Comment on ‘Vitiligo in a COVID‐19‐vaccinated patient with ulcerative colitis: coincidence?’: Type I interferons as possible link between COVID‐19 vaccine and vitiligo

Dear Editor

We read with interest the article by Aktas and Ertuğrul ¹ published recently in Clinical and Experimental Dermatology. ¹ The authors describe a 58‐year‐old man with ulcerative colitis who developed symmetrically distributed vitiligo facial patches about 1 week after receiving the first dose of mRNA vaccine. ¹ The authors then pondered on the possible underlying immunological mechanism. We would like to highlight the possible link of Type I interferons (IFN‐I) and their main cellular source, the plasmacytoid dendritic cell (pDC), which may explain vitiligo development after COVID‐19 vaccine.

The significant role that IFN‐I and pDCs play against coronaviruses including COVID‐19 has recently been established. ² Having plasma cell morphology, pDCs are a unique subset of DCs that play an important role in innate immunity through their ability to sense nucleic acids via their Toll‐like receptors, (TLR)9 and TLR7, located in endosomal compartments. ³ Upon activation of TLR7/9, pDCs produce massive amounts of IFN‐I, which chiefly function in antiviral immunity. Essentially, pDCs are the most potent producers of IFN‐I, which are crucial cytokines functioning in the control of viral replication by inducing gene expression. ² , ³ pDCs also contribute to the adaptive immunity by regulating other immune cells through IFN‐I and proinflammatory cytokines. Coronaviruses, including COVID‐19, have been shown to be strong inducers of IFN‐I by being effective pDC stimulators. ² Additionally, COVID‐19 vaccines, including adenovirus (DNA delivered within nonreplicating recombinant adenovirus vector systems) and mRNA vaccines, incite immunity to COVID‐19 by producing high levels of viral spike proteins. ⁴ Whereas adenovirus vaccines interact with multiple pattern‐recognition receptors (especially TLR9), mRNA vaccines interact with various endosomal (particularly TLR7) and cytosolic innate sensors (inflammasome components). ⁴ Notwithstanding these variations, both kinds of vaccines converge on IFN‐I production, which possibly occurs through pDC‐mediated immune response. ⁴ However, non‐pDC‐mediated innate immune responses may also be at play.

Concerning vitiligo pathogenesis, multiple complex pathogenic factors contribute to the pathogenic hallmark of epidermal melanocyte loss, among which the leading hypothesis is vitiligo being an immune‐mediated inflammatory disorder involving adaptive and innate immunity. ⁵ Both IFN‐I and pDCs were first shown to be important mechanistic players in vitiligo when the presence of pDCs was demonstrated to be part of the inflammatory infiltrate in progressive vitiligo with local production of human myxovirus resistance protein 1 (MxA), the tissue expression of which is considered as a surrogate marker of local tissue MxA production. ⁵ The intense MxA expression demonstrated in perilesional areas close to the remaining melanocytes that were surrounded by noticeable T‐cell inflammatory infiltrate suggested that IFN‐I production and pDC recruitment is an early event in vitiligo progression. ⁵ Further evidence of an important role of IFN‐I and pDCs in vitiligo comes from clinical observations. ⁵ Vitiligo or vitiligo‐like hypopigmentation can be induced by treatment of patients with recombinant IFN‐α or at the site of application of imiquimod, a TLR‐7 agonist known to enhance IFN‐α production by being a potent pDC activator. ⁵ Finally, vitiligo is often associated with inflammatory diseases such as lupus, alopecia areata and psoriasis, for which evidence suggests an important role for IFN‐Is and pDCs in their underlying pathogenesis. ³ , ⁵ Given this, the ability of COVID‐19 vaccine to induce IFN‐I leading to induction of vitiligo would not then be surprising.

In summary, COVID‐19 infection or vaccination is capable of activating an IFN‐I‐mediated immune response that may serve as a trigger to IFN‐driven inflammatory disorders such as vitiligo in genetically predisposed persons.