Characterizing the Autoimmune Responses in Dermatitis Herpetiformis
Lehtola, Henna (2023)
Lehtola, Henna
2023
Bioteknologian ja biolääketieteen tekniikan maisteriohjelma - Master's Programme in Biotechnology and Biomedical Engineering
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
Hyväksymispäivämäärä
2023-05-05
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202304264548
https://urn.fi/URN:NBN:fi:tuni-202304264548
Tiivistelmä
Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease (CD) associated with an itchy blistering rash typically on the elbows, knees and buttocks. The disease is driven by the response to dietary gluten and characterized by granular deposits of immunoglobulin A (IgA) targeting transglutaminase (TG) 3 in the papillary dermis. The skin symptoms disappear by following a strict gluten-free diet (GFD), but the anti-TG3 IgA deposits may persist in the skin for years after starting the diet. Although DH is considered a T cell mediated disease, the T cell responses are still poorly understood in DH. Plenty of cytokines, e.g. interleukin (IL)-4, IL-8 and IL-17, have been linked to DH. To date, no conclusive evidence has been presented, however, for their exact role in the DH pathogenesis. Therefore, comprehensive systemic cytokine profil-ing studies are needed. While CD is considered a T helper (TH) 1-mediated autoimmune disorder, TH2-type cytokines seem to dominate the molecular findings linked to DH. The primary aim of this thesis was to characterize the systemic cytokine profile of DH patients and to evaluate whether it involves different effector T cell population than seen in CD, further explaining the cutaneous manifestation of DH. The second aim was to investigate the tissue origin of the circulating cytokines in DH patients.
First, we used multiplex cytokine assay to characterize the serum cytokine pattern of untreated DH patients. Second, we investigated the serum cytokine response of treated DH patients to gluten re-exposure using enzyme-linked immunosorbent assay (ELISA). Lastly, we used indirect immunofluorescence microscopy to study the cytokine expression in the two primary disease associated tissues - the skin and the small intestinal epithelium. We compared the cytokine expression to CD patients without skin lesions. As controls, we included patients with other skin diseases without CD or DH, and healthy subjects.
To our knowledge, this study presents the first comprehensive T cell cytokine profiling of DH patients. The results showed significant variation in the cytokine levels between untreated DH patients. IL-23 was the most elevated T cell cytokine in the serum of DH patients with high-er average concentration compared to CD patients and controls. Treated DH patients did not respond to the gluten re-exposure through serum IL-4, IL-6, IL-8 or IL-23. Finally, we found perilesional and intestinal expression of IL-4, IL-6 and IL-23 in DH patients concurrent with the cytokine profiling. These findings suggest that the response to gluten in DH patients might be mainly mediated by TH2- and TH17 T cell subsets. The cutaneous expression of IL-4 as well as the intestinal expression of IL-23 could be characteristic for DH. Moreover, the elevated serum IL-8 potentially reflects increased secretion from the small intestine in DH patients.
In view of these results, this study suggests that the differences in the cytokine pattern of CD and DH patients could lead to these two separate manifestations of systemic gluten-induced autoimmune response. This supports the hypothesis of a switch occurring in the TH -profile during the development of gluten-induced autoimmune response in DH, and potentially explains the two manifestations of CD. However, the exact role of the characterized cytokines in the patho-genesis of DH remains to be established.
First, we used multiplex cytokine assay to characterize the serum cytokine pattern of untreated DH patients. Second, we investigated the serum cytokine response of treated DH patients to gluten re-exposure using enzyme-linked immunosorbent assay (ELISA). Lastly, we used indirect immunofluorescence microscopy to study the cytokine expression in the two primary disease associated tissues - the skin and the small intestinal epithelium. We compared the cytokine expression to CD patients without skin lesions. As controls, we included patients with other skin diseases without CD or DH, and healthy subjects.
To our knowledge, this study presents the first comprehensive T cell cytokine profiling of DH patients. The results showed significant variation in the cytokine levels between untreated DH patients. IL-23 was the most elevated T cell cytokine in the serum of DH patients with high-er average concentration compared to CD patients and controls. Treated DH patients did not respond to the gluten re-exposure through serum IL-4, IL-6, IL-8 or IL-23. Finally, we found perilesional and intestinal expression of IL-4, IL-6 and IL-23 in DH patients concurrent with the cytokine profiling. These findings suggest that the response to gluten in DH patients might be mainly mediated by TH2- and TH17 T cell subsets. The cutaneous expression of IL-4 as well as the intestinal expression of IL-23 could be characteristic for DH. Moreover, the elevated serum IL-8 potentially reflects increased secretion from the small intestine in DH patients.
In view of these results, this study suggests that the differences in the cytokine pattern of CD and DH patients could lead to these two separate manifestations of systemic gluten-induced autoimmune response. This supports the hypothesis of a switch occurring in the TH -profile during the development of gluten-induced autoimmune response in DH, and potentially explains the two manifestations of CD. However, the exact role of the characterized cytokines in the patho-genesis of DH remains to be established.