Proteases in Helminth- and Allergen- Induced Inflammatory Responses

Abstract

Proteolytic activity is a central biochemical property that endows molecules with intrinsic allergenicity. Thus, the cysteine protease of dust mite, Der p1, the aspartic protease of cockroach, Bla g 2, the serine protease of Aspergillus fumigatus and the bacterial subtilisins are all major allergenic molecules responsible for the increase in asthma and atopic conditions worldwide. These proteases induce Th2-driven inflammatory responses in the airways by disrupting the epithelial cell junctions so that these, and other molecules, gain access to, and alter the function of, underlying cells of the innate immune system (dendritic cells, mast cells, basophils and macrophages) and B and T cells. Helminth parasites secrete proteases to gain entry into their hosts, and to feed on and migrate through tissues. Their action leads to tissue damage and the activation of inflammatory responses dominated by elevated IgE, eosinophilia and Th2 cells, much like allergenic responses. In certain situations, such as in acute infections (especially with zoonotic helminths), proteases secreted by helminths may sensitise individuals to allergens. However, the anti-inflammatory responses observed in chronic helminthiases, involving IL-10 and TGFBeta, that are primarily responsible for controlling immune-mediated damage to the host that is initiated by secreted proteases, coincidentally protects against similar inflammatory damage by allergens.

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

“…Whether helminth proteases can mediate these effects by targeting DC is at the moment unclear; however, based on the observations that numerous allergens are known to be cysteine proteases [56] and that the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, has been found to prime monocyte-derived DC for Th2 polarization in a protease dependent manner [57], it is conceivable that such helminth-derived proteases have the potential to favor Th2 polarization through functional modulation of DC.…”

Signaling pathways activated by a protease allergen in basophils

“…A similar strategy likely is used to detect enzymatic activities of proteins secreted by multicellular parasites. Secreted proteases are necessary for helminth reproduction and life cycles in their hosts (6), and it has been hypothesized that specific innate immune mechanisms have evolved to detect their proteolytic activity (7). Interestingly, many allergens lack unique structural features that might allow recognition by the immune system, but, like helminths, allergens can exhibit proteolytic activity (8), and it has been hypothesized that they incidentally activate the same pathways activated by helminth proteases and elicit similar type 2 responses (7,9).…”

Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond

“…[97][98][99] Interestingly, allergen extracts and helminths excretory/secretory products often share similar properties that can lead to Type 2-associated responses. For example, both are rich in proteases 100 that can promote Th2 differentiation through protease-activated receptor 2 101-103 directly on T cells 102 or indirectly by inducing IL-33 or thymic stromal lymphopoietin production by tissue cells 104,105 or IL-13 production by macrophages. 106 In addition, both allergens and helminths are known to increase numbers and activity of type extract; AsE = Anisakis simplex extract; CR = cockroach; HDM = house dust mite.…”