Into the Breach (Enzymes That Cut up Proteins)

OUTLOOK ALLERGIES STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY GSCHMEISSNER/SCIENCE PHOTO STEVE The orderly layers of healthy skin contrast with the eruptions of eczema (right image). SKIN is a recessive monogenic condition, caused by mutations to the SPINK5 gene. The normal version of SPINK5 encodes a protein that inhibits the activity of certain skin proteases Into the breach (enzymes that cut up proteins). These ser- ine proteases are needed for everyday skin renewal, but if they become active too early, A focus on skin barrier disorders has opened up new as happens with Netherton syndrome, they thinking about how allergies kick in. destroy the younger layers of skin before they mature. Bacteria and other organisms present in the environment also produce proteases, BY CLAIRE AINSWORTH cause allergies — the idea that the epithelium such as those found in pollen and in the drop- is a major player could explain several phe- pings of that bane of asthma sufferers, the n the autumn of 2005, Alan Irvine, a nomena, including why people with atopic house dust mite, whose proteases Der p I and dermatologist at Trinity College Dublin, eczema often go on to get a set of other aller- Der p II damage epithelia. noticed something unusual about a gies. The epithelium is being targeted in new In 2001, a team at the Wellcome Trust Icohort of patients with ichthyosis vulgaris approaches to allergy treatments. Stephen Centre for Human Genetics in Oxford, UK, — a dry, scaly skin disease. Irvine had been Holgate, a clinician and asthma researcher at showed that a particular variant of SPINK5 working with geneticist Irwin McLean at Southampton University, UK, describes it as was strongly associated with eczema and University of Dundee, UK, whose team had “the new boy on the block”. asthma in families with atopy, but who did recently identified two mutations in the gene not have Netherton syndrome. This sug- behind the inherited disorder. But Irvine’s REVEALING MUTATIONS gested to the researchers that lesions in the new observation pointed to something much The conventional view of allergies is that some epithelial barrier might be predisposing bigger: a radical new explanation of what people have an inherited tendency to develop people to eczema, and that the atopy might causes allergic diseases. multiple allergies — a condition known as be secondary. Irvine had spotted that far more ichthyo- atopy — because of a faulty immune response, Three years later came the breakthrough sis vulgaris patients also had atopic eczema dominated by the activity of Th2 lymphocytes involving McLean’s team in Dundee and compared to the general population. Could and a type of antibody called immunoglobulin Irvine’s team in Dublin. Their work focused their skin be at fault? Indeed, could epithe- E (IgE). A decade ago, however, hints started on the filaggrin lium defects be responsible for other aller- emerging that this wasn’t the entire story. gene FLG, which gies too, such as asthma, allergic rhinitis and One clue came from research into a rare This theory shifts is needed to help food allergies, rather than a misfiring adap- skin disease called Netherton syndrome. the blame from keratinocytes form tive immune system as was widely believed? Netherton sufferers have fragile, scalded- the adaptive and moisturise the While the two hypotheses are not mutually looking skin prone to cracking, and they immune response skin’s outer imper- exclusive — faults in both could combine to develop rampant atopy. Netherton syndrome to the innate one. meable layer, the S12 | NATURE | VOL 479 | 24 NOVEMBER 2011 ALLERGIES OUTLOOK is thought that leaky skin allows allergens to penetrate the body and prime the immune SCOPE FOR TREATMENT system for an allergic reaction. Recent work in a murine model tested the concept. Mice Fixing the barriers lacking filaggrin have dry, flaky skin that is abnormally thin and porous; if such mice Academic researchers and pharmaceutical have their skin smeared with ovalbumin, a companies are already investigating protein abundant in egg white, they develop therapies that bolster the integrity of a systemic IgE allergic response to it, while epithelia as a treatment for allergies. normal mice do not. For example, Irwin McLean and “Dermatologists had always said they colleagues at University of Dundee, UK, STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY GSCHMEISSNER/SCIENCE PHOTO STEVE thought that eczema was primarily a skin are searching for small molecules that disease, and that the effects throughout the could boost the production of filaggrin body were secondary to that,” says Brown. and perhaps other components of In the past few years, the field has exploded, the skin barrier machinery in eczema extending the faulty epithelium idea to allergic patients. They are also investigating drugs rhinitis (porous nasal epithelium) and food that could help epithelial cells ‘ignore’ allergies (leaky gut epithelium). so-called nonsense mutations to the FLG The intriguing thing about this theory gene — nonsense mutations are the most is that it shifts the blame from the adaptive common mutations in the filaggrin gene immune response to the innate one. Epider- in northern Europeans, and cause the mal cells, long thought to form only a pas- cell’s protein synthesis machinery to halt sive barrier to invaders, are now emerging part way through translating the genetic as players. Keratinocytes not only present code into the protein. antigens to immune cells, they also secrete Certain kinds of antibiotics called cytokines such as thymic stromal lymphopoi- aminoglycosides are already known to let etin (TSLP), which drives atopic march cells read-through nonsense mutations, (see ‘Marching with allergies’, page S14) as and drugs based on the read-though well as other cytokines that fan the Th2- approach are in clinical trials for other dominated immune response. “The epidermis genetic diseases such as cystic fibrosis. stratum corneum. Only about 1 in 100 north- is quite immunologically active,” says Irvine. McLean and his colleagues have been ern Europeans has ichthyosis vulgaris resulting “It isn’t just inert bricks and mortar.” awarded a patent covering the use of read- from mutations in the FLG gene, but 1 in 10 through drugs, including aminoglycosides northern Europeans is heterozygous, carrying ASTHMATIC COMPLICATIONS such as the off-patent antibiotic one mutated copy and one normal copy. Irvine Meanwhile, asthma researchers are question- gentamicin, for the treatment of ichthyosis noted that the heterozygous carriers, although ing the idea that the adaptive immune system vulgaris and other atopic conditions. free of full-blown ichthyosis, nonetheless had is the sole trigger of allergy. Over the past Such drugs would enable cells to bypass overly creased palms and unusually dry skin, 20 years or so, a growing body of work has nonsense mutations and thereby restore suggesting that it was more fragile than nor- shown that the airway epithelium seems to be filaggrin production. The treatment could mal. They compared 50 children with ichthy- more fragile in asthma patients. For example, help the skin develop a more natural, osis vulgaris with 200 unaffected individuals Holgate’s team in Southampton has shown stronger structure. Gentamicin, however, and found a remarkably strong association that tight junctions, the massive protein has harmful side effects, so the team is between FLG mutations and eczema. complexes that help hold cells together in screening for alternative read-though epithelia, do not assemble properly in the drugs and is following a number of leads MORE THAN SKIN DEEP airways of asthmatic patients. Other teams in cell and animal models. Subsequent work, says Irvine, showed that have found that faults in different protein Another way of strengthening the eczema patients who carry FLG mutations complexes also involved in epithelial cell epithelium is to help it repair itself. The tend to have a more severe form of eczema, junctions are linked to asthma and that the airway epithelium of asthma patients and are more disposed to develop a series of airway epithelium in asthmatics is poorly is known to be poor at self-repair, but other allergies too, a phenomenon known repaired following injury. experiments in tissue culture suggest as the ‘atopic march’ . The finding that filag- What’s more, studies of cultured lung that its ability to regenerate improves grin mutations are strongly associated with epithelia show that several common triggers of in response to growth factors. Holgate’s asthma was a particular surprise, since filag- asthma also disrupt cell junctions, particularly team at Southampton University, UK, is grin is not expressed in the lung. Further- in epithelia from asthmatic patients. And some currently testing the safety and efficacy more, McLean’s dermatologist colleague allergens compound their effect by stimulating of keratinocyte growth factor (KGF) on Sara Brown, also at Dundee, found a strong the immune system. The house dust mite pro- asthma patients. KGF is present in the skin association between filaggrin mutations tease allergen Der p II, for instance, interacts and the lining of the gut, where it promotes and peanut allergy. Filaggrin has not been with innate immune cell receptors called the growth of cells that help repair damage detected in the gut, but is found in the lining Toll-like receptors, triggering a ‘danger signal’ and maintain tissue strength. Work by of the mouth as well as in the skin. that attracts the attention of the adaptive other researchers in Lille and Paris, These and other findings, including the immune response. “If you add that to the France, on a rat model of asthma suggests link between atopy and another rare fragile epithelial weakness,” says Holgate, “you have a that KGF can reduce inflammation and skin disorder called peeling skin syndrome, perfect storm.” ■ leakiness in the airway epithelium, as are consistent with the idea that allergies are well as making it more resistant to being triggered by a leaky epidermis.

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