JAK-STAT Pathway and the Genetic Underpinnings of Alopecia Areata
The JAK-STAT pathway is a proinflammatory signaling pathway used by cytokines in alopecia areata1,2
It can be simplified into three main signaling strata2:
- Specific ligands (interferons [IFNs], interleukins [ILs], other cytokines, and hormones) bind to the cell surface receptor
- Intracellular Janus kinases (JAKs, which include JAK1, JAK2, JAK3, TYK2) are kinases that activate the signal transducer and activator of transcription (STAT) proteins
- STAT then translocates to the cell nucleus and promotes expression of certain genes critical in maintaining innate and adaptive immunity
Cytokines such as IFN-γ and IL-15 mediate their downstream effects through the JAK-STAT pathway.1,3
Waning of immune privilege during the anagen phase allows hair follicles to be targeted by CD8+ T cells and NKG2D+ cells, followed by a marked IFN-γ response and upregulation of γ-chain cytokines (IL-15, IL‑2, IL-7, and IL-21).2
Ligand binding induces dimerization of receptor-associated JAKs, which activates the JAK-STAT pathway. Receptor-associated JAKs then bind to ATP and become active, continuing the signaling cascade.3
Activation of STAT transcription factors leads to their translocation to the nucleus, where they regulate the transcription of genes involved in the production of proinflammatory cytokines. Studies suggest that these proinflammatory cytokines are responsible for disease maintenance in alopecia areata.1,2
Secretion of IL-15 by follicular epithelial cells leads to the recruitment and activation of cytotoxic T cells, which secrete IFN-γ. This causes a positive feedback loop, as IFN-γ binds to follicular epithelial cell receptors to activate JAK-STAT signaling for further secretion of IL-15.1,4
Researchers suggest that abnormal levels of cytokines at hair follicles feed the cycle of an overactive JAK-STAT signaling cascade causing inflammation and hair loss.4
Genetic inheritance may have a role in causing alopecia areata5:
In a study, 10% to 52% of affected pediatric patients can identify a family member with alopecia areata.6
The observed concordance rate from a study on identical twins with alopecia areata is 55%.7
A genome-wide association study analysis in humans identified 14 genetic loci associated with alopecia areata. Notably, the majority are involved in immune function.8
Family members may have other autoimmune diseases that are associated with alopecia areata, further supporting a genetic predisposition.6
Related Resources
Chapter 3: The JAK-STAT Pathway in Alopecia Areata
This video shows the JAK-STAT pathway in alopecia areata.
References
- Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043-1049. doi:10.1038/nm.3645
- Triyangkulsri K, Suchonwanit P. Role of Janus kinase inhibitors in the treatment of alopecia areata. Drug Des Devel Ther. 2018;12:2323-2335. doi:10.2147/DDDT.S172638
- O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-328. doi:10.1146/annurev-med-051113-024537
- Divito SJ, Kupper TS. Inhibiting Janus kinases to treat alopecia areata. Nat Med. 2014;20(9):989-90. doi:10.1038/nm.3685
- Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466(7302):113-117. doi:10.1038/nature09114
- Fricke ACV, Miteva M. Epidemiology and burden of alopecia areata: a systematic review. Clin Cosmet Investig Dermatol. 2015;8:397-403. doi:10.2147/CCID.S53985
- Jackow C, Puffer N, Hordinsky M, et al. Alopecia areata and cytomegalovirus infection in twins: genes versus environment? J Am Acad Dermatol. 1998;38:418-425. doi:10.1016/s0190-9622(98)70499-2
- Pratt CH, King LE Jr, Messenger AG, et al. Alopecia areata. Nat Rev Dis Primers. 2017;3:17011. doi:10.1038/nrdp.2017.11
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