VITILIGO AND JAK: THE UNDERLYING STORY

Vitiligo develops in genetically susceptible individuals when environmental triggers induce stress responses in the skin, causing an autoimmune response1 in which melanocytes are targeted and destroyed by CD8+ T-cells.2 IFN-γ-driven JAK‑STAT signaling plays a central role in disease pathogenesis.2

TRIGGER EVENT:

An environmental trigger combined with genetic factors leads to melanocyte stress, causing an inflammatory response.3

Image of an environmental trigger combined with genetic factors leading to melanocyte stress, causing an inflammatory response

IMMUNE ACTIVATION:

Innate immune cells activate CD8+ T-cells that target melanocytes and release IFN-γ.3

Image of innate immune cells activating CD8+ T-cells that target melanocytes and release IFN-γ

JAK-STAT ACTIVATION AND INFLAMMATORY CYCLE TRIGGERING:

IFN-γ activates the JAK-STAT pathway (by binding to JAK 1 and 2) to induce production of CXCL9/10 (immune mediators) by keratinocytes. More autoreactive T-cells are attracted to the site and continue the inflammatory cycle by producing more IFN-γ (in a positive feedback loop).3-5

Image of JAK-STAT activation and inflammatory cycle triggering

MELANOCYTE DEATH AND DEPIGMENTATION:

T-cell-mediated melanocyte death leads to depigmentation. This creates a hostile environment for melanocytes.3,5

Image of T-cell-mediated melanocyte death, leading to depigmentation

Process of repigmentation

Repigmentation may occur once the inflammatory response is suppressed and melanocyte precursors are stimulated to proliferate, migrate, and become mature melanocytes which can slowly begin to produce pigment.8 The main sources of melanocytes and melanocyte precursors are the hair follicles and the epidermis at the lesion borders.8 The precise molecular and cellular mechanisms underlying vitiligo repigmentation still remain to be confirmed.9

Repigmentation is a gradual process that can take weeks to months depending on the location of the lesion on the body.8

Image displaying the process of repigmentation

Repigmentation occurs most quickly in areas with a greater density of hair follicles8:

Higher density of hair follicles More rapid repigmentation

  • Face
  • Arms
  • Forearms
  • Thighs
  • Legs
  • Abdomen
  • Back

Medium density of hair follicles Slower repigmentation

  • Back of Hands
  • Fingers
  • Feet
  • Toes

Low density of hair follicles Rarely repigment

  • Palms
  • Soles
  • Pale-side of wrists
  • Genitals
  • Mucosal or semimucosal surfaces
  • Areas with white terminal hairs

PATTERNS OF REPIGMENTATION

There are 3 clinical patterns of repigmentation, illustrated below. In addition, a combined pattern of repigmentation may not fit any single pattern and instead shows features of several types.8

Image showing perifollicular skin repigmentation pattern

Perifollicular8,10

Image showing marginal skin repigmentation pattern

Marginal8,10

Image showing diffuse skin repigmentation pattern

Diffuse8,10

Review who gets vitiligo and why, as well as how it affects them.

Revisit Vitiligo

References

1. Manga P, Elbuluk N, Orlow SJ. Recent advances in understanding vitiligo. F1000Res. 2016;5:F1000 Faculty Rev-2234. doi:10.12688/f1000research.8976.1

2. Damsky W, King BA. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol. 2017;76(4):736-744. doi:10.1016/j.jaad.2016.12.005

3. Strassner JP, Harris JE. Understanding mechanisms of autoimmunity through translational research in vitiligo. Curr Opin Immunol. 2016;43:81-88. doi:10.1016/j.coi.2016.09.008

4. Frisoli ML, Essien K, Harris JE. Vitiligo: mechanisms of pathogenesis and treatment. Annu Rev Immunol. 2020;38:621-648. doi:10.1146/annurev-immunol‑100919-023531

5. Howell MD, Kuo FI, Smith PA. Targeting the Janus kinase family in autoimmune skin diseases. Front Immunol. 2019;10:2342. doi:10.3389/fimmu.2019.02342

6. Migayron L, Boniface K, Seneschal J. Vitiligo, from physiopathology to emerging treatments: a review. Dermatol Ther (Heidelb). 2020;10(6):1185-1198. doi:10.1007/s13555-020-00447-y

7. Taneja N, Sreenivas V, Sahni K, Gupta V, Ramam M. A cross-sectional study of spontaneous repigmentation in vitiligo. Indian J Dermatol Venereol Leprol. 2020;86(3):240-250. doi:10.4103/ijdvl.IJDVL_409_18

8. Birlea SA, Goldstein NB, Norris DA. Repigmentation through melanocyte regeneration in vitiligo. Dermatol Clin. 2017;35(2):205-218. doi:10.1016/j.det.2016.11.015

9. Gan E, Eleftheriadou V, Esmat S, et al. Repigmentation in vitiligo: position paper of the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res. 2016;30(1):28-40. doi:10.1111/pcmr.12561

10. Falabella R. Vitiligo and the melanocyte reservoir. Indian J Dermatol. 2009;54(4):313-318. doi:10.4103/0019-5154.57604