Benign bacteria help T cells signal skin infection

Benign bacteria on our skin partner with T cells to alert the immune system to the presence of dangerous pathogens, according to research recently published online in the journal Science.

The NIH press release explains the science very well, probably better than I could, so I have copied their text below.

The most relevant point that I can see is that this work shows that microbes living on healthy skin have an important role in our immune system. It's a philosophical question whether the microbes are separate from us--or are part of us, even though they don't share our DNA. If you overuse antibiotic ointments (that is, apply them for periods longer than required to treat an infection), you are killing off helpful microbes and weakening your immune response.

NIH team describes protective role of skin microbiota
Commensal bacteria and immune cells work together to fight harmful microbes

WHAT: A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction with microbes in the environment.

Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin—collectively known as the skin microbiota—also have a beneficial role. Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin. Their findings appear online on July 26th in Science.

The investigators colonized germ-free mice (mice bred with no naturally occurring microbes in the gut or skin) with the human skin commensal Staphylococcus epidermidis. The team observed that colonizing the mice with this one species of good bacteria enabled an immune cell in the mouse skin to produce a cell-signaling molecule needed to protect against harmful microbes. The researchers subsequently infected both colonized and non-colonized germ-free mice with a parasite. Mice that were not colonized with the bacteria did not mount an effective immune response to the parasite; mice that were colonized did.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues—skin, gut, lung—have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities.

This study provides new insights into the protective role of skin commensals, and demonstrates that skin health relies on the interaction of commensals and immune cells. Further research is needed, say the authors, to determine whether skin disorders such as eczema and psoriasis may be caused or exacerbated by an imbalance of skin commensals and potentially harmful microbes that influence the skin and its immune cells.

"Red skin syndrome" hyped, but real

A while ago I got a news alert linking to a disturbing press release claiming that topical steroids, commonly prescribed to treat eczema, were in some cases intensifying disease symptoms.

From the release:

Using mild over-the-counter hydro-cortisone creams to a range of prescription steroid creams, one's skin can become addicted in less than two weeks of usage and develop worsening symptoms that appear to the [sic] be simply spreading Eczema. However the problem is worsening from the medication.

Press releases usually contain news. So what is news here? The release was published by a 501 (c) (3) nonprofit called “The International Topical Steroid Addiction Network,” founded by a dermatologist, Marvin Rapaport, and Kelly Palace, a former patient of Rapaport's. Rapaport practices in Beverly Hills, California.

It's not news that strong steroids are bad for you. But I hadn’t heard of the phenomenon described by ITSAN before. As I always do when I hear of unfamiliar scientific or medical concepts, I turned to PubMed, the NIH’s database of published papers. I performed searches for "topical steroid addiction," "corticosteroid addiction," and "steroid addiction." In my experience, well-established concepts leap out of PubMed with thousands of hits.

Topical steroid addiction just barely surfaced above the noise at first. It’s hard to find, but it’s there—in three papers by Rapaport. 

But then, as I dug around, more results began to appear. The problem is that the papers all use different words to describe the central condition, which (on the face at least) is most precisely labeled “steroid-induced rosacealike dermatitis,” commonly called “red skin syndrome.” A review for practicing physicians can be found here.

The first case of red skin syndrome was reported in 1957. So “topical steroid addiction,” as described by ITSAN, is a real, if not new, condition. I don’t know how many patients it affects, but according to some PubMed results I found, it is well-known in India and China, where it may be emerging because stronger steroids are now being more widely prescribed--and perhaps more casually used.

In my opinion ITSAN’s site is garish and alarmist (do they really need that banner image of a crying girl?) and their focus on Rapaport comes across as promotional. In the "About Us" section, they ask:

Could the reason for this huge increase [in the incidence of eczema in the West over the past 30 years] be the use of topical steroids causing Steroid Induced (spreading) Eczema, an iatrogenic (adj.where a medical treatment causes a condition) skin disease?

In a word: no. But the information on the FAQ section of their site looks useful. If you think topical steroids are your biggest problem, then why not stop cold turkey and see if you experience the flareup and cooldown that seem to be typical of addiction?

Will we see gene therapy for eczema?

The European Commission is close to approving the first gene therapy in the Western world, according to the New York Times.

The treatment, called Glybera and developed by the Dutch company uniQure, treats a rare condition in which people are unable to break down fat-carrying molecules.

Gene therapy is one way that I imagine patients of the future might be cured of eczema. Glybera gives us a peek into how that might happen.

In gene therapy, doctors replace a patient’s faulty gene with a good one. The large protein filaggrin is currently the best candidate for eczema gene therapy. Several studies have linked filaggrin mutations to a higher risk of developing eczema.

Filaggrin gene therapy would have to be applied early in life. This is because in our current understanding, eczema is caused by a skin barrier defect that allows allergies to develop after a critical time window. Filaggrin mutations cause a faulty skin barrier. So you’d have to fix filaggrin early, because waiting too long would allow allergies to develop, after which fixing filaggrin solves only half the problem.

Glybera is a biotherapeutic, a gene (length of DNA) that is attached to a well-characterized and benign virus. Doctors will inject Glybera into leg muscles, where the virus infects cells and incorporates itself and the therapeutic gene into the patient's DNA—but only in leg muscle cells, presumably because Glybera gets absorbed locally. Then the patients will be able to break down the fat-carrying molecules, and their blood will no longer be overloaded with fat.

A biotherapeutic for eczema would likely be an intact filaggrin gene incorporated into a similar virus.

Gene therapy for the skin would have to be restricted to skin cells. You could accomplish this with a topical cream or ointment applied in the clinic. I'm guessing you would want to treat your whole skin, not just spots that were flaring up at the time.

How long will it last? The effects of Glybera apparently last for years, probably because muscle cells live a long time. Skin cells are a different matter—they are turning over continually. This could turn out to make gene therapy for skin conditions near-impossible.

But perhaps you could take regular doses—pills or injections—of a gene therapy that includes a genetic switch that turns on only in skin cells.

The critical early window for developing allergies in eczema patients could turn out to be a bonus in disguise. Maybe filaggrin gene therapy would only be required during a window of a few years, after which it could be discontinued and allergies would never develop.

Obviously extensive clinical trials for safety would be necessary. I could imagine this type of therapy becoming available within two decades. My grandchildren could be among the first to benefit.

The NEA should join Faster Cures nonprofit group

Unless you live under a rock, you’ve probably heard of the Michael J. Fox Foundation for Parkinson’s Research. Fox, the "Back to the Future" etc. megastar who developed early onset Parkinson’s disease, created the foundation to back research leading to a cure.

The Michael J. Fox Foundation is only one of many members of The Research Acceleration and Innovation Network (TRAIN). TRAIN is a child of Faster Cures, the nonprofit patient advocacy organization based in Washington, DC.

Look at the list of TRAIN member organizations. Isn’t it amazing how many diseases there are for which we need scientists and entrepreneurs to develop cures?  But I don’t see the National Eczema Association on the list. I think the NEA should join TRAIN.

Although most of the diseases represented on the member list are terminal or degenerative, and eczema is neither, those of us who suffer from it can attest that it seriously affects, and in the worst cases ruins, our quality of life.

According to the Faster Cures website,

[TRAIN] was established to create opportunities for medical research innovators to discuss and tackle the challenges that cut across diseases. It is a group of unique nonprofit foundations that fund medical research across a spectrum of diseases, from breast cancer to Parkinson's disease. In many cases TRAIN's member foundations have been created by patients and their families who are frustrated by the slow pace of change in the traditional medical research system. They represent the kind of organizations that are fast becoming the engine behind innovation in disease research--collaborative, mission-driven, strategic in their allocation of resources, and results-oriented. They are organizations that have a singular focus on, and a significant stake in, getting promising therapies from the laboratory bench to the patient's bedside as rapidly as possible.

There’s no reason that I can see that the NEA shouldn’t be part of TRAIN. It looks easy to join. What would it get us? From what I can see, TRAIN provides good models for how to set up sponsored research programs, preclinical and clinical trial templates, agreements for how to share biological samples, etc. I don’t run a patient advocacy organization, so I don’t know firsthand how useful this sort of thing could be, but I imagine that it would be a lot easier to grab a template for a clinical trial than to write one from scratch. 

I read Fox’s biographical book “Always Looking Up,” published in 2009. His optimism is infectious. Read that book. You won’t regret it!

Do you have a tattoo?

Last Sunday, people-watching at a park with the family, I remarked to my wife how some people like to get tattoos on their necks or arms. You just can't miss a neck tattoo. It conveys a certain je ne sais quoi. Actually, in California, it conveys that you belong to a gang.

"Why would you get a tattoo?" I asked.

"Well, my sister has a giant eagle tattooed on her back," she said.

I didn't know that. My sister-in-law is a bit of a daredevil, and as she nears 40 with two kids, still enjoys the flying trapeze.

"Yes, she did it in her 20s."

And here I must admit that I did, briefly, in my 20s, consider getting a tattoo. It was during my summer in the Canadian military reserves, at Camp Gagetown, New Brunswick. A bunch of mates and I were off-duty at the Canadian equivalent of the Px, as it was too early to start drinking. One guy pointed out a tattoo parlor. "Hey, let's all get tattoos," he said. There was a folder with art samples you could ask to have permanently inked into your skin. I examined the catalog. It seemed to consist exclusively of logos of heavy-metal bands. Jazz being more my thing, I excused myself to get an icecream cone, while my mate rolled up his sleeve, indicating his preference to display an image of Mötley Crüe's "Dr Feelgood" on his bicep until the day he died.

I wonder whether he still feels good about that decision.

That summer was remarkable for me. My eczema completely cleared up. I suspect it was because, being a trooper, I was ordered around the whole time and never had to make a decision for myself. (I kid you not--on the first day, we spent hours learning how to take one step forward.) No decisions, no stress. The warrant officer could singe my ears blue with profanities, informing me that the way I was shouldering my rifle was far from ideal. It didn't matter. I just marched where I was told.

But even then, with perfect skin, I knew that getting a tattoo would be a bad idea. I think I've had eczema on every square inch of my skin since then. Every square inch. What does eczema do to a tattoo? If you scratch, does the ink get torn up and the picture blotched? I'd think so.

Have you gotten a tattoo?