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Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis
Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposition factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B...
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| Format: | Thesis |
| Language: | English |
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Department of Clinical Laboratory Sciences
2023
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| _version_ | 1867613422494941184 |
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| access_status_str | Open Access |
| author | Scibiorek, Martyna |
| author2 | Brombacher, F |
| author_browse | Brombacher, F Scibiorek, Martyna |
| author_facet | Brombacher, F Scibiorek, Martyna |
| author_sort | Scibiorek, Martyna |
| collection | Thesis |
| description | Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposition factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells are involved in skin sensitization to allergens is unclear. Clinical studies investigating the efficacy of monoclonal antibody to IgE such as omalizumab and ligelizumab do not show efficacy in AD patients. However, targeting IL-4/IL-13 signalling axis with dupilumab show efficacy in AD. We investigated the importance of interleukin 4 receptor alpha (IL- 4Rα) signalling specifically on B and T cells to understand the requirement of this signalling axis in epicutaneous skin sensitisation during AD. We investigated 3 models of AD using House dust mite (HDM), Ovalbumin (OVA) and low-calcemic analog of vitamin D (MC903) on mouse strains lacking IL-4Ra on various B and T cells. We used mb1creIL-4Rα-/lox (mice lacking IL-4Rα on B cells), iLcKCre IL-4Rα-/lox (mice lacking IL-4Rα on all T cells), LcKCre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ and CD8+ T cells), CD4Cre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ Tcells), Foxp3Cre IL-4Rα-/lox (mice lacking IL-4Rα on Foxp3+ T regulatory cells) and IL-4Rα-/lox littermate controls. We analysed cellular infiltrate in the skin and inguinal lymph nodes (LN) by flow cytometry, histology of the skin, serum antibodies and cytokines by ELISA. Mice lacking IL-4Rα-responsive B cells showed a reduced serum IgE levels, but no significant differences in epidermal thickening compared to littermate control in HDM or MC903 models. Mice investigated in the T cell arm of the study showed reduced epidermal thickening in pan-T cell IL-4Rα knock-out, but not in groups lacking IL-4Rα signalling in adaptive T cells, suggesting importance of IL4/IL13 signalling axis in ydT cells during AD. Overall, our results suggest that deletion of IL-4Rα on innate T cells regulates inflammatory response in atopic dermatitis. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/37016 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:35:54.009Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Department of Clinical Laboratory Sciences |
| publisherStr | Department of Clinical Laboratory Sciences |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/37016 Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis Scibiorek, Martyna Brombacher, F Hadebe, S atopic dermatitis interleukin 4 receptor alpha allergy T cells B cells murine model Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposition factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells are involved in skin sensitization to allergens is unclear. Clinical studies investigating the efficacy of monoclonal antibody to IgE such as omalizumab and ligelizumab do not show efficacy in AD patients. However, targeting IL-4/IL-13 signalling axis with dupilumab show efficacy in AD. We investigated the importance of interleukin 4 receptor alpha (IL- 4Rα) signalling specifically on B and T cells to understand the requirement of this signalling axis in epicutaneous skin sensitisation during AD. We investigated 3 models of AD using House dust mite (HDM), Ovalbumin (OVA) and low-calcemic analog of vitamin D (MC903) on mouse strains lacking IL-4Ra on various B and T cells. We used mb1creIL-4Rα-/lox (mice lacking IL-4Rα on B cells), iLcKCre IL-4Rα-/lox (mice lacking IL-4Rα on all T cells), LcKCre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ and CD8+ T cells), CD4Cre IL-4Rα-/lox (mice lacking IL-4Rα on CD4+ Tcells), Foxp3Cre IL-4Rα-/lox (mice lacking IL-4Rα on Foxp3+ T regulatory cells) and IL-4Rα-/lox littermate controls. We analysed cellular infiltrate in the skin and inguinal lymph nodes (LN) by flow cytometry, histology of the skin, serum antibodies and cytokines by ELISA. Mice lacking IL-4Rα-responsive B cells showed a reduced serum IgE levels, but no significant differences in epidermal thickening compared to littermate control in HDM or MC903 models. Mice investigated in the T cell arm of the study showed reduced epidermal thickening in pan-T cell IL-4Rα knock-out, but not in groups lacking IL-4Rα signalling in adaptive T cells, suggesting importance of IL4/IL13 signalling axis in ydT cells during AD. Overall, our results suggest that deletion of IL-4Rα on innate T cells regulates inflammatory response in atopic dermatitis. 2023-02-23T10:14:13Z 2023-02-23T10:14:13Z 2021 2022-11-23T10:17:06Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/37016 eng application/pdf Department of Clinical Laboratory Sciences Faculty of Health Sciences |
| spellingShingle | atopic dermatitis interleukin 4 receptor alpha allergy T cells B cells murine model Scibiorek, Martyna Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| thesis_degree_str | Doctoral |
| title | Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| title_full | Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| title_fullStr | Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| title_full_unstemmed | Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| title_short | Investigating role of IL-4 receptor alpha (IL-4Ra) in murine models of atopic dermatitis |
| title_sort | investigating role of il 4 receptor alpha il 4ra in murine models of atopic dermatitis |
| topic | atopic dermatitis interleukin 4 receptor alpha allergy T cells B cells murine model |
| url | http://hdl.handle.net/11427/37016 |
| work_keys_str_mv | AT scibiorekmartyna investigatingroleofil4receptoralphail4rainmurinemodelsofatopicdermatitis |