Investigating the epithelial barrier and immune signatures in the pathogenesis of equine insect bite hypersensitivity

Abstract

Insect bite hypersensitivity (IBH) is a Th-2, IgE-mediated dermatitis of horses caused by bites of insects of the genus Culicoides that has common features with human atopic dermatitis. Together with Th-2 cells, the epithelial barrier plays an important role in development of type I hypersensitivities. In order to elucidate the role of the epithelial barrier and of the skin immune response in IBH we studied the transcriptome of lesional whole skin of IBH-horses (IBH-LE; n = 9) in comparison to non-lesional skin (IBH-NL; n = 8) as well as to skin of healthy control horses (H; n = 9). To study the "baseline state" of the epithelial barrier, we investigated the transcriptome of non-lesional epidermis in IBH-horses (EPI-IBH-NL; n = 10) in comparison with healthy epidermis from controls (EPI-H; n = 9). IBH-LE skin displayed substantial transcriptomic difference compared to H. IBH-LE was characterized by a downregulation of genes involved in tight junction formation, alterations in keratins and substantial immune signature of both Th-1 and Th-2 types with particular upregulation of IL13, as well as involvement of the hypoxic pathway. IBH-NL shared a number of differentially expressed genes (DEGs) with IBH-LE, but was overall more similar to H skin. In the epidermis, genes involved in metabolism of epidermal lipids, pruritus development, as well as IL25, were significantly differentially expressed between EPI-IBH-NL and EPI-H. Taken together, our data suggests an impairment of the epithelial barrier in IBH-affected horses that may act as a predisposing factor for IBH development. Moreover, these new mechanisms could potentially be used as future therapeutic targets. Importantly, many transcriptional features of equine IBH skin are shared with human atopic dermatitis, confirming equine IBH as a natural model of skin allergy.

Immunopathogenesis and immunotherapy of Culicoides hypersensitivity in horses: an update

“…23 This finding has been confirmed in a transcriptome study, where IL-13 as well as its receptor transcripts IL13RA1 and IL13RA2 (Figure 1) were upregulated in CH lesional skin compared to skin from healthy controls. 17 This is in line with recent studies in humans, where IL-13 has been suggested to be the key Th2 cytokine driving inflammation in the periphery, while IL-4 has a more central effect. 24 IL-13 is thought to play a major role in the inflammatory reaction underlying human atopic dermatitis (AD), where IL-13 is overexpressed locally and has a significant impact on the recruitment of inflammatory cells, contributing to alterations of the skin microbiome and to a decrease in the epidermal barrier function.…”

“…Combination of TLR ligand and allergic cytokine milieu further increased TSLP expression, indicating a potential mechanism for exacerbations in CH. 36 A recent study 17 comparing the transcriptome of lesion CH skin to skin from healthy controls has demonstrated important changes in the barrier epithelium: genes affecting processes of epithelial cell differentiation, desmosome organisation as well as regulation of epithelial morphogenesis were enriched, while, contrary to the situation in human AD, the expression of most of the genes involved in terminal differentiation of keratinocytes, such as filaggrin, involucrin and loricrin, was not changed in CH lesions compared to healthy skin. However, small prolinerich protein (SPRR), another component of the cornified layer, as well as other members of the SPRR family, were significantly upregulated in CH lesions.…”

“… Summary of the differentially expressed genes (DEGs) identified by Cvitas et al 17 . indicating changes in nonlesional epidermis of Culicoides hypersensitivity (CH)‐affected horses compared to epidermis of healthy horses.…”

Atopic Dermatitis in Domestic Animals: What Our Current Understanding Is and How This Applies to Clinical Practice

“…One study in atopic horses showed ultrastructural abnormalities on electron microscopy when compared to normal horses [ 127 ] but it is unclear if this is the result of inflammation or may be suggestive of some primary impairment of the skin which could facilitate the epicutaneous absorption of the allergen and increased risk for allergic sensitization. A recently published study on horses with insect hypersensitivity compared the transcriptome in the epidermis of allergic horses with that of normal horses [ 128 ] and suggested skin impairment in insect allergic horses. It is possible that some of these allergic horses were also atopic.…”

C-Type Lectins in Veterinary Species: Recent Advancements and Applications

“…For instance, a possible involvement of Dectin-1 in sterile inflammation and postpartum placenta retention was suggested in cows, since higher numbers of Dectin-1-expressing uterine macrophages were detected in retention-affected cows compared to cows with a regular afterbirth [ 85 ]. Allergic hypersensitivity and immunopathology can also be mediated by CTLs: in horses, Dectin-1, Dectin-2, and macrophage lectin 2 (MGL/Clec10a) may contribute to severe allergic dermatitis following insect bites [ 86 ]. Similar findings were also obtained for mice and men, as Dectin-1 −/− mice were largely protected against Aspergillus fumigatus -initiated corneal keratitis [ 87 ] and Dectin-1 blockade using the antagonist laminarin alleviated the severity of fungal keratitis in human patients [ 28 ].…”