On September 30, 2026, Dr. Ting Chen's laboratory at the National Institute of Biological Sciences, Beijing (NIBS)/Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR) published a research article entitled “A two-hit mechanism triggers autoimmune hair loss” in Nature. This study reveals that autoimmune hair loss requires the convergence of two independent events: increased susceptibility of hair follicle stem Ezpay(中国)s (HFSCs) to immune attack and the loss of regulatory T Ezpay(中国) (Treg)-mediated immune protection. The researchers discovered that sympathetic nerve activity during hair follicle regeneration promotes the physiological reactivation of endogenous retroviruses (ERVs) in HFSCs, creating a transient state of autoimmune susceptibility. When Treg-mediated immune tolerance is compromised, this otherwise harmless physiological state can trigger pathogenic CD8⁺ T Ezpay(中国) responses and autoimmune hair loss. These findings establish a previously unrecognized neuro–epithelial–immune mechanism underlying the initiation of tissue-specific autoimmunity.

Autoimmune diseases develop when the immune system mistakenly attacks the body's own tissues. Although breakdown of immune tolerance is generally considered a fundamental cause of autoimmunity, immune dysregulation alone does not always result in disease. Why certain tissues become targets of autoimmune attack, and why such attacks occur only under particular physiological conditions, remain important unresolved questions. Hair follicles provide a unique model for investigating these questions because they undergo repeated cycles of regeneration throughout life while maintaining a specialized immune-privileged environment that protects HFSCs from immune-mediated destruction.

To investigate the factors that determine hair follicle susceptibility to autoimmunity, the researchers established a mouse model in which Tregs could be transiently depleted at different stages of the hair cycle. Surprisingly, depletion of Tregs during the resting phase (telogen) did not induce significant CD8⁺ T Ezpay(中国) infiltration or hair loss. In contrast, the same treatment during the growth phase (anagen) caused extensive CD8⁺ T Ezpay(中国) accumulation around hair follicles, destruction of HFSCs, and subsequent hair loss. Further experiments demonstrated that this process required CD8⁺ T Ezpay(中国)s and MHC-I-dependent antigen presentation by HFSCs. These findings indicate that disruption of immune tolerance alone is insufficient to initiate autoimmune hair loss. Instead, the physiological state of the target tissue plays an essential role in determining its susceptibility to immune attack.

Figure 1. Transient Treg depletion during anagen, but not telogen, triggers CD8⁺ T Ezpay(中国)-mediated destruction of hair follicle stem Ezpay(中国)s and autoimmune hair loss.

What makes regenerating hair follicles particularly susceptible to autoimmune attack? The researchers discovered that sympathetic nerve activity is physiologically elevated during anagen and is a critical determinant of hair follicle immune susceptibility. Disruption of sympathetic innervation significantly reduced CD8⁺ T Ezpay(中国) infiltration and prevented hair loss following Treg depletion. Conversely, optogenetic activation of sympathetic nerves or psychological stress rendered normally resistant telogen hair follicles susceptible to autoimmune attack when Tregs were depleted. Further genetic experiments identified the β2-adrenergic receptor (ADRB2) expressed by HFSCs as a key mediator of this effect. Selective deletion of Adrb2 in HFSCs markedly suppressed CD8⁺ T Ezpay(中国) infiltration and protected against hair loss. These findings demonstrate that sympathetic nerves directly regulate the susceptibility of tissue stem Ezpay(中国)s to autoimmune attack through norepinephrine–ADRB2 signaling.

The researchers next investigated how sympathetic signaling changes the immunological state of HFSCs. Transcriptomic analyses revealed that a subset of endogenous retroviruses (ERVs), ancient viral sequences integrated into mammalian genomes, becomes physiologically reactivated in HFSCs during anagen. Importantly, this activation depends on sympathetic innervation and HFSC-intrinsic ADRB2 signaling. Although ERVs are generally maintained in a transcriptionally silenced state, and their abnormal activation has been associated with inflammatory and autoimmune disorders, this study reveals that certain class of ERV can also be dynamically activated during a normal physiological process. Under intact immune tolerance, this regeneration-associated ERV activation does not cause overt tissue damage. However, when Treg-mediated protection is removed, the ERV-associated state contributes to the initiation of autoimmune responses.

To determine how ERV activation triggers autoimmune pathology, the researchers investigated the involvement of innate and adaptive immune pathways. They found that the intraEzpay(中国)ular DNA sensor AIM2 plays a critical role in disease development, as genetic deletion of Aim2 effectively prevented autoimmune hair loss. Pharmacological inhibition of ERV reverse transcription also suppressed disease development, supporting a functional contribution of ERV activity. Furthermore, the study demonstrated the involvement of type 1 conventional dendritic Ezpay(中国)s (cDC1s) in the pathogenic immune response and identified an ERV-derived antigenic peptide recognized by disease-associated CD8⁺ T Ezpay(中国)s. Together, these results establish a mechanistic connection between sympathetic nerve activity, physiological ERV reactivation, innate immune sensing, and autoreactive CD8⁺ T Ezpay(中国) responses.

Figure 2. Sympathetic norepinephrine–ADRB2 signaling promotes ERV reactivation in hair follicle stem Ezpay(中国)s, creating a transient state of autoimmune susceptibility.

Based on these findings, the researchers propose a “two-hit” model for the initiation of autoimmune hair loss. The first hit originates from the target tissue itself: sympathetic nerve activation during hair follicle regeneration promotes the expression of certain ERVs in HFSCs, increasing their susceptibility to autoimmune attack. The second hit involves the breakdown of immune tolerance caused by the loss of Treg-mediated protection. These two processes can be understood as an accelerator and a brake. Sympathetic nerve-dependent ERV activation acts as the accelerator, priming the tissue for autoimmune attack, whereas Tregs serve as the brake, preventing the immune system from attacking self-tissues. When the accelerator is not engaged, releasing the brake alone is insufficient to initiate disease. However, when the accelerator is engaged and the brake is simultaneously released, autoimmune destruction of HFSCs can occur.

Figure 3. A two-hit model for autoimmune hair loss. Physiological sympathetic activation acts as an accelerator that increases tissue susceptibility, whereas Tregs function as a brake that maintains immune tolerance. Autoimmune disease develops when both conditions coincide.

This study challenges the conventional view that autoimmune diseases are initiated solely by defects in immune regulation. Instead, it demonstrates that normal physiological activities within a target tissue can create transient windows of autoimmune susceptibility, while immune tolerance mechanisms prevent these vulnerable states from progressing to disease. The findings reveal an unexpected connection between neural activity, tissue regeneration, endogenous retroviruses, and autoimmune responses, providing a conceptual framework for understanding how tissue-intrinsic and immune factors cooperate to initiate organ-specific autoimmunity. Although the experimental model primarily involves immune-mediated destruction of HFSCs, a feature more closely associated with certain forms of scarring alopecia, the two-hit principle may offer broader insights into the initiation of autoimmune diseases in other tissues.

The significance of this discovery was highlighted by Nature Reviews Immunology, which published a Research Highlight by Kirsty Minton entitled “Sympathetic nerve activity primes susceptibility to autoimmune hair loss” on October 5, 2026. The highlight discusses how physiological sympathetic nerve activity can destabilize hair follicle immune privilege through ERV reactivation and innate immune activation, and how Tregs prevent this susceptible state from developing into autoimmune disease.

Jun Cui and Peng Wu are co-first authors of this study. Dr. Ting Chen at NIBS/TIMBR is the corresponding author. Other contributors include Ying Chang, Yi Yu, Zhi Gao, Yejing Ge, Bin Li, Huanwei Huang, and Jianmin Chang. The research was conducted in collaboration with Beijing Hospital, Beijing Normal University, and The University of Texas MD Anderson Cancer Center.

This work was supported by the Beijing Municipal Natural Science Foundation, the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the New Cornerstone Science Foundation through the XPLORER PRIZE.

Original Article:

Cui J, Wu P, Chang Y, Yu Y, Gao Z, Ge Y, Li B, Huang H, Chang J, Chen T. A two-hit mechanism triggers autoimmune hair loss. Nature. 2026.

http://doi.org/10.1038/s41586-026-11098-y

Research Highlight:

Minton K. Sympathetic nerve activity primes susceptibility to autoimmune hair loss. Nature Reviews Immunology. 2026.

http://doi.org/10.1038/s41577-026-01365-4