10.5826/dpc.1401a95
Introductionː The roles of anti-adhesive podocalyxin (PODXL), ant-angiogenetic tumstatin/Col-IVα3 and neuroinflammation and innate immunity modulator Chitinase 1 (CHIT-1) in the etiology of vitiligo have not been studied yet.
Objectives: This study was planned to detect changes in serum PODXL, tumstatin/Col-IVα3 and CHIT1 levels in vitiligo patients.
Methods: This case-controlled study was performed on a total of 50 patients, 25 with vitiligo and 25 healthy controls. Participants in the vitiligo and control groups were matched in pairs for age and sex. At least 8-10 hours of overnight fasting, venous blood samples were taken from the participants in both groups and serum levels of podocalyxin, tumstatin/Col-IVα3 and CHIT 1 levels were measured by sandwich enzyme immunoassay.
Results: In the classification made according to the vitiligo European Task Force evaluation criteria, 18 of 25 vitiligo patients were in the slowly progressive phase and 7 patients were in the active progressive phase. Serum podocalyxin levels increased significantly in the vitiligo group compared to the controls (7.03±2.09 ng/ml vs. 4.99±1.20 ng/ml, p&lt;0.02). However, serum tumstatin levels in vitiligo patients showed a significantly lower course compared to controls (4.88±1.76 ng/ml vs. 6.05±2.19 ng/nl, p&lt;0.03). Serum CHIT-1 levels of vitiligo patients (42.4±7.22 ng/ml) were found to be significantly higher than the serum levels of the control group (34.5±5.33 ng/ml) (p&lt;0.01).
Conclusion: Increased podocalyxin and CHIT1 levels versus decreased tumstatin levels are new biomarkers that support the role of anti-adhesive, anti-angiogenic and neuroinflammatory pathways in the formation of vitiligo.
text/xml
2160-9381
3843
en
Şule Gençoğlu
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
immunity
Circulating Podocalyxin, Tumstatin/Col-IVα3 and Chitinase 1: New Culprits in Vitiligo Occurrence
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2024-01-31
2023-09-10
2024-01-31
2024-02-21
e2024095
Dermatol Pract Concept
Introductionː The roles of anti-adhesive podocalyxin (PODXL), ant-angiogenetic tumstatin/Col-IVα3 and neuroinflammation and innate immunity modulator Chitinase 1 (CHIT-1) in the etiology of vitiligo have not been studied yet.
Objectives: This study was planned to detect changes in serum PODXL, tumstatin/Col-IVα3 and CHIT1 levels in vitiligo patients.
Methods: This case-controlled study was performed on a total of 50 patients, 25 with vitiligo and 25 healthy controls. Participants in the vitiligo and control groups were matched in pairs for age and sex. At least 8-10 hours of overnight fasting, venous blood samples were taken from the participants in both groups and serum levels of podocalyxin, tumstatin/Col-IVα3 and CHIT 1 levels were measured by sandwich enzyme immunoassay.
Results: In the classification made according to the vitiligo European Task Force evaluation criteria, 18 of 25 vitiligo patients were in the slowly progressive phase and 7 patients were in the active progressive phase. Serum podocalyxin levels increased significantly in the vitiligo group compared to the controls (7.03±2.09 ng/ml vs. 4.99±1.20 ng/ml, p&lt;0.02). However, serum tumstatin levels in vitiligo patients showed a significantly lower course compared to controls (4.88±1.76 ng/ml vs. 6.05±2.19 ng/nl, p&lt;0.03). Serum CHIT-1 levels of vitiligo patients (42.4±7.22 ng/ml) were found to be significantly higher than the serum levels of the control group (34.5±5.33 ng/ml) (p&lt;0.01).
Conclusion: Increased podocalyxin and CHIT1 levels versus decreased tumstatin levels are new biomarkers that support the role of anti-adhesive, anti-angiogenic and neuroinflammatory pathways in the formation of vitiligo.
Şule Gençoğlu
2024/01/31
10.5826/dpc.1401a95
e2024095
Department of Dermatology, Gozde Academy Hospitals, Malatya, Turkey
2160-9381
immunity
en
e2024095
Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C et al. Differential Enzymatic Activity of Common Haplotypic Versions of the Human Acidic Mammalian Chitinase Protein. J. Biol. Chem. 2009;284:19650–8.
Circulating Podocalyxin, Tumstatin/Col-IVα3 and Chitinase 1: New Culprits in Vitiligo Occurrence
https://dpcj.org/index.php/dpc/article/download/3843/2460
     Circulating Podocalyxin, Tumstatin/Col-IVα3 and
     Chitinase 1: New Culprits in Vitiligo Occurrence
                                                          Şule Gençoğlu


Department of Dermatology, Gozde Academy Hospitals, Malatya, Turkey



Key words: Vitiligo, inflammation, adhesion, angiogenesis, immunity
Citation: Gençoğlu S. Circulating Podocalyxin, Tumstatin/Col-IVα3 and Chitinase 1: New Culprits in Vitiligo Occurrence. Dermatol Pract
Concept. 2024;14(1):e2024095. DOI: https://doi.org/10.5826/dpc.1401a95
Accepted: December 26, 2023; Published: January 2024
Copyright: ©2024 Gençoğlu. 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: None.
Corresponding Author: Şule Gençoğlu, MD, Department of Dermatology, Gozde Academy Hospitals, Gozde Academy Hospital, Ankara
Asfaltı 6. Km. No:219 (Makro Market Karşısı.) Malatya, Turkey. Phone: +9(0) 422 238 25 25 E-mail: sulegencoglu2309@gmail.com




  ABSTRACT             Introduction: The roles of anti-adhesive podocalyxin (PODXL), anti-angiogenetic tumstatin/
                       Col-IVα3 and neuro-inflammation and innate immunity modulator Chitinase 1 (CHIT-1) in the
                       ­etiology of vitiligo have not been studied yet.
                       Objectives: This study was planned to detect changes in serum PODXL, tumstatin/Col-IVα3 and
                       CHIT1 levels in vitiligo patients.
                       Methods: This case-controlled study was performed on a total of 50 patients, 25 with vitiligo and
                       25 healthy controls. Participants in the vitiligo and control groups were matched in pairs for age and
                       sex. At least 8-10 hours of overnight fasting, venous blood samples were taken from the participants
                       in both groups and serum levels of podocalyxin, tumstatin/Col-IVα3 and CHIT 1 levels were measured
                       by sandwich enzyme immunoassay.
                       Results: In the classification made according to the vitiligo European Task Force evaluation criteria,
                       18 of 25 vitiligo patients were in the slowly progressive phase and 7 patients were in the active pro-
                       gressive phase. Serum podocalyxin levels increased significantly in the vitiligo group compared to the
                       ­controls (7.03±2.09 ng/ml vs. 4.99±1.20 ng/ml, p<0.02). However, serum tumstatin levels in vitiligo
                        ­patients showed a significantly lower course compared to controls (4.88±1.76 ng/ml vs. 6.05±2.19 ng/nl,
                         p<0.03). Serum CHIT-1 levels of vitiligo patients (42.4±7.22 ng/ml) were found to be significantly
                         higher than the serum levels of the control group (34.5±5.33 ng/ml) (p<0.01).
                       Conclusion: High podocalyxin and CHIT1versus low tumstatin levels are new biomarkers that
                       ­support the role of anti-adhesive, anti-angiogenic and neuroinflammatory pathways in the formation
                        of vitiligo.




Original Article | Dermatol Pract Concept. 2024;14(1):e2024095                                                                       1
Introduction                                                       Basal membrane expression of tumstatin is controlled by ma-
                                                                   trix metalloproteinase-9, and when it binds to alphaV beta3
Vitiligo is the most common autoimmune, polygenic and mul-         integrin it also blocks new endothelial formation [8]. To
tifactorial cutaneous depigmentation disease ­characterized        demonstrate apical/basal membrane and keratinocytes dam-
by selective loss of melanocytes and melanin pigment [1].          age, we evaluated the levels of Podocalyxin (PODXL), an
­Although it varies according to the population studied, the       anti-adhesive molecule. PODXL is a glycosylated ­sialomucin
incidence in the general population approaches is 0.5%-            of the CD34 family expressed on apical cell surfaces [10, 11].
2.9% [2]. The absence of melanocytes leads to depigmen-            The expression of PODXL levels in the vascular endothe-
tation and a skin appearance characterized by chalky-white         lium, mesothelial cells and neurons in addition to the apical
macules [3]. Although the critical role of inherent and envi-      membranes may help us to explain the membrane damage in
ronmental factors in the development of the disease is well        the dermis-stratum basale region [12].
known, a complex set of mechanisms consisting of oxidative
stress, angiogenesis and proinflammatory pathway defects
lie behind the autoimmune picture [4]. According to the con-
                                                                   Objectives
vergence theory, the progressive loss of melanocytes is caused     The aim of this study was We tried to determine whether
by more than one factor or mechanism, suggesting that the          there is a defect in innate immunity by measuring serum
disease develops on a multifactorial basis [4–6]. As a result      Chitinase 1 (CHIT-1) levels. CHIT1 is a member of a chiti-
of a defect in the innate and adaptive immune system, the          nase family produced and secreted by macrophages and neu-
immune attack to the basal cell layer, where melanocytes are       trophils and has a critical role in the homeostasis of innate
located, damages both melanocytes and neighboring basal            immunity [13]. Its levels increase in autoimmune reactions
cells. The close neighborhood of the dermis and basal layer        and Th2-mediated inflammation [14]. There is no study
cells contains abundant sensorial, vascular and neuronal           investigating serum PODXL, tumstatin and CHIT-1 levels
components, which are necessary structures for melanocytes         in studies on etiology in vitiligo patients. Since vitiligo is
to be exposed to immune attack [1, 4].                             thought to develop at the dermis-stratum basal border as a
    Although the disease is characterized by the loss of mela-     result of melanocyte-keratinocyte separation due to endothe-
nocytes, all cells in the vicinity of the dermis and basal plate   lial damage and basement membrane disruption, PODXL,
should be affected by the immune attack, albeit at different       Col-IVα3 and 1 CHIT-1 protein analysis was performed to
rates [6]. If the loss of melanocyte causes degeneration and       represent each parameter [3-6].
detachment in neighboring cells, some degradation products
must be going into the systemic circulation.
                                                                   Methods
    The main initiator in the formation of both segmental
and non-segmental forms of vitiligo is an external or internal     This case-controlled study was performed on a total of
injury. This is followed by an increase in the release of in-      50 patients, 25 with vitiligo and 25 healthy controls. Par-
flammatory cytokines and neuropeptides and a widespread            ticipants in the vitiligo and control groups were matched in
vasodilation process at the dermis-stratum basale border.          pairs for age and sex. Patients over 45 years of age were not
Changes in the vascular bed cause a large number of immune         included in the study due to possible age-related changes in
cells from the dermal segment to target melanocytes and            the dermis vascular endothelium. A total of 25 patients diag-
neighboring cells in the basal segment [5, 6]. As a result, the    nosed with nonsegmental vitiligo (NSV) or segmental vitiligo
chain of autoimmune reactions that occur in the affected area      (SV) according to the 2011 international vitiligo classifica-
leads to the loss of melanocytes, leading to the emergence of      tion constituted the study group [15]. Mucosal, acrofacial,
the disease picture characterized by depigmentation [4, 6, 7].     generalized, universal and mixed localized forms formed
This study was designed considering that proinflammatory           NSV, while unisegmental, bisegmental or multisegmental vit-
reactions occurring at the dermis-stratum basale border pro-       iligos formed the SV group. The control group was selected
vide detachment and degeneration in melanocytes, keratino-         from 25 healthy individuals without systemic disease and
cytes, basal and dermis cells through (i) vascular endothelial     depigmented skin lesions. The diagnosis of vitiligo was made
damage, (ii) apical/basal membrane protein degradation and         by two experienced dermatologists based on the typical clin-
(iii) innate immunity [3–6]. To confirm the presence of vas-       ical appearance of the depigmented lesions and the images
cular endothelial destruction, we measured the levels of tum-      obtained in the Wood ‘s lamp examination.
statin, the NC1 domain of type IV collagen alpha 3, which is          Vitiligo was diagnosed in the presence of an amelatonic,
widely expressed in the vascular basement membrane.                sharp-edged and chalky-white macular lesion. We strength-
    Tumstatin is a breakdown product of type 4 collagen and        ened our diagnosis in the presence of a sharply demar-
prevents endothelial proliferation and angiogenesis [8, 9].        cated, bright blue-white fluorescent lesion on Wood’s light



2                                                                      Original Article | Dermatol Pract Concept. 2024;14(1):e2024095
examination. Since no biopsy or laboratory test was required       0.153 ng/mL. The measuring range of the Collagen type IV
for the diagnosis of vitiligo, these procedures were not per-      alpha 3 kit was 0.2–70 ng/mL, and the minimum measurable
formed. All applications in the study were carried out in ac-      level was 0.12 ng/mL. The measurement range of the CHIT 1
cordance with the principles of the Declaration of Helsinki.       kit was 0.5–120 ng/mL, and the minimum measurable level
The study was initiated after the protocol was approved by         (sensitivity) was 0.433 ng/mL.
the Malatya turgut özal universty ethics review board and
patient consent was obtained.                                      Statistical Analysis
    Due to the close relationship between vitiligo and other       All analyses were performed on IBM SPSS Statistics for
autoimmune diseases, patients diagnosed with Hashimoto             ­Windows, Version 21.0 (IBM Corp., Armonk, NY, USA).
thyroiditis, Addison disease, psoriasis, diabetes mellitus, sys-   For the normality check, the Shapiro-Wilk test was used.
temic lupus erythematosus or melanoma-associated leuco-            Data are given as mean ± standard deviation for continu-
derma and those with other endocrinopathy were excluded            ous variables according to normality of distribution and as
from the study. Patients with a history of systemic or topical     frequency (percentage) for categorical variables. Continuous
drug-induced depigmentation were also excluded from the            variables were analyzed with the independent samples t test
study. Patients who were pregnant or lactating, those who          or Mann Whitney U test. Categorical variables were ana-
had acute viral or bacterial infections and those who had          lyzed with the chi-square test or Fisher’s exact test. Pearson,
an additional dermatological disease were not included in          Spearman correlation coefficients was calculated to evaluate
the study. Cases with a family history of depigmented skin         relationships between serum markers and other variables.
lesions and a tendency to depigmentation due to topical or         P<0.05 was accepted as statistically significant.
systemic drug application were not included in the control
group. Similarly, those with a history of autoimmune and
endocrine diseases were not included in the control group.
                                                                   Results
    Age, gender, medical history, family history and body          Demographic data of both groups as well as serum podoca-
mass index (BMI) of the participants in both groups were           lyxin, CHIT-1 and tumstatin levels are presented in Table 1 in
recorded. In the classification made according to the vitiligo     detail. The number of participants in the vitiligo and healthy
European Task Force evaluation criteria, 18 of 25 vitiligo         control groups was similar. Although the mean age of the
patients were in the slowly progressive phase and 7 patients       vitiligo group was higher than the control group, the dif-
were in the active progressive phase. After at least 8-10 hours    ference did not reach statistical significance. Similarly, the
of overnight fasting, venous blood samples were taken from         BMI values of both groups were similar and consistent with
the participants in both groups and stored at - 20◦ C until        the overweight category values. The number of male partici-
analysis. Blood samples were collected on the third day of the     pants in both groups was determined as 16 and the number
menstrual cycle in female participants of reproductive age.        of female participants as 9. Since there was male dominance

Measurement of Serum Podocalyxin, Collagen
Type IV Alpha 3 and CHIT 1 Levels by Sandwich                           Table 1. Comparison of Demographic
Enzyme Immunoassay                                                 Characteristics and Potential New Serum Markers
Podocalyxin, collagen type IV alpha 3 and CHIT 1 levels               pf Patients in Vitiligo and Control Groups.
were measured in frozen-thawed serum samples using the                                    Vitiligo        Control       p-values*
quantitative sandwich enzyme immunoassay principle.                 N (%)                25 (50%)        25 (50%)          0.23
Commercially available human podocalyxin ELISA kit                  Age (years)         40.12±6.33 38.92±5.13µ             0.08
(Sunred Biotechnology Company, Shanghai, CHINA), col-               BMI (kg/m2)          26.3±3.98       25.8±4.11         0.44
lagen type IV alpha 3 kit (Bioassay Technology Laboratory,          Gender (Female          F:9            F:9              NA
Shanghai, CHINA) and human CHIT 1 ELISA kits (Sunred                or male)                M:16           M:16
Biotechnology Company, Shanghai, CHINA) were used for               Podocalyxin          7.03±2.09       4.99±1.20        <0.02
the measurements. Measurements were made in accordance              (ng/ml)
with the procedures specified in the catalogues. The absor-         Tumstatin            4.88±1.76       6.05±2.19        <0.03
bance of each sample was measured on the Bio-Tek ELx800             (collagen type
device at a wavelength of 450 nanometers. Concentrations            IV alpha 3)
of absorbances were calculated with the formula obtained            (ng/ml)
using the standard curve graph.                                     CHIT-1 (ng/ml)       42.4±7.22       34.5±5.33        <0.01
    The measuring range of the podocalyxin kit was                 *Results are given as Mean±SD. µP<0.05 was considered significant.
0.2–60 ng/mL, and the minimum measurable level was                 NA: Not applicable.CHIT: Chitinase 1; BMI: Body Mass Index



Original Article | Dermatol Pract Concept. 2024;14(1):e2024095                                                                     3
in the vitiligo group, appropriate selection was made in the           different serum markers that have not been studied before.
control participants as well.                                          These are, respectively, melanocyte adhesion defect, endo-
    Serum podocalyxin levels increased significantly in the            thelial dysfunction characterized by vascular collagen deg-
vitiligo group compared to the controls (7.03±2.09 ng/ml vs.           radation, and inherent defect in innate immunity. Our first
4.99±1.20 ng/ml, p<0.02). However, serum tumstatin levels in           focus is on melanocyte degeneration and depigmentation
vitiligo patients showed a significantly lower course compared         due to adhesion defect of melanocytes. For this purpose,
to controls (4.88±1.76 ng/ml vs. 6.05±2.19 ng/nl, p<0.03).             we evaluated serum levels of podacalyxin (PODXL), an
Serum CHIT-1 levels of vitiligo patients (42.4±7.22 ng/ml)             anti-adhesive molecule. PODXL was significantly higher
were found to be significantly higher than the serum levels            in vitiligo patients compared to healthy controls. In the
of the control group (34.5±5.33 ng/ml) (p<0.01). There was             presence of high PODXL, strong adhesion of melanocytes
no significant correlation between demographic characteris-            to keratinocytes does not occur because the conditions are
tics and serum ELISA markers in neither vitiligo nor control           not suitable for a healthy adhesion. Oxidative stress, in-
group. Figure 1 shows the distribution of serum podocalyxin,           flammation and mechanical effects can cause melanocytes
CHIT-1 and tumstatin levels between the groups.                        to separate and disappear easily in the presence of high
                                                                       anti-adhesive PDXL [19]. It has been previously reported

Conclusions                                                            that the expression of anti-adhesive molecules such as Te-
                                                                       nascin is increased in vitiligo patients [20]. Because PDXL
Although studies on the etiology and treatment of vitiligo             is expressed on apical ? epidermal surfaces, basal mem-
have gained weight in the last three decades, the data on              brane, vascular endothelium, and neurons, its increased
the diagnosis, treatment and how this disease occurs dates             expression in vitiligo patients may affect all cells in these
back to ancient times [16, 17]. The fact that autoimmune               regions [12]. Especially since the keratinocytes are affected
diseases such as Hasimoto, diabetes mellitus, alopecia and             by the increase in PDXL will prevent the adhesion of
Addison are more common in vitiligo patients suggested that            melanocyte and keratinocyte, melenocytes will lose their
vitiligo is also an autoimmune pathology [18]. However, a              attachment sites. Since keratinocytes and melanocytes to-
general consensus has not yet been reached on the mech-                gether form an “epidermal-melanin unit”, damage to one
anisms that trigger autoimmunity. Many factors have been               may cause damage to the other [21]. The risk of oxidative
held responsible in the etiology. Melanocyte adhesion defect           stress is higher because the keratinocytes of vitiligo pa-
and melanocyte degeneration due to oxidative stress, micro-            tients are defective in terms of mitochondria content [22].
vascularization defects due to vascular endothelial damage,            In the presence of increased reactivated oxygen species,
uncontrolled neuropeptide release from local nerve endings,            the melanin-keratinocyte unit will be damaged, and mela-
and inherent defects in innate immunity were the most fre-             nocyte loss and depigmentation will also accelerate. Since
quently accused mechanisms [16, 18].                                   there are no knock out models of the anti-adhesive effects
    In the current study, we will focus focused on three               of PODXL, we do not have clear data on the defective ex-
of the possible mechanisms of vitiligo etiology through                pression of this molecule in vitiligo.




         Figure 1. Graphical representation of the distribution of podocalyxin, CHT-1 and tumstatin levels in vitiligo and control
         groups.



4                                                                           Original Article | Dermatol Pract Concept. 2024;14(1):e2024095
    Since PODXL inhibits binding via adapter proteins in          For tumstatin to act, αVβ3 integrin receptors are needed in
many cells, it may cause loss of melanocytes by disrupt-          newly formed pathological vessels [26]. Decreased tumsta-
ing the integrity of the epidermal-melanin unit [23]. While       tin levels in vitiligo patients may increase neovascularization
PODXL is necessary for the continuation of the functions of       and blood flow by stimulating endothelial proliferation. In-
many organs such as kidney, pancreas, and breast, its patho-      creased angiogenesis and detection of VEGFR2 positive en-
logical expression may lead to the emergence of different         dothelial cells in animals with inherentdeletion of Col-IVα3/
diseases, including cancer [11, 24]. Since these functions of     tumstatin support the role of tumstatin in the vasculariza-
PODXL in cell adhesion under physiological conditions will        tion defect in vitiligo patients [26]. When our results and
be impaired in case of PODXL overexpression, it may con-          literature data are evaluated together, we can suggest that
tribute to melanocyte loss and disease progression in vitiligo    defective serum tumstatin release in vitiligo patients may
patients. Therefore, PODXL can be a new marker that may           contribute to neoangiogenesis and lesion spread. More clear
contribute to the formation of vitiligo, or it can be used as a   results can be obtained by staining tumstatin, MMP-9 and
potential biomarker in the differentiation of segmental and       integrin receptors in biopsy samples from vitiligo lesions.
nonsegmental vitiligo. In addition, it may offer an oppor-           The third etiological mechanism we focus on to explain
tunity to develop new treatment options if the relationship       is the tinherent defect in innate immunity. For this purpose,
of PODXL with vitilgo pathogenesis and subtypes is under-         we measured serum Chitinase 1 (CHIT-1) levels in vitiligo
stood more clearly.                                               patients. We found a significant increase in CHIT-1 levels
    The second etiological mechanism we focus on is endo-         in vitiligo patients compared to the control group. CHIT-1
thelial dysfunction and increased neovascularization due to       produced and released by macrophages and neutrophils is
type IV collagen alpha 3 destruction in the vascular basement     involved in the regulation of innate immunity [13]. CHIT-1
membrane. For this purpose, we measured serum tumstatin           is elevated in autoimmune reactions and T hepler-mediated
levels. We encountered significantly reduced serum tumsta-        inflammatory reactions [29]. Increased serum CHIT-1 lev-
tin levels in vitiligo patients compared to the control group.    els in vitiligo are compatible with the autoimmune and in-
Tumstatin is a molecule derived from the destruction of type      flammatory nature of the disease and can be considered as
IV collagen alpha 3 (Col-IVα3) in the vascular b
                                               ­ asement          evidence of impaired innate immunity. Although increased
membrane and is an angiogenesis inhibitor that blocks             CHIT1 levels are observed in many disease groups requir-
new endothelial formation and neovascularization [25, 26].        ing macrophage activation, CHIT1 also plays a critical role
­Decreased tumstatin levels in vitiligo patients may cause in-    in the regulation of inflammation and innate immune re-
creased endothelial proliferation and subsequent new and          sponse [30]. Although mammals do not have chitin or chitin
irregular neovascularization. In the presence of increased        synthases genes, they can synthesize this molecule by enzy-
vascularity and defective endothelium, melanocytes will be        matic activity [31]. It is known that the level of chitinases
more exposed to cytotoxic T cells, as there will be more          increases in neurodegenerative disorders such as multiple
blood flow to the vitiligo area. Consistent with our findings,    sclerosis, Alzheimer’s disease or amyotrophic lateral sclerosis
Doppler flowmetry studies have reported that blood flow in        with neuroinflammation [30, 32]. As the increase in CHIT1
segmental vitiligo areas is increased by more than three times    will increase the degradation of chitin, intermediate mole-
compared to healthy areas [27]. With increased blood flow,        cules such as chitinase-like proteins are formed and act in
especially melanocyte-specific cytotoxic T cells reaching the     innate immunity similar to host defense enzymes [14]. Since
epidermal-melanin unit and binding to melanocytes may             abnormal sympathetic innervation and defective neuropep-
lead to rapid depigmentation and the emergence of vitiligo        tide secretion are involved in the etiology of vitiligo [16], in-
clinic [28].                                                      creased CHIT1 levels may trigger neuroinflammation in the
    The basic mechanisms that initiate vascular basal mem-        epidermal-melanin unit, resulting in impaired innate immu-
brane damage and lead to neovascularization in vitiligo are       nity and loss of melanocytes. However, it may be possible to
unknown. The most accepted theory is that catecholamines          reach a clearer conclusion by demonstrating CHIT1 overex-
and neuropeptides released uncontrollably from sympathetic        pression in biopsies obtained from areas affected by vitiligo.
neurons initiate both vascular damage and vasodilation [16].         Despite the small number of participants, our study has
Our study suggests that vascular damage occurs because the        clinical value in terms of investigating three new molecules
conversion of type 4 collagen in the vascular basement mem-       for vitiligo etiology as a possible etiological factor for the
brane to tumstatin is prevented due to immune attack. Under       first time. This study may lead to the development of new
normal conditions, tumstatin levels are increased by break-       drug options for the treatment of vitiligo by showing the
ing down type 4 collagen in the vascular wall and neovas-         anti-adhesive effect of PODXL, the anti-angioinherent effect
cularization is prevented [8, 25]. Matrix metalloproteinase       of tumstatin and the effects of CHIT1 on neuroinflammation
9 is involved in the formation of tumstatin from Col-IVα3.        and innate immunity in vitiligo patients.



Original Article | Dermatol Pract Concept. 2024;14(1):e2024095                                                                   5
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6                                                                             Original Article | Dermatol Pract Concept. 2024;14(1):e2024095
