The immunopathogenesis of Alopecia Areata

Bain, Kym A. (2020) The immunopathogenesis of Alopecia Areata. PhD thesis, University of Glasgow.

Abstract

Alopecia areata (AA) is an organ specific polygenic autoimmune disease that causes patchy hair loss which can develop to affect the entire scalp and body. The inflammatory response driving AA is considered to be dominated by NKG2D+ CD8 T cells, however the immune mechanisms driving hair loss are not sufficiently understood. Current treatments for AA, which include immunosuppressants, are often ineffective especially for severe AA. JAK inhibitors are useful for promoting hair regrowth, however they may be associated with side effects and disease relapse following treatment cessation.

Extensive immune profiling of peripheral blood and lesional AA skin was conducted to identify novel mechanisms of disease pathogenesis. Multiplex cytokine analysis indicated that AA is associated with a distinct type 17 and type 2 cytokine signature, characterised by increased circulating levels of IL-17A, IL-17F, IL-21, IL-23, IL-31, IL-33 and IL-17E/-25. The frequency of CCR6+ CD4 T cells are increased in AA circulation, supporting the involvement of a Th17 response in AA pathogenesis. Stratification of the AA cohort revealed that changes in the frequency of CCR6+ CD4 T cell populations are related to individuals with mild disease. Atopy is common in AA cohorts, however stratification indicated that the increase in circulating type 17 and type 2 cytokines are enriched in both atopic and non-atopic cohorts. We also observed an increase in the frequency of circulating transitional B cells, but this phenotype is specifically related to atopic AA individuals. Global transcriptomic analysis of AA skin from individuals with stable disease indicated enrichment of a macrophage signature characterised by expression of CD163, CD209 and CD206. Macrophages are known to be important for normal hair growth. Thus, it is proposed that the follicular inflammatory environment disrupts the homeostatic functions of macrophages, and that macrophages contribute to mechanisms maintaining hair loss.

This study provides novel observations indicating distinct systemic and tissue immune signatures, and indicates how features of the immune response are related to specific disease pathotypes. This study also implicates macrophages as pathogenic mediators of AA, and suggests that modulation of macrophage activity represents a novel therapeutic strategy for AA.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Alopecia areata, autoimmunity, hair follicles, immunophenotyping, RNAseq, cytokines, T cells, B cells, macrophages.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Funder's Name: Medical Research Scotland (MEDRESSC)
• Supervisor's Name: Milling, Professor Simon, Astrand, Dr Annika and McInnes, Professor Iain
• Date of Award: 2020
• Depositing User: Kym A Bain
• Unique ID: glathesis:2020-81826
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Dec 2020 10:55
• Last Modified: 07 Aug 2024 10:01
• Thesis DOI: 10.5525/gla.thesis.81826
• URI: https://theses.gla.ac.uk/id/eprint/81826