KEYSTONE, COLO. - Lack of the keratin-binding protein filaggrin in the skin's epidermis contributes to immune dysregulations that serve to retard defenses against allergens and microbes such as Staphylococcus aureus, helping pave the way for atopic dermatitis and, possibly, a lifetime of allergies.
Learning how those allergens work in concert with an inflammatory cytokine called thymic stromal lymphopoietin (TSLP) may illuminate a key link between filaggrin deficiency and a "Th2-type milieu," thus helping researchers develop an agent that could prevent atopy, Dr. Donald Y. M. Leung reported at a meeting on allergy and respiratory diseases.
Dr. Donald Y. M. Leung
Such an agent would be a welcome addition to current options for the management or prevention of atopic dermatitis (AD), which has a higher prevalence in young children than do food allergies, asthma, and allergic rhinitis.
"Atopic dermatitis is one of the few diseases where we can actually see what's going on, using biopsy or noninvasive techniques, to actually sample which of the proteins are changing and then intervene, I think, in a very scientific way," said Dr. Leung, head of the division of pediatric allergy and clinical immunology at National Jewish Health in Denver and editor-in-chief of the Journal of Allergy and Clinical Immunology.
Because AD is strongly associated with food allergies, some of which progress to asthma, preventing the disease could serve a much larger purpose. Research has shown that breakdown of skin barrier defenses opens the door not only to S. aureus, but also to the herpes simplex virus. The role of filaggrin and lipid deficiency in the negation of barrier mechanisms at the skin's mechanical, chemical, and cellular layers – which in turn may spur the advance of AD to a more persistent level of eczema or to asthma – also has been well studied. And filaggrin-deficient mice have demonstrated high levels of systemic atopic sensitization (J. Allergy Clin. Immunol. 2009;124:485-93).
But even though a lack of filaggrin has been associated with increased microbial invasion, the fact that some patients with filaggrin mutations do not develop AD and others outgrow their AD suggests that other factors are at play in progression of the disease, Dr. Leung said at the meeting, sponsored by National Jewish Health.
Less well understood is TSLP's relative contribution to inflammation and the processes that lead to the atopic march. The responsibility TSLP shares with other causal factors, such as infection, allergen exposure, and the barrier-damaging effects of the AD itch-scratch cycle, have not been well quantified. What researchers do know is that TSLP is commonly found in atopic skin, the gut of food allergy patients, and the lungs of asthmatics.
Dr. Leung calls it the "cytokine of the moment."
"T cells are educated in the milieu of the skin," he explained. "The skin is probably the most highly IgE-inducing organ in the body. There are multiple cytokines, like TSLP and IL-4, which can be released from mast cells, that augment the Th2 response. If one made a systemic anti-TSLP, in theory, and if we knew when to use it, it could reverse atopy."
Researchers are still working to characterize the timing of TSLP production by keratinocytes. Another riddle is just when during the course of a progressing atopic disease any anti-TSLP product should be introduced.
"Because people who come to us often have established disease, we may need to be intervening so early in the disease that we will not get there until we have the right biomarkers," Dr. Leung said.
Dr. Leung reported having no significant disclosures.