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Dissertation
Immune mechanisms driving alopecia areata: roles for effector T cells and pro-inflammatory pathways
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008541
Abstract
Alopecia areata (AA) is a common autoimmune disease affecting approximately 2% of the global population. Clinically, AA presents as small defined patches of hair loss on the scalp, and in more severe cases can progress to complete loss of scalp or body hair. Disease onset most commonly occurs before the age of 40 and is associated with increased rates of psychological comorbidities including depression and anxiety, resulting in a diminished quality of life. The hair follicle is an immune privileged organ, and the loss of this privilege is thought to be a key driver of disease development. Lesional skin is characterized by dense lymphocytic infiltration of the hair follicle, particularly around the bulb region. In recent years, Janus kinase (JAK) inhibitors have emerged as an effective treatment strategy for AA and have recently received FDA approval. Despite favorable clinical outcomes, not all patients respond to treatment, highlighting the need for a more comprehensive understanding of the immune mechanisms that drive disease.
The C3H/HeJ mouse strain develops spontaneous AA-like disease characterized by non-scarring hair loss and T cell infiltration of the follicle. Prior studies have identified NKG2D expressing CD8 T cells as key effector cells mediating destruction of the hair follicle through type II interferon dependent pathways. More recently, there has been a growing appreciation that additional immune cell populations and pro-inflammatory pathways may contribute to disease pathogenesis, however, specific mechanisms involved have not been clearly defined. The goal of my thesis work aimed to investigate the role of effector T cells and pro-inflammatory pathways in the development of AA.
In this work, I demonstrate that CD4 T cells from the SDLNs of AA mice have the ability to transfer disease and exhibit an effector Th1 transcriptional and phenotypic profile. The pathogenic capacity of these cells was dependent on endogenous CD8 T cells, host IFN-g signaling, and CD4 T cell derived IFN-g production. Human AA skin showed a similar Th1 profile, highlighting the translational relevance of these findings. Beyond Th1 responses, I found elevated expression of chemokines and chemokine receptors in AA skin that promote CD8 T cell migration and retention in the skin. Additionally, AA skin exhibited increased IL-17 protein and transcript levels, and mice deficient in IL-17 receptor signaling showed delayed disease onset and reduced disease severity. Finally, disruption of NKG2D signaling reduced disease development but did not fully prevent AA, indicating it is not strictly required to sustain pathogenic CD8 T cell activity. Together, these findings define new mechanistic roles for effector T cells and pro-inflammatory pathways in AA, expanding our understanding of disease pathogenesis and identifying new potential targets for therapeutic intervention.
Details
- Title: Subtitle
- Immune mechanisms driving alopecia areata: roles for effector T cells and pro-inflammatory pathways
- Creators
- Samuel J. Connell
- Contributors
- Ali Jabbari (Advisor)Stanley Perlman (Committee Member)Nitin Karandikar (Committee Member)Vladimir Badovinac (Committee Member)Scott Lieberman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008541
- Publisher
- University of Iowa
- Number of pages
- xix, 170 pages
- Copyright
- Copyright 2026 Samuel J. Connell
- Language
- English
- Date submitted
- 02/04/2026
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 155-170).
- Public Abstract (ETD)
Autoimmune diseases occur when the immune system, which normally protects us from infections, targets healthy tissues instead. Alopecia areata (AA) is an autoimmune disease in which the body’s immune system wrongly attacks hair follicles (HF), leading to patchy non-scarring hair loss. AA affects approximately 2% of people worldwide and often occurs at a young age. Because hair loss is a physical change, individuals with AA experience significant emotional distress, including anxiety and depression. Although treatments are available that can stimulate hair regrowth, they do not work for all patients and may cause serious side effects. To develop safer and more effective therapies, it is important to better understand how the immune system damages the HF in AA. Previous research has shown that the skin around the HF is highly inflammatory and that CD8 T cells, a type of immune cell, directly attacks the HF.
The goal of my thesis work is to better understand the how other immune cells and inflammatory signals contribute to AA. Using a mouse model of AA, which closely resembles human disease, I found that a type of immune cell known as helper CD4 T cells can lead to hair loss by driving inflammation. I also identified other inflammatory signals in the skin and showed that disrupting these signals can reduce the rate and severity of disease. Together, my findings improve our understanding of how immune cell driven inflammation leads to hair loss in AA, highlighting new biological pathways that could be targeted to improve future treatments.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9985176873102771
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