# Aire-dependent regulation of spontaneous autoimmune-mediated alopecia

> **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $26,848

## Abstract

ABSTRACT
This proposal will enable the applicant to acquire mentored research training and develop into a productive,
independent physician-scientist in the field of dermatology.
Alopecia areata (AA) is an autoimmune skin disease, characterized by patchy non-scarring hair loss, with no
cure. AA is caused by inappropriate activation of autoreactive T cells that target and damage keratinocytes of
anagen hair follicles (HFs) due to the collapse of HF immune privilege (IP). Why anagen HFs undergo IP collapse
is not well-understood. Recently, Janus kinase inhibitors (JAKi) have shown clinical efficacy in AA patients by
suppressing immune-cell activity at the HF, however, JAKi do not work for all AA patients. A better mechanistic
understanding of JAK-STAT regulation can lead to more effective AA treatments. Our preliminary data indicates
that we have a novel AA-like mouse model that exhibits spontaneous alopecia in mice genetically null for
autoimmune regulator (Aire-/-). Aire is a transcriptional regulator expressed in medullary thymic epithelial cells
that eliminates autoreactive T cells. We and others have recently shown that Aire is also expressed in epidermal
and follicular keratinocytes. Increasing clinical evidence also supports the importance of Aire in AA, as patients
with loss-of-function mutations in AIRE have an increased risk of developing AA. We observe adult female
C57BL/6 Aire-/- (germline) mice spontaneously develop AA-like lesions (n=35/73). Skin biopsies from alopecic
Aire-/- mice resemble human AA lesions on macroscopic, histopathologic, and molecular levels. Additionally, we
observed upregulation in JAK-STAT signaling in Aire-/- skin lesions and AIRE-deficient cultured keratinocytes
alongside downregulated expression of PIAS1, a STAT1 inhibitor. These findings suggest that 1) Aire is a
critical regulator of HF IP in AA and 2) AIRE is a key suppressor of JAK-STAT signaling in keratinocytes.
This proposal will address current gaps in our understanding of HF IP and JAK-STAT signaling in AA. In Aim 1,
we hypothesize that the loss of either thymic or keratinocyte Aire contribute to HF IP collapse. To test this, we
will harvest CD8+NKG2D+ T cells from alopecic Aire-/- mice, subcutaneously inject them into Aire+/+ mice and
monitor them for AA onset. Cytolytic T cell activity will be assessed via keratinocyte co-culture experiments. The
results of these studies will reveal whether thymic Aire loss is sufficient to trigger HF IP collapse. In parallel, we
will test whether skin-specific deletion of Aire is sufficient to trigger HF IP collapse by utilizing tamoxifen-treated
Airefl/flK5-CreERT2 mice. In Aim 2, we hypothesize that AIRE contributes to the regulation of IFNγ-JAK-STAT
signaling in cultured keratinocytes. To test this, we will determine how AIRE influences the PIAS1, STAT1, and
the PIAS1-STAT1 complex, assess which AIRE domains are required for JAK-STAT signaling, and identify the
AA cytokines and chemokines expressed by AIRE-/- ke...

## Key facts

- **NIH application ID:** 10464297
- **Project number:** 1F31AR079902-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Natella Maglakelidze
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $26,848
- **Award type:** 1
- **Project period:** 2022-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464297

## Citation

> US National Institutes of Health, RePORTER application 10464297, Aire-dependent regulation of spontaneous autoimmune-mediated alopecia (1F31AR079902-01A1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10464297. Licensed CC0.

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