Surprise: Th2 cells, inflammation high in both allergic, non-allergic eczema

When I talked to Jon Hanifin last year he mentioned an intriguing fact: eczema comes in two general types. About 80% of atopic eczema patients have allergies and high levels of IgE antibodies. But twenty per cent of patients have eczema without allergies.

The technical term for allergic eczema is “extrinsic” atopic dermatitis; the non-allergic kind is “intrinsic” AD.

Production of IgE—and most antibodies—is activated by type 2 helper T cells. So scientists have generally assumed that extrinsic AD patients had overactive type 2 helper T cells. But new research shows that type 2 helper T cells are overactive in both intrinsic and extrinsic AD patients.

The scientists, led by Emma Guttman-Yassky at Rockefeller University in New York City, analyzed skin and blood samples from 42 extrinsic and 9 intrinsic AD patients, looking at molecular and cellular differences in the immune system and the skin.

They found that type 2 helper T cell activation is actually higher in intrinsic AD patients than extrinsic AD patients. In fact, markers of inflammation in general are higher in intrinsic AD.

Figure 6 from the paper. Scientists now resort to "word clouds" to convey the complexity of molecular biology!

The results are surprising. Patients with intrinsic AD generally do not go on to develop asthma or allergic rhinitis; yet if you just looked at their helper T cells you’d think they were guaranteed to experience even more severe allergies than those suffered by extrinsic AD patients.

So what's keeping down the IgE levels in intrinsic AD? In the paper, the authors speculate freely, but so far there is no answer.

It also appears that a special class of helper T cells known as type 17 (so-called because they produce the signaling molecule IL-17A) are also more active in intrinsic than extrinsic AD. It’s not clear yet how scientists might  use this knowledge to design therapies more specific than current T cell-suppressing options such as ciclosporin, which can have severe side effects.

The research suggests that future T-cell related therapies will likely be similar for intrinsic and extrinsic AD, despite the different nature of the disease in the two patient groups.

Hat tip to KMO.

Scientists find a molecule that recruits white blood cells to site of allergic itch

A type of white blood cells called neutrophils combines with helper T cells to create inflammation due to skin contact with allergen, a group of scientists led by Raif Geha at Harvard Medical School has shown in a mouse model of eczema.

The researchers showed that by blocking the neutrophils' ability to produce a signaling molecule called leukotriene B4 (LTB4), they could prevent the accumulation of both neutrophils and T cells, and hence inflammation, in skin that had been mildly irritated and exposed to a model antigen.

The research was published in the journal Immunity. [paper] [media summary]

The scientists were investigating the role of neutrophils, which are attracted to the site of scratching. They suggest that blocking LTB4's interaction with its receptor (not necessarily by the drug they used, bestatin) could prevent sudden eczema flares in patients that were exposed to something they were allergic to.

The research doesn't sound immediately useful to me, as the real problem with eczema--or atopic dermatitis--is that in general we don't know the cause, and flares aren't usually triggered by direct exposure to something you're allergic to. But it is interesting to learn that neutrophils are flooding scratched skin, and that they are recruiting other neutrophils and T cells--I would like to see whether a drug reducing this phenomenon might calm down itch. As always, the details are in the drug discovery process: finding something that works, isn't toxic and doesn't have weird side effects.
  

Scots could benefit from vitamin D in the winter

A moderate dose of ultraviolet light during the winter months increases the levels of vitamin D in the blood and appears to put a brake on the T-cell arm of the immune system--which could reduce the severity of autoimmune disease, a new small-scale study on a group of Scottish patients has shown.

The research was led by Mark Vickers and Anthony Ormerod, a professor and clinical reader in dermatology, respectively, at the University of Aberdeen. It was reported in the Journal of Allergy and Clinical Immunology.

The trial was conducted between December and March, 2012. Before and after exposing 24 subjects repeatedly to the equivalent of a quarter of a day's worth of summer sunlight, the scientists measured blood levels of vitamin D; the fraction of white blood cells comprised of "regulatory" T cells; and the degree to which T cells expanded their numbers when stimulated.

Regulatory T cells are a subset of T cells known to suppress the activity of other T cells. According to Wikipedia, "Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer, and facilitate organ transplantation." Eczema with an allergic component qualifies as an autoimmune disease.

The scientists found that, after two weeks' exposure to UV, vitamin D levels increased by 50%; after four weeks, by 100%. The fraction of regulatory T cells increased threefold, and other classes of T cells reacted less vigorously to stimulation.

While I am always interested in the connection between vitamin D, T cells, and eczema--I wonder whether this study really tells us anything new. The American Academy of Dermatology says there is no safe recommended level of exposure to UV (because of the risk of skin cancer).
The connection between vitamin D and regulatory T cells appears to be well-established, according to a PubMed search I just did. And everyone knows that regulatory T cells suppress other T cells.

Having spent several years in the north of Scotland myself, I well know how little sunlight the Scots get in the winter. Were the subjects' vitamin D levels low to begin with? I bet they were. Could they benefit from supplements? Almost certainly.

Especially since, as I recall, the Scottish diet consists largely of chips, lager, and cigarettes!

An immune link between the gut and the skin in eczema

New research led by Raif Geha at Children's Hospital Boston has revealed how the immune system connects the gut to the skin, and thus how food allergies may affect the skin.

The connection is made by helper T cells. Geha and his team were investigating, in mice, how it is that an allergic reaction that the body has to a food--and we all know that the usual way that food enters the body is when we eat it--can manifest as an eczema-type reaction when the food is rubbed on the skin. Not eaten; rubbed on the skin.

The authors of the paper claim that this is a common occurrence but I beg to differ. I've never heard of it. But they put a lot of work (and taxpayers' money) into their experiments, and their results are intriguing.

Helper T cells are white blood cells whose job it is to detect foreign material in the body, and when it's detected, to stimulate B cells to produce antibodies. What I didn't know was that there are distinct populations of T cells, determined by molecules embedded in their outer membranes, which home in on different regions of the body. Some go to the gut; some to the skin; presumably, some to the lungs, etc. What happens is that the molecules in their membranes will bind specifically to "adhesion molecules" that are found in these different regions. A T cell that homes to the gut will stick to the adhesion molecules in the gut but not the skin.

And Geha and colleagues find that T cells that originally home to the gut can be reprogrammed to head to the skin instead. They immunized mice with the egg protein ovalbumin, and then later observed what happened when ovalbumin was applied to the skin of the mice. Normal mice developed eczema-like inflammation at that spot. Mice that had been genetically engineered with T cells that did not have the skin-homing surface molecule CCR4 did not show signs of eczema. In a truly gruelling series of experiments carried out late at night by grad student slaves, the authors showed that the initial immunization generated a bunch of gut T cells specifically programmed to hunt down ovalbumin; the body then modified these T cells to head to the skin. The reprogramming takes place in the lymph nodes.

I find this fascinating; I didn't know there was such a pathway. It could be that (in the way distant future) someone will develop a way to treat eczema patients with well-defined food allergies, and in these patients prevent the food-antigen-specific T cells from homing to the skin.

The research raises one huge question for me, though. Most eczema related to food allergy does not occur because we rub food on our skin. (At least, I know that I'm allergic to parmesan, but I sure as hell don't go rubbing it on the backs of my knees.) So what is going on to connect the gut to the skin and cause inflammation in the majority of eczema patients?