Combating Stress by Targeting Innate Immunity to Stop the War against Melanocytes in Vitiligo

Vitiligo is an autoimmune skin disease characterized by loss of melanin-producing melanocytes, resulting in appearance of white macules on the skin. It is a complex disease involving not only genetics but immune, environmental, and psychosocial components as well as oxidative stress and intrinsic melanocyte defects. Research over the last 10 years or so has demonstrated the role of the type I IFN (i.e., IFN-I) pathway as a characteristic feature of autoimmune diseases, including vitiligo (Bertolotti et al., 2014Bertolotti A. Boniface K. Vergier B. Mossalayi D. Taieb A. Ezzedine K. et al.Type I interferon signature in the initiation of the immune response in vitiligo.Pigment Cell Melanoma Res. 2014; 27: 398-407Crossref PubMed Scopus (106) Google Scholar). Furthermore, the importance of IFN-γ secretion, CD8+ T cells, and excessive oxidative stress is established in immune-mediated melanocyte destruction (Li et al., 2017Li S. Zhu G. Yang Y. Jian Z. Guo S. Dai W. et al.Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes.J Allergy Clin Immunol. 2017; 140: 177-189.e9Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). However, the effect of IFN-I on IFN-γ production in vitiligo and the exact mechanisms promoting oxidative stress–induced IFN-γ production in the skin remained largely unknown. In their recent publication in the Journal of Investigative Dermatology, Lee et al., 2023Lee E.J. Kim J.Y. Yeo J.H. Park S. Bae Y.J. Kwon I.J. et al.ISG15-USP18 dysregulation by oxidative stress promotes IFN-γ secretion from CD8+ T cells in vitiligo [e-pub ahead of print].J Invest Dermatol. 2023; (accessed August 23, 2023)https://doi.org/10.1016/j.jid.2023.08.006Abstract Full Text Full Text PDF Scopus (1) Google Scholar provide the causative link between these innate and adaptive factors and the cascade of early events that ultimately lead to melanocyte destruction. They propose stress-induced mechanisms to involve dysregulation of the innate immune genes ISG15 and USP18 in melanocytes and keratinocytes, leading to increased cutaneous expression of ISG15 and subsequent production of IFN-γ by cytotoxic CD8+ T cells; the hallmark cytokine of vitiligo pathogenesis. Both ISG15 and USP18 are induced by type I IFN signaling and play a critical role in innate immunity against viral infection. ISG15 is a ubiquitin-like effector protein capable of inducing secretion of IFN-γ from CD8+ T cells, and USP18 (a deubiquitinase or DUB) negatively regulates its activity to suppress excessive IFN-I signaling. Congenital deficiencies in ISG15 have confirmed its critical role in skin homeostasis and elimination of oxidative stress (Malik et al., 2022Malik M.N.H. Waqas S.F.U.H. Zeitvogel J. Cheng J. Geffers R. Gouda Z.A.E. et al.Congenital deficiency reveals critical role of ISG15 in skin homeostasis.J Clin Invest. 2022; 132e141573Crossref Scopus (12) Google Scholar). In their article, Lee et al., 2023Lee E.J. Kim J.Y. Yeo J.H. Park S. Bae Y.J. Kwon I.J. et al.ISG15-USP18 dysregulation by oxidative stress promotes IFN-γ secretion from CD8+ T cells in vitiligo [e-pub ahead of print].J Invest Dermatol. 2023; (accessed August 23, 2023)https://doi.org/10.1016/j.jid.2023.08.006Abstract Full Text Full Text PDF Scopus (1) Google Scholar initially demonstrated that hydrogen peroxide (H2O2) and HMGB1 treatment increased ISG15 in most skin cells, and this expression was much more pronounced in patients with vitiligo compared to the expression in healthy controls. Knocking out USP18 in normal human melanocytes resulted in the same IFN-I signature and ROS levels as in vitiligo melanocytes, whereas USP18 depletion in keratinocytes increased extracellular ISG15 and vitiligo-associated cytokines. In PBMCs, incubation with ISG15 induced some IFN-γ production by human embryonic kidney 293T cells, which was potentiated in the presence of IL-15, suggesting that ISG15 and IL-15 act synergistically to induce systemic IFN-γ production by T cells. Interestingly, the investigators report that USP18 levels were not induced as expected but in fact suppressed in vitiligo melanocytes. The investigators showed this to be attributable to hypermethylation of the USP18 promoter region in vitiligo melanocytes and nonlesional vitiligo skin. Demonstrating that oxidative stress in healthy skin cells can promote methylation of the USP18 promoter, they propose this to be the mechanism driving H2O2-induced USP18 downregulation in vitiligo. It is interesting to note that this hypermethylation is seen in normal-appearing skin of patients with vitiligo, suggesting that these changes precede depigmentation. This observation is consistent with the findings of a number of other studies demonstrating that normal-appearing skin of patients with vitiligo is not normal at all and that susceptibility to the innate immunity response to oxidative stress may be present throughout the entire skin surface of patients with vitiligo. If dysregulation in ISIG15 and/or USP18 is responsible for subsequent detrimental cascade of events leading to melanocyte destruction, the aim of swinging the balance is not only to suppress ISG15 production but also to upregulate USP18. Because hypomethylation can be associated with carcinogenesis and chromosomal rearrangements, targeting IFN-stimulated gene with systemic type I IFN antagonists or anti-IFN mAbs may prove beneficial in patients with vitiligo. This approach has been demonstrated in patients with systemic lupus erythematosus using mAb targeting BDCA2 (receptor on plasmacytoid dendritic cells whose engagement inhibits the release of IFN-α) (Werth et al., 2022Werth V.P. Furie R.A. Romero-Diaz J. Navarra S. Kalunian K. van Vollenhoven R.F. et al.Trial of anti-BDCA2 antibody Litifilimab for cutaneous lupus erythematosus.N Engl J Med. 2022; 387: 321-331Crossref PubMed Scopus (31) Google Scholar) and in those with psoriasis using TYK2 inhibitors such as deucravacitinib (Strober et al., 2023Strober B. Thaçi D. Sofen H. Kircik L. Gordon K.B. Foley P. et al.Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program for Evaluation of TYK2 inhibitor psoriasis second trial.J Am Acad Dermatol. 2023; 88: 40-51Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Whether this approach would result in clinical efficacy for patients with vitiligo remains to be tested, but it seems likely that targeting the ISIG15–USP18 axis as an initial trigger of oxidative stress and DNA damage in vivo requires closer inspection. Moreover, whether the same mechanisms are implicated in other damage-associated molecular pattern– and pathogen-associated molecular pattern–induced early triggers of vitiligo such as environmental exposure to UV and/or house dust mites (HDMs) (Bzioueche et al., 2023Bzioueche H. Boniface K. Drullion C. Marchetti S. Chignon-Sicard B. Sormani L.L. et al.Impact of house dust mite in vitiligo skin: environmental contribution to increased cutaneous immunity and melanocyte detachment.Br J Dermatol. 2023; 189: 312-327Crossref Scopus (4) Google Scholar) remains to be examined. In both UV- and HDM-induced melanocyte death, oxidative stress, DNA damage, and initiation of innate immunity are important contributors to melanocyte fragility. It would be interesting to look at how and whether type I IFN levels can be modified by directly fighting oxidative stress with new-generation antioxidants (Fontas et al., 2021Fontas E. Montaudié H. Passeron T. Oral gliadin-protected superoxide dismutase in addition to phototherapy for treating non-segmental vitiligo: a 24-week prospective randomized placebo-controlled study.J Eur Acad Dermatol Venereol. 2021; 35: 1725-1729Crossref Scopus (10) Google Scholar). There are increasing data pointing to the importance of the innate immune system in initiation of vitiligo (reviewed by Boniface et al., 2021Boniface K. Passeron T. Seneschal J. Tulic M.K. Targeting innate immunity to combat cutaneous stress: the vitiligo perspective.Front Immunol. 2021; 12613056Crossref Scopus (16) Google Scholar). This new study by Lee et al., 2023Lee E.J. Kim J.Y. Yeo J.H. Park S. Bae Y.J. Kwon I.J. et al.ISG15-USP18 dysregulation by oxidative stress promotes IFN-γ secretion from CD8+ T cells in vitiligo [e-pub ahead of print].J Invest Dermatol. 2023; (accessed August 23, 2023)https://doi.org/10.1016/j.jid.2023.08.006Abstract Full Text Full Text PDF Scopus (1) Google Scholar consolidated these findings; furthermore, it proposes a working model to link innate and adaptive immunity in vitiligo, that is, initial oxidative stress, leading to alarmin-induced production of type I IFN, leading to subsequent production of IFN-γ by cytotoxic T cells. The most interesting aspect of this study illustrates how ISG15 and IL-15 (a vitiligo activity–like cytokine) work synergistically to increase IFN-γ production by cytotoxic CD8+ T cells through activation of LFA-1 or CD11a/CD18 receptor on CD8+ T cells and reveals that this effect was specific to IFN-γ production because perforin and granzyme B were not affected. LFA-1 is a key integrin that regulates leukocyte adhesion and migration in inflamed tissues. What these results imply is that the use of LFA-1 antagonists or blocking interactions with its ligands (ICAM1-3) may prove to be useful in combating depigmentation. Successful repigmentation was reported in a patient with vitiligo after treatment with efalizumab (Wakkee et al., 2008Wakkee M. Assen Y.J. Thio H.B. Neumann H.A.M. Repigmentation of vitiligo during efalizumab.J Am Acad Dermatol. 2008; 59: S57-S58Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar); however, this remains to be formally tested in the clinic on a greater number of patients. In addition, blocking IL-15 at the early silent autoimmune stage is likely to be an important strategy to inhibit early IFN-γ production and not only subsequent recruitment and retention of memory T cells in the skin but also by inhibiting NK activity. Phase II clinical trials are currently underway to determine whether blocking IL-15 or IL-15 receptor can effectively induce repigmentation in patients with vitiligo. This new study significantly adds to our understanding of the pathways involved in early triggers of skin intrinsic susceptibility, which we can aim to target for prevention of oxidative stress–induced melanocyte loss. Over the last decade, the role of innate immunity in vitiligo has become undisputable, and in this study, Lee et al., 2023Lee E.J. Kim J.Y. Yeo J.H. Park S. Bae Y.J. Kwon I.J. et al.ISG15-USP18 dysregulation by oxidative stress promotes IFN-γ secretion from CD8+ T cells in vitiligo [e-pub ahead of print].J Invest Dermatol. 2023; (accessed August 23, 2023)https://doi.org/10.1016/j.jid.2023.08.006Abstract Full Text Full Text PDF Scopus (1) Google Scholar describe how this innate dysfunction directly leads to activation of long-term autoimmunity. Our challenge is to recognize these initial danger pathways in susceptible individuals and act upon them before this bridge is crossed and before the direct, powerful attack on melanocytes begins.