FUTURE OF ATOPIC, ASTHMA, ECZEMA TREATMENTS AND RESEARCH PROGRESS

• SPINK5 is a serine protease inhibitor that is believed to inhibit environmental proteases, such as those from bacteria or allergens that penetrate the skin, and therefore act as a barrier to infection, and allergy. In addition, it maintains the balance between the formation of skin sloughing/release of keratinocytes in the outer layer of the skin, the stratum corneum, and the maintenance of a barrier. This is done by antagonising cellular proteases.

• It is known that 1/3 of all AD patients suffer severe bacterial infections in the skin. These patients have lesions, of which are colonized in 90% of the time, by Staphylococcus aureus. Interestingly, in all the strains in AD individuals, these bacteria have high proteolytic activity vs. the low levels of activity found in healthy individuals which carry this bacteria.

• Many AD individuals also have high IgE titres specific for allergens from the ubiquitous house-dust mite Dermatophagoides pteronyssinus. This critter, received its name because it feeds on human skin that is shed from the outermost cornified layer. It comes from the Greek work meaning “eater of skin.”

• These dust-mites contain numerous proteins and have numerous pathogenetic mechanisms in order to survive. Der p I, Der p II are the main house-dust-mite allergens. These allergens are present in faecal pellets and are proteases that have profound effects on epithelial cells and the skin. These proteases are known to disrupt intercellular adhesion molecules, increase paracellular permeability, and can initiate cell death. Basically, these proteins damage the barrier effect of the skin, by releasing more skin cells, of which the dust mite can consume. This in turn, leads to an easier entry point for bacteria to penetrate the skin, and lead to an inflammatory response, that results in the redness, pain, and itchiness that is seen in eczema.

• SPINK5 is believed to be important in suppressing this proteolytic activity

• Loss of SPINK5 (through genetic mutations) is known to cause Netherton’s disease, which is a generalized congenital erythroderma. These patients also always develop atopic disease, including hay fever, food allergy, urticaria and asthma. Unfortunately, these patients do not survive much long after birth. This effect clearly shows that specific proteins that maintain the barrier function of the skin are essential to prevent atopy.

• Inhibition of protease activity might also be a new approach in the therapy of AD

• A recent small study showed that a1-proteinase inhibitor was effective in the treatment of AD

References:

Cookson W. The immunogenetics of asthma and eczema: A new focus on the epithelium. Nature Reviews Immunology 4, 978-988 (2004)