10.5826/dpc.1304S2a314S
Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of melanocytes. The better understanding of the disease mechanisms is currently undergoing a significant dynamism, opening a new era in therapeutic development. The pathophysiology of vitiligo has attracted the attention of researchers for years and many advances have been made in clarifying the crosstalk between the cellular players involved in the development of vitiligo lesions. The understanding of the complex interactions between epidermal cells (i.e.  melanocytes and keratinocytes), dermal fibroblasts, and immune cells, led to a better characterization of the signals leading to the loss of melanocytes. Recent advances highlighted the role resident T memory cells in the development and recurrence of lesions. This narrative review aims to give an overview of the mechanisms leading to melanocyte disappearance in vitiligo, with a focus on the intercellular interaction network involved in the activation of the local skin immune response.
text/xml
2160-9381
3921
en
Katia  Boniface
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
cytokines
Aetiopathogenesis of Vitiligo
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-12-19
2023-10-06
2023-12-19
2024-01-25
e2023314S
Dermatol Pract Concept
Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of melanocytes. The better understanding of the disease mechanisms is currently undergoing a significant dynamism, opening a new era in therapeutic development. The pathophysiology of vitiligo has attracted the attention of researchers for years and many advances have been made in clarifying the crosstalk between the cellular players involved in the development of vitiligo lesions. The understanding of the complex interactions between epidermal cells (i.e.  melanocytes and keratinocytes), dermal fibroblasts, and immune cells, led to a better characterization of the signals leading to the loss of melanocytes. Recent advances highlighted the role resident T memory cells in the development and recurrence of lesions. This narrative review aims to give an overview of the mechanisms leading to melanocyte disappearance in vitiligo, with a focus on the intercellular interaction network involved in the activation of the local skin immune response.
Katia  Boniface
2023/12/19
10.5826/dpc.1304S2a314S
e2023314S
University of Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France
2160-9381
cytokines
en
e2023314S
Le Poole IC, Mehrotra S. Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo. J Investig Dermatol Symp Proc. 2017;18:S38–45. [PMID: 28941492].
Aetiopathogenesis of Vitiligo
https://dpcj.org/index.php/dpc/article/download/3921/2435
                              Aetiopathogenesis of Vitiligo
                                                           Katia Boniface1


1 University of Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France



Key words: vitiligo, melanocytes, keratinocytes, fibroblasts, immune cells, resident memory T cells, cytokines
Citation: Boniface K. Aetiopathogenesis of Vitiligo. Dermatol Pract Concept.2023;13(4)S2:e2023314S. DOI: https://doi.org/10.5826/
dpc.1304S2a314S
Accepted: December 11, 2023; Published: December 2023
Copyright: ©2023 Boniface. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: Katia Boniface received grants from Calypso Biotech, LEO Pharma, Pfizer, Pierre Fabre, Sanofi, and has a patent on
MMP9 inhibitors and uses thereof in the prevention or treatment of a depigmenting disorder and three-dimensional model of depigmenting
disorder.
Corresponding Author: Katia Boniface: Bordeaux University, CNRS, ImmunoConcept, UMR 5164, F-33000 Bordeaux, France katia.
boniface@u-bordeaux.fr




  ABSTRACT             Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of
                       melanocytes. The better understanding of the disease mechanisms is currently undergoing a signifi-
                       cant dynamism, opening a new era in therapeutic development. The pathophysiology of vitiligo has
                       attracted the attention of researchers for years and many advances have been made in clarifying the
                       crosstalk between the cellular players involved in the development of vitiligo lesions. The understand-
                       ing of the complex interactions between epidermal cells (i.e. melanocytes and keratinocytes), dermal
                       fibroblasts, and immune cells, led to a better characterization of the signals leading to the loss of
                       melanocytes. Recent advances highlighted the role resident T memory cells in the development and
                       recurrence of lesions. This narrative review aims to give an overview of the mechanisms leading to
                       melanocyte disappearance in vitiligo, with a focus on the intercellular interaction network involved in
                       the activation of the local skin immune response.




Introduction                                                             is high, corresponding to about 80% of the risk, whereas
                                                                         environmental factors account for 20% [2,3]. Indeed, four
The pathophysiology of vitiligo is complex and involves                  large-scale GWAS, three of which were carried out on Euro-
combinatorial factors (genetic predisposition, environmen-               pean and North American populations and one on an Asian
tal triggers, intrinsic melanocyte abnormalities, oxidative              (Chinese) populations, identified more than fifty vitiligo
stress), leading to an exaggerated activation of the innate              susceptibility genes [4–7]. Interestingly, most of these genes
and adaptive immune response (Fig. 1) [1]. Genome wide                   are associated with proteins related to innate, adaptive or
association studies (GWAS) have improved the understand-                 regulatory immune responses. Others regulate cell apoptosis
ing of the genetic architecture of vitiligo. It is considered that       and some genes are related to proteins regulating melanocyte
the overall risk of vitiligo linked to genetic determinants              function. This review discusses how the crosstalk between



Review | Dermatol Pract Concept. 2023;13(4)S2:e2023314S                                                                              1
Figure 1. Pathophysiological mechanisms of vitiligo. In a genetically predisposed individual and under environmental triggers, epidermal
cells (keratinocytes and melanocytes) will release danger signals (e​​​​​​​.g.: HSP70), leading to the activation of the innate immune system.
IFNγ-producing innate lymphoid cells (ILC1) or IFNα-producing plasmacytoid dendritic cells will induce the production of chemokines,
such as CXCL9, CXCL10, or CXCL16 by epidermal and dermal cells. Melanocytes expressing the CXCR3B subunit can be impacted by the
interaction with these ligands. Together, these events will induce local activation of resident memory T cells and the recruitment of circulating
T cells expressing CXCR3 and NKG2D and producing elevated levels IFNγ and TNFα, leading to the loss of melanocytes and depigmentation.




epidermal, dermal, and immune cells leads to melanocyte                   targets to prevent the initiation of disease-causing autoim-
disappearance in vitiligo.                                                munity [15]. Indeed, HMGB1 can induce the production of
                                                                          chemokines, such as ligand (C-X-C motif) CXCL16 or inter-
Initiation of the Disease: Bridging Oxidative Stress,                     leukin (IL)-8 by epidermal cells (melanocytes and keratino-
Epidermal, Dermal Cells and the Activation                                cytes), which are important for the recruitment of immune
of the Innate Immune Response                                             cells [11]. CRT may induce apoptosis of melanocytes and
For many years, it has been considered that melanocytes lo-               the release of membrane debris important for immunogenic-
cated in the non-lesional pigmented skin of vitiligo patients             ity [10]. Lastly, several studies from the group of Le Poole
are more sensitive to oxidative stress by releasing elevated              emphasized the role of HSP70i in vitiligo [13,16–18], and
levels of reactive oxygen species (ROS), associated with an               our group showed its involvement in the activation of innate
imbalance in the antioxidant system [8]. Keratinocytes and                immunity and the production of type I interferon (IFN) [14].
fibroblasts also display increased levels of ROS [9]. This ac-                Keratinocytes also play an important role in the physio-
cumulation of ROS leads to several intracellular events such              pathology of vitiligo. Structural alterations of keratinocytes
as DNA abnormalities and premature apoptosis that induce                  have been observed in the non-lesional skin of patients, with
the release of several melanocyte peptides as well as abnor-              abnormal thickening of the epidermis due to an increase in
mal melanocyte function and melanin production [8].                       the spinous layer [19]. Alterations of basal and suprabasal
    Melanocytes produce pro-inflammatory signals such as                  keratinocytes, in particular vacuolar degeneration and spon-
damage-associated-molecular patterns (DAMPs) and chemo-                   giosis, are sometimes found [20]. At the peri-lesional site
kines, leading to the activation of the immune response and               (at the edge of the lesions, where melanocytes are still pres-
the recruitment of immune cells. Among these danger signals,              ent), keratinocytes have the capacity to produce several fac-
inducible heat shock protein 70 (HSP70i), calreticulin (CRT)              tors that contribute to the generation of a pro-inflammatory
or high mobility group B1 (HMGB1) proteins are the most                   environment, such as stem cell factor (SCF), endothelin-1
evaluated in vitiligo [10–14]. These DAMPs released in the                (ET-1), and pro-inflammatory cytokines like IL-1β, IL-6,
extracellular environment are likely bridging cellular stress             and tumor necrosis factor (TNF)-α. Danger signals produced
and the autoimmune response directed against melanocytes                  locally in the skin are responsible for the activation of the
in vitiligo, and could therefore represent interesting potential          pyrin domain of NOD like receptor (NLR) proteins, such


2                                                                                   Review | Dermatol Pract Concept. 2023;13(4)S2:e2023314S
as NLRP3, an inflammasome activating protein, promoting              Vitiligo: Mainly a Type 1 Skewed
the secretion of IL-1β and IL-18 [21]. In addition, kerati-          Immune Response
nocytes from vitiligo non-lesional and peri-lesional skin re-        Analyses of vitiligo peri-lesional and lesional skin revealed
lease chemokines involved in the recruitment of T cells in           upregulation of type-1 associated pathways. Vitiligo is
the skin, like CXCL9, CXCL10, and CXCL16. CXCL9 and                  consistently associated with an infiltration of CD8 T cells
CXCL10, induced by IFNγ (an important cytokine in the                producing high levels of IFNγ and TNFα. These T cells are
physiopathology of vitiligo), bind to their cognate receptor         characterized by the expression of the receptor CXCR3 that
CXCR3 expressed on immune cells, and most T cells in vit-            respond CXCL9 and CXCL10, which are highly expressed
iligo patients skin express CXCR3 [14,22–24]. In addition,           in the skin of patients [24,41–44]. Targeting the CXCR3-
Xu et al. recently showed in a mouse model of vitiligo that          CXCL9 and CXCL10 axis in vitiligo seems to be a promising
IFNγ-responsive dermal fibroblasts, through their release of         therapeutic strategy in vitiligo [43,45]. Our group showed
chemokines, are active players in the homing of CD8 T cells          that natural killer group 2 member D (NKG2D) defines a
to the skin [25].                                                    subset of highly functional memory CD8 T cells in vitiligo
   Another innate inflammatory signature found increased             and may represent a potential therapeutic target [46]. This
in peri-lesional areas of vitiligo is the IFNα pathway, which        type-1 immune response appears to be a key driver of mela-
contributes to the activation of antigen-presenting cells in         nocyte loss in vitiligo and participates in every stage of the
the skin and the production of chemokines to reinforce the           pathogenesis. To date, IFNγ and TNFα immune pathways
recruitment of other immune populations at the peri-lesional         are the most studied in vitiligo. The binding of IFNγ to its
site [26,27]. IFNα production is linked to the presence of           receptor induces a signaling dependent of the Janus kinase
plasmacytoid dendritic cells and induces the release of              (JAK) and signal transducer and activator of transcription
chemokines such as CXCL9 and CXCL10 by epidermal cells               (STAT) pathways, in particular the activation of JAK1/2 and
[14,26]. In addition, the presence of innate immune lym-             STAT1. Interestingly, JAK inhibition appears to be a reliable
phoid type 1 cells (ILC1) in vitiligo skin has been recently         strategy to treat patients and ruxolitinib cream (a topical
demonstrated, which respond to non-specific stimuli and              JAK 1 and JAK 2 inhibitor) is now approved both in US and
produce significant amounts of IFNγ during the initiation of         EU for the management of vitiligo [47–49]. IFNγ induces
the disease, leading to early melanocyte apoptosis [28].             the production of CXCL9 and CXCL10 by keratinocytes,
                                                                     amplifying the inflammation and the recruitment of immune
Progression Phase of the Disease: Involvement                        cells expressing CXCR3 which will promote the progression
of a Cutaneous Immune Memory Response                                of vitiligo [14]. IFNγ and TNFα also have a direct impact
Following these initial events, vitiligo skin is characterized       on the function of melanocytes by decreasing the pigmen-
by the presence of a localized T cell infiltrate close to the epi-   tation process [50–55]. We recently demonstrated that the
dermis and residual melanocytes, mainly consisting of CD8            combined activity of these two cytokines induces the disrup-
T cells. Recent studies highlighted the involvement of resident      tion of E-cadherin expression, the main protein responsible
memory T cells (TRM) in disease pathogenesis [24,27,29–31].          for the adhesion of melanocytes to keratinocytes, leading to
TRM are long-lived memory T cells that persist in tissues like       their destabilization and detachment [53]. In addition, Tu-
the skin and are characterized by a specific transcriptional         lic et al. showed that melanocytes are able to express the B
program [32,33]. They express characteristic cell surface            isoform of CXCR3 in response to IFNγ, making them more
markers involved in their retention in the tissue, such as CD69,     susceptible to apoptosis in response to CXCL10 [28].
CD103, or CD49a, the latter marker defining a subset of TRM             Additional cytokines and signaling pathways may also
cells with cytotoxic properties [29,34–36]. It is now clear that     be involved in vitiligo pathogenesis. For example, elevated
the micro environment plays a crucial role in the formation          levels of IL-17 and IL-23 are found in the serum and/or skin
and regulation of TRM. Indeed, the expression of CD103 is            of vitiligo patients, and IL-17 has been reported to regulate
dependent on transforming growth factor (TGF)-β [36], and            melanocyte function and survival [56]. However, targeting
a growing number of studies reported the involvement of              IL-17 in vitiligo patients did not show a major benefit [57].
several pro-inflammatory cytokines involved in TRM homeo-            Type-2-related cytokines have been reported increased in vit-
stasis, such as IL-15, IL-12, IL-18, IL-33, IFNγ, TNFα [32].         iligo patients’ blood, and few studies showed an inhibition
The presence of TRM in vitiligo skin is undoubtedly linked           of melanogenesis in response to IL-4 and IL-13 [58–62]. Our
to the recurrence of lesions on previously affected anatomi-         group found that vitiligo skin is also associated with a type-2
cal sites that have repigmented following treatment [37], as         immune response and an increased production of IL-13 by
shown in psoriasis or atopic dermatitis [38–40]. Therefore,          T cells [27]. In addition, Jin et al. reported that IFNγ-induced
owing to their functional role in the pathogenesis of vitiligo,      dermal fibroblasts to release CCL2 and CCL8, inducing a
targeting TRM appears as a reliable therapeutic strategy.            type-2 cytokine profile in vitiligo skin lesion [63]. However,


Review | Dermatol Pract Concept. 2023;13(4)S2:e2023314S                                                                            3
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