, the University of California, San Diego, Children's Hospital Boston, Oregon Health & Science University, the University of Bonn (Germany), Technische Universitt Mnchen (Germany) and Johns Hopkins Bloomberg School of Public Health contributed as well.
 

Cort

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Fascinating stuff Diesel - love to hear those pistons pumping. Love the connection with the gut. It makes me wonder about the blood:brain barrier as well - another area that has to maintain the right kind of permeability. It sounds like a whole new realm of research.

This seems so much like the gut;
close the breaks that let irritants in and water out and subsequently drive the inflammation and dryness that is characteristic of the disease,
 
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Fascinating stuff Diesel - love to hear those pistons pumping. Love the connection with the gut. It makes me wonder about the blood:brain barrier as well - another area that has to maintain the right kind of permeability. It sounds like a whole new realm of research.

This seems so much like the gut;
So true. The puzzle starts piecing together. It's just a matter of time.
 

Glynis Steele

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And don't forget that d-lactic acid crosses the bbb, and causes symptoms very similar to CFS, severe lethargy, changes in gait, slurred speech, or difficulty in speaking, hyperventilation, confusion, disorientation, dizziness, the feeling of being drunk without having had a drink, headaches, jaw clenching, carb craving and irritability.

BW

Glynis
 

Mark

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I find this very exciting as well: for me personally it fits very well with a theory I've had for ages about my own illness. One of my major symptoms is skin irritation/sensitivity without rash, and the way that works in practice is pretty bizarre, but without going into details now I've long believed that there has to be some sub-cutaneous protective barrier that is broken in me and that allows certain types of chemicals/pathogens to pass straight through and get inside when they normally couldn't. My other major symptom is IBS (these are the two things I'm left with, as sensitivities, after dramatically improving everything else while on the methylation block-clearing protocol) so...I would be surprised if my tight junctions are intact...

The interesting clue I have on this is a singular event around about the time of onset (also around the time when I started getting weird cold sweats at night) which I've recently read described in just the same terms I would describe it on a site for "Morgellon's Disease". I stayed overnight at a friend's house, and had a horrific night of itching in the bed I slept in. It was similar, but different, to the type of itching I have permanently now whenever my skin touches new clothing, bedding, soft seating, etc. In this one-off onset event, it felt like millions of minute insects or microbes were crawling around under my skin: first, gradually, in patches, but accelerating and seemingly a cascade reaction which felt like it was spreading throughout my whole body. It really did feel like there was something living, insect-like...moving...so I reckon I can relate to where that part of the Morgellon's description comes from...though that's just what it feels like of course, and attributing it to a living parasite is a leap, and an assumption. "They" call the Morgellon's phenomenon "delusional parasitosis" of course, on the basis that it must be a delusion because "they" can't see anything...hmmm...who's really deluded here?...
 
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ScienceDaily (Feb. 9, 2011) — So-called barrier sites -- the skin, gut, lung -- limit the inner body's exposure to allergens, pollutants, viruses, bacteria, and parasites. Understanding how the immune system works in these external surfaces has implications for understanding such inflammatory diseases as asthma, psoriasis, IBD, and food allergies, all of which occur at the body's barriers.
David Artis, PhD, professor of Microbiology at the University of Pennsylvania School of Medicine, and Gregory F. Sonnenberg, a predoctoral fellow in the Artis lab, have identified an immune cell population that acts as the body's border patrol with the outside world. They discovered that these lymphoid tissue inducer cells maintain immunity in the intestine of mice. The research appeared in the most recent online issue of Immunity.
Following infection by Citrobacter rodentium -- a model of human E. coli infection in the gut -- this cell population was the dominant source of IL-22, a molecule that helps in the immune response during the early phases of infection. When the inducer cells were eliminated from the intestine of the experimental mice, immunity was impaired, affecting the production of anti-microbial proteins required to fight infection. The mice eventually died.
This discovery could also represent a new line of research for HIV/AIDS, says Artis, since there is a breakdown of barrier immunity in the gut (a reservoir for HIV) that can lead to full blown AIDS. Therapeutics to target such immune cells could be an important new way to combat AIDS.

The research was funded by the National Institute of Allergy and Infectious Diseases, the Burroughs Welcome Fund, and the Crohn's and Colitis Foundation of America.