Skin-infiltrating T cells and cytokine expression in Icelandic horses affected with insect bite hypersensitivity: a possible role for regulatory T cells.
Abstract: Equine insect bite hypersensitivity (IBH) is a seasonally recurrent, pruritic skin disorder caused by an IgE-mediated reaction to salivary proteins of biting flies, predominantly of the genus Culicoides. The aim of this study was to define T cell subsets and cytokine profile in the skin of IBH-affected Icelandic horses with particular focus on the balance between T helper (Th) 1, Th2 and T regulatory (Treg) cells. Distribution and number of CD4+, CD8+ and Forkhead box P3 (FoxP3)+ T cells were characterized by immunohistochemical staining in lesional and non-lesional skin of moderately and severely IBH-affected horses (n=14) and in the skin of healthy control horses (n=10). Using real-time quantitative reverse transcription-polymerase chain reaction, mRNA expression levels of Th2 cytokines (Interleukin (IL)-4, IL-5, IL-13), Th1 cytokines (Interferon-γ), regulatory cytokines (Transforming Growth Factor β1, IL-10) and the Treg transcription factor FoxP3 were measured in skin and blood samples. Furthermore, Culicoides nubeculosus specific serum IgE levels were assessed. Lesions of IBH-affected horses contained significantly higher numbers of CD4+ cells than skin of healthy control horses. Furthermore, the total number of T cells (CD4+ and CD8+) was significantly increased in lesional compared to non-lesional skin and there was a tendency (p=0.07) for higher numbers of CD4+ cells in lesional compared to non-lesional skin. While the number of FoxP3+ T cells did not differ significantly between the groups, the ratio of Foxp3 to CD4+ cells was significantly lower in lesions of severely IBH-affected horses than in moderately affected or control horses. Interestingly, differences in FoxP3 expression were more striking at the mRNA level. FoxP3 mRNA levels were significantly reduced in lesional skin, compared both to non-lesional and to healthy skin and were also significantly lower in non-lesional compared to healthy skin. Expression levels of IL-13, but not IL-4 or IL-5, were significantly elevated in lesional and non-lesional skin of IBH-affected horses. IL-10 levels were lower in lesional compared to non-lesional skin (p=0.06) and also lower (p=0.06) in the blood of IBH-affected than of healthy horses. No significant changes were observed regarding blood expression levels of Th1 and Th2 cytokines or FoxP3. Finally, IBH-affected horses had significantly higher Culicoides nubeculosus specific serum IgE levels than control horses. The presented data suggest that an imbalance between Th2 and Treg cells is a characteristic feature in IBH. Treatment strategies for IBH should thus aim at restoring the balance between Th2 and Treg cells.
Copyright © 2010 Elsevier B.V. All rights reserved.
Publication Date: 2010-12-01 PubMed ID: 21168921DOI: 10.1016/j.vetimm.2010.11.016Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This study investigates the involvement of different types of T cells and cytokine protein profiles in the skin condition, insect bite hypersensitivity (IBH) in Icelandic horses. The research found imbalances in T helper cells and regulatory T cells in IBH-affected horses, suggesting potential therapeutic approaches based on restoring this balance.
Objective and Importance of the Study
- The central aim of this study was to identify the types of T cells and their accompanying cytokine protein profiles in the skin of Icelandic horses affected by a skin disorder called insect bite hypersensitivity (IBH). This is an IgE-mediated reaction to salivary proteins from biting flies, especially in the genus Culicoides, that causes recurrent skin irritation.
- The findings provide insight into the types and distribution of immune cells involved in IBH in horses, and they suggest potential new treatment strategies for restoring immune balance in affected animals.
Research Procedures and Findings
- The researchers characterized the distribution and number of different T cell types (CD4+, CD8+ and FoxP3+) in the skin of both moderately and severely IBH-affected horses, and compared these with healthy control horses.
- They found a significantly higher number of CD4+ cells in the skin lesions of horses with IBH compared to the skin of healthy horses. The total number of T cells (both CD4+ and CD8+) was also higher in lesioned skin compared to non-lesioned skin.
- They went further to measure the expression levels of different types of cytokines (proteins that mediate and regulate immune and inflammatory responses), including Th2 cytokines (IL-4, IL-5, IL-13), Th1 cytokines (Interferon-γ), regulatory cytokines (Transforming Growth Factor β1, IL-10) and the Treg transcription factor FoxP3 in both skin and blood samples.
- Although the number of FoxP3+ T cells did not differ significantly between the groups, a noticeable observation was that the ratio of FoxP3 to CD4+ cells was significantly lower in lesions from severely affected horses than in moderately affected or control animals.
- IBH-affected horses also had significantly higher specific serum IgE levels against Culicoides nubeculosus than the control horses, indicating an immune response to this specific type of biting fly.
Implications for Future Treatment Strategies
- The results of this research suggest that an imbalance between Th2 cells, which typically help to coordinate immune responses, and Treg cells, which help keep the immune system in check, is a key feature of IBH in horses.
- Given this imbalance, the researchers suggested that future treatments for IBH should seek to restore balance between Th2 and Treg cells. This could potentially help alleviate symptoms of IBH and improve the horse’s quality of life.
Cite This Article
APA
Heimann M, Janda J, Sigurdardottir OG, Svansson V, Klukowska J, von Tscharner C, Doherr M, Broström H, Andersson LS, Einarsson S, Marti E, Torsteinsdottir S.
(2010).
Skin-infiltrating T cells and cytokine expression in Icelandic horses affected with insect bite hypersensitivity: a possible role for regulatory T cells.
Vet Immunol Immunopathol, 140(1-2), 63-74.
https://doi.org/10.1016/j.vetimm.2010.11.016 Publication
Researcher Affiliations
- Institute for Experimental Pathology, University of Iceland, Keldur, v/Vesturlandsveg, 112 Reykjavík, Iceland.
MeSH Terms
- Animals
- Biopsy / veterinary
- CD4 Antigens / analysis
- CD4-Positive T-Lymphocytes / metabolism
- CD8 Antigens / analysis
- CD8-Positive T-Lymphocytes / metabolism
- Ceratopogonidae / immunology
- Cytokines / analysis
- Cytokines / biosynthesis
- Enzyme-Linked Immunosorbent Assay / veterinary
- Forkhead Transcription Factors / analysis
- Forkhead Transcription Factors / biosynthesis
- Horses / immunology
- Hypersensitivity, Immediate / blood
- Hypersensitivity, Immediate / etiology
- Hypersensitivity, Immediate / immunology
- Hypersensitivity, Immediate / veterinary
- Immunoglobulin E / blood
- Insect Bites and Stings / blood
- Insect Bites and Stings / immunology
- Insect Bites and Stings / veterinary
- Interleukin-13 / analysis
- Interleukin-13 / biosynthesis
- Lymphocyte Count / veterinary
- Pruritus / blood
- Pruritus / etiology
- Pruritus / veterinary
- Reverse Transcriptase Polymerase Chain Reaction / veterinary
- Skin / pathology
- T-Lymphocytes, Regulatory / metabolism
Citations
This article has been cited 11 times.- Jebbawi F, Chemnitzer A, Dietrich M, Pantelyushin S, Lam J, Rhiner T, Keller G, Waldern N, Canonica F, Fettelschoss-Gabriel A. Cytokines and chemokines skin gene expression in correlation with immune cells in blood and severity in equine insect bite hypersensitivity. Front Immunol 2024;15:1414891.
- Cox A, Stewart AJ. Insect Bite Hypersensitivity in Horses: Causes, Diagnosis, Scoring and New Therapies. Animals (Basel) 2023 Aug 4;13(15).
- Cvitas I, Oberhaensli S, Leeb T, Marti E. Equine keratinocytes in the pathogenesis of insect bite hypersensitivity: Just another brick in the wall?. PLoS One 2022;17(8):e0266263.
- Birras J, White SJ, Jonsdottir S, Novotny EN, Ziegler A, Wilson AD, Frey R, Torsteinsdottir S, Alcocer M, Marti E. First clinical expression of equine insect bite hypersensitivity is associated with co-sensitization to multiple Culicoides allergens. PLoS One 2021;16(11):e0257819.
- Cvitas I, Oberhänsli S, Leeb T, Dettwiler M, Müller E, Bruggman R, Marti EI. Investigating the epithelial barrier and immune signatures in the pathogenesis of equine insect bite hypersensitivity. PLoS One 2020;15(4):e0232189.
- Hallamaa R, Batchu K. Phospholipid analysis in sera of horses with allergic dermatitis and in matched healthy controls. Lipids Health Dis 2016 Mar 2;15:45.
- Meulenbroeks C, van der Lugt JJ, van der Meide NM, Willemse T, Rutten VP, Zaiss DM. Allergen-Specific Cytokine Polarization Protects Shetland Ponies against Culicoides obsoletus-Induced Insect Bite Hypersensitivity. PLoS One 2015;10(4):e0122090.
- Klumplerova M, Vychodilova L, Bobrova O, Cvanova M, Futas J, Janova E, Vyskocil M, Vrtkova I, Putnova L, Dusek L, Marti E, Horin P. Major histocompatibility complex and other allergy-related candidate genes associated with insect bite hypersensitivity in Icelandic horses. Mol Biol Rep 2013 Apr;40(4):3333-40.
- Lewis DH, Chan DL, Pinheiro D, Armitage-Chan E, Garden OA. The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells. J Vet Intern Med 2012 May-Jun;26(3):457-82.
- Hamza E, Gerber V, Steinbach F, Marti E. Equine CD4(+) CD25(high) T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro. Immunology 2011 Nov;134(3):292-304.
- Andersson LS, Swinburne JE, Meadows JR, Broström H, Eriksson S, Fikse WF, Frey R, Sundquist M, Tseng CT, Mikko S, Lindgren G. The same ELA class II risk factors confer equine insect bite hypersensitivity in two distinct populations. Immunogenetics 2012 Mar;64(3):201-8.
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