10.5826/dpc.1203a118
introduction: IL-15 as a member of the immunoregulatory cytokines family is associated with the development of the autoimmune or chronic inflammatory disease. 
objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with pemphigus
vulgaris and assess the association of IL-15 with anti-desmoglein antibodies and the severity of
the disease.
methods: fifty-three individuals affected with active pemphigus Vulgaris and 38 age and gender-matched healthy controls were enrolled in this study. Clinical characteristics and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) were assessed. Serum levels of IL-15 (pg/mL) and anti-desmoglein antibodies (Dsg1, 3) were measured.
Result: The serum level of IL-15 in the patient group was assumed to be statistically higher than
that of the control group (3.71 ± 1.5 vs. 0.79 ± 1.03 (p&lt; 0.001)). A positive correlation was found
between serum levels of IL-15 and severity of pemphigus Vulgaris measured by ABSIS (r=0.5,
p=0.04). No significant relationship was detected between the serum level of IL-15 and antidesmoglein antibodies (Dsg1 or Dsg3). (p=0.6 and p=0.9, respectively).
Conclusion: our findings showed that levels of IL‐15 were elevated in the sera of pemphigus
patients and were related to disease severity. An increase in serum level of Il-15 in patients with
pemphigus Vulgaris and its relation with disease severity suggest that this cytokine may play a
role in the pathogenesis of the disease and targeting IL-15 will likely provide a new
perspective on the treatment of this disease.
text/xml
2160-9381
1965
en
Nikoo Mozafari
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Pemphigus vulgaris; interleukin-15; anti-Desmoglein; IL-15; ABSIS
Elevated Serum Levels of Interleukin-15 in Pemphigus Vulgaris Patients: A Potential Therapeutic Target
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-07-28
2021-08-17
2022-07-28
2022-09-13
e2022118
Dermatol Pract Concept
introduction: IL-15 as a member of the immunoregulatory cytokines family is associated with the development of the autoimmune or chronic inflammatory disease. 
objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with pemphigus
vulgaris and assess the association of IL-15 with anti-desmoglein antibodies and the severity of
the disease.
methods: fifty-three individuals affected with active pemphigus Vulgaris and 38 age and gender-matched healthy controls were enrolled in this study. Clinical characteristics and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) were assessed. Serum levels of IL-15 (pg/mL) and anti-desmoglein antibodies (Dsg1, 3) were measured.
Result: The serum level of IL-15 in the patient group was assumed to be statistically higher than
that of the control group (3.71 ± 1.5 vs. 0.79 ± 1.03 (p&lt; 0.001)). A positive correlation was found
between serum levels of IL-15 and severity of pemphigus Vulgaris measured by ABSIS (r=0.5,
p=0.04). No significant relationship was detected between the serum level of IL-15 and antidesmoglein antibodies (Dsg1 or Dsg3). (p=0.6 and p=0.9, respectively).
Conclusion: our findings showed that levels of IL‐15 were elevated in the sera of pemphigus
patients and were related to disease severity. An increase in serum level of Il-15 in patients with
pemphigus Vulgaris and its relation with disease severity suggest that this cytokine may play a
role in the pathogenesis of the disease and targeting IL-15 will likely provide a new
perspective on the treatment of this disease.
Nikoo Mozafari
2022/07/28
10.5826/dpc.1203a118
e2022118
Skin research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Dermatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2160-9381
Pemphigus vulgaris; interleukin-15; anti-Desmoglein; IL-15; ABSIS
en
e2022118
Elevated Serum Levels of Interleukin-15 in Pemphigus Vulgaris Patients: A Potential Therapeutic Target
https://dpcj.org/index.php/dpc/article/download/1965/1668
                    Dermatology Practical & Conceptual


            Elevated Serum Levels of Interleukin-15 in
             Pemphigus Vulgaris Patients: a Potential
                       Therapeutic Target
      Maedeh Kheirodin1, Zohreh Tehranchinia2,Yasaman Ketabi2, Soheil Tavakolpour2,
   Sahar Dadkhahfar2, Masoomeh Faghankhani3, Hassan Vahidnezhad3, Nikoo Mozafari2,4


1 School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Skin research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia,
  PA, United States
4 Department of Dermatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran



Key words: pemphigus vulgaris, interleukin-15, anti-desmoglein, IL-15, ABSIS
Citation: Kheirodin M, Tehranchinia Z, Ketabi Y, et al. Elevated serum levels of interleukin-15 in pemphigus Vulgaris patients: A potential
therapeutic target. Dermatol Pract Concept. 2022;12(3):e2022118. DOI: https://doi.org/10.5826/dpc.1203a118
Accepted: November 13, 2021; Published: July 2022
Copyright: ©2022 Kheirodin et al. 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: The present study was founded by Skin Research Center, Shahid Beheshti University of Medical Sciences.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Nikoo Mozafari, MD, Shahrdari St , Tajrish Sq ,Skin Research Center, Shohada-e-Tajrish, Hospital,Tehran, Iran Tel
Number: (98) 21-22741507, fax: (98) 21-22741508 E-mail: nikoo_md@yahoo.com




  ABSTRACT             Introduction: Pemphigus vulgaris (PV) is a rare autoimmune disease that causes painful blistering.
                       Interleukin-15 (IL-15) as a member of the immunoregulatory cytokines family is associated with the
                       development of the chronic inflammatory or autoimmune disease. There is not much information
                       available in the literature on the exact role IL-15 plays in PV.
                       Objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with PV and
                       assess the association of IL-15 with anti-desmoglein antibodies and the severity of the disease.
                       Methods: Fifty-three individuals affected with active PV and 38 age- and gender-matched healthy
                       controls were participated in this study. Disease severity was assessed using Autoimmune Bullous Skin
                       Disorder Intensity Score (ABSIS). Serum levels of IL-15 (pg/mL) and anti-desmoglein antibodies (Dsg1, 3)
                       were determined.
                       Results: In the patient group, IL-15 serum levels were statistically higher than those in the control
                       group (3.71 ± 1.5 vs. 0.79 ± 1.03, P < 0.001). A positive correlation was found between serum levels
                       of IL-15 and ABSIS (r = 0.5, P = 0.04). We found no significant correlation between serum concentra-
                       tions of IL-15 and antidesmoglein antibodies (Dsg1 or Dsg3).
                       Conclusions: An increase in serum level of IL-15 in patients with PV and its relationship with disease
                       severity suggest that this cytokine possibly contributes to the pathogenesis of the disease and targeting
                       IL-15 will likely provide a new insight into the treatment of this disease.




Original Article | Dermatol Pract Concept. 2022;12(3):e2022118                                                                            1
Introduction                                                         study. Among 53 patients, 37 cases were newly diagnosed
                                                                     while 16 cases were presented with relapse during minimal
Pemphigus vulgaris (PV) is a rare autoimmune disorder that           therapy (5-10 mg prednisolone per day). PV was diagnosed
causes painful blisters and erosions on the skin and mucosa          based on clinical evidence, histopathologic findings, Direct
[1]. PV is caused by environmental and genetic factors that          Immune-Fluorescence examination and the detection of se-
lead to immunological impairments. Auto-antibodies against           rum autoantibodies by ELISA. Participants with any history
the desmosomal adhesion proteins of epidermal keratino-              of inflammatory/autoimmune diseases, hematologic and
cytes, desmoglein3 and/or desmoglein 1, lead to the loss of          solid malignancies, viral hepatitis, and HIV were excluded.
epidermal cell adhesion and development of erosive lesions           This study was approved by the ethical committee of our skin
[1,2]. To date, different cytokines, such as osteopontin, inter-     research center (ethical code: IR.SBMU.SRC.REC.1395.41).
leukin (IL)-4 and IL-21 have been suggested to be associated         Prior to enrollment in the study, all participants provided
with disease pathogenesis and severity [3-5]. These cytokines        written informed consent.
contribute to rising proinflammatory responses and produc-
tion of autoantibodies through differentiation of naïve T-cells      Clinical and Laboratory Data
into effector T -ells, increased B-cell responses, and favors a      All the patients enrolled in the study had an active disease,
class switch to IgG4. Interfering with the function of them          defined as the development of at least 3 de novo blisters/
using monoclonal antibodies, such as dupilumab for IL-4/             erosions, which do not heal spontaneously within one week.
IL-4 receptor could be probably effective in treating some           The Autoimmune Bullous Skin Disorder Intensity Score
PV patients [6,7]. In contrast, regulatory cytokines, such as        (ABSIS) was used to assess the severity of the disease. The
TGF-β and IL-35-dependent mechanisms could mediate res-              ABSIS provides a maximum score of 206 (150 points for
toration of self-tolerance, which had been broken in patients        skin involvement, 11 points for oral involvement, and 45
with autoimmune diseases [8,9]. However, the role of some            points for subjective oral discomfort) [16]. The score is
less studied cytokines, such as IL-15 has remained controver-        determined by calculating the percentage of blisters in-
sial. To our best knowledge, 3 studies have assessed the serum       volvement and erosions on the skin, along with weighting
levels of IL-15 in PV patients. Two have reported increased          factors at the stage of the blistering and erosions, respec-
serum levels of IL-15 and one suggested suppressed produc-           tively. Discomfort during eating and drinking is also consid-
tion of IL-15 as compared to the healthy controls [10-12].           ered [16]._ENREF_16
    IL-15 is a glycoprotein cytokine produced by multiple cell
types including monocytes, macrophages, dendritic cells, fi-         Cytokine Measurements
broblasts, and epithelial cells. It is well known that IL-15 con-
                                                                     For evaluating the level of IL-15 and anti-desmogleins (Dsg),
tributes to the survival and proliferation of T-cell [13]. It also
                                                                     10 ccs venous blood of each participant was collected. The
increases the proliferation of B lymphocytes and promotes their
                                                                     blood samples were centrifuged to gather the serums. Then,
differentiation into the plasma cells [13,14]. Recent studies have
                                                                     the serums were frozen at –80°C. After gathering all the sam-
indicated that inhibiting IL-15 with various methods may be
                                                                     ples, levels of IL-15 were measured by an ELISA kit (Dia-
the goal of appropriate treatment to reduce inflammation [14].
                                                                     clone,France), according to the manufacturer’s instructions.
                                                                     Using the ELISA method (Euroimmun AG) anti-Dsg 1 and 3
Objectives                                                           antibodies were measured in patients. Values ≥ 20 of relative
IL-15 is involved in the pathogenesis of a variety of auto-          units per milliliter (RU/ml) were considered positive.
immune diseases such as Sjogren disease, Behcet disease,
systemic lupus erythematous (SLE) and rheumatoid arthritis           Statistical Analysis
(RA) [3,15]_ENREF_14. There has been little information              Findings were respectively expressed as mean ± standard de-
about the exact role of IL-15 in pemphigus pathogenesis or           viation or as number (percentage) for continuous variables
how IL-15 production relates to the severity of pemphigus.           and categorical data, respectively. Independent samples t test
    In this regard, the goal of this study was to assess the serum   and non-parametric Mann–Whitney U test were applied to
levels of IL-15 in patients with PV and to find out whether          compare the means of continuous variables and chi squared
IL-15 levels were associated with severity of their disease.         test was used for categorical variables. Analysis of variance
                                                                     (ANOVA test) was used for comparing means between vari-
Methods                                                              ables. To determine if there was a linear relationship between
                                                                     variables, Pearson correlation testing was performed. We
Patients                                                             used the statistical package of SPSS version 16.0.0. (SPSS Inc.)
To evaluate the serum levels of IL-15, 53 individuals with           To analyze the data. The level of significance was considered
active PV and 38 healthy individuals were enrolled in this           as P values less than 0.05.


2                                                                        Original Article | Dermatol Pract Concept. 2022;12(3):e2022118
Results                                                              anti-Dsg3 (r = 0.006, P = 0.9) antibodies. Serum levels of
                                                                     IL-15 were positively correlated with PV severity according
Patient Characteristics                                              to total ABSIS (r = 0.5, P = 0.04).
Fifty-three patients with PV (35 females and 18 males) and               In the patients group, there was no significant dif-
38 healthy individuals (24 women and 14 men) were enrolled           ference in the mean levels of serum IL-15 between men
in the study. The control group was frequency-matched to             and women or between patients with cutaneous, muco-
cases by gender and age. The mean ages of patients and               sal, or mucocutaneous forms of the disease (P = 0.9 and
control subjects were equal to 45.62 ± 12.27 and 44.21 ±             0.09, respectively). There was a significant correlation
13.15, respectively. The baseline demographics and clinical          between pemphigus severity (ABSIS score) and anti-
characteristics of the participants have been presented in Ta-       Dsg3 (r = 0.3, P = 0.01) and anti-Dsg1 levels (r = 0.6,
ble 1. The two groups were comparable in age, gender, and            P < 0.001)._ENREF_15
comorbidities (Table 1).

                                                                     Conclusions
Serum Levels of IL-15
PV patients had significantly higher levels of IL-15 than con-       In this study, we have evaluated plasma levels of IL-15 in pa-
trols. The mean serum levels of IL-15 ± SD in PV patients            tients with PV in the active phase of the disease and searched
were 3.71 ± 1.5 pg/ml, while for healthy controls were 0.79          for a potential relationship between levels of IL-15 and the
± 1.03 pg/ml, which was statistically different (P < 0.001).         severity of the disease. We have found that levels of IL-15 are
Figure 1 demonstrates the IL-15 levels in these two groups.          significantly higher in patients compared to healthy controls.
In patients with PV, no significant correlations were detected       Our study group results were comparable to those previ-
between IL-15 levels and anti-Dsg1 (r = 0.06, P = 0.6) or            ously reported [10,11].




              8.00




              6.00
      IL 15




              4.00
                                                                                                  *
                                                                                                  *
                                                                                                  *



              2.00




              0.00

                                            PATIENT                                          CONTROL
                                                                 PARTICIPANT


Figure 1. Serum IL-15 concentrations (pg/ml) in patients with pemphigus in comparison to healthy controls. Overall, IL-15 levels in the
pemphigus group were higher than that of the control group (P < 0.001).
IL-15 = Interleukin-15.



Original Article | Dermatol Pract Concept. 2022;12(3):e2022118                                                                       3
           Table 1. Baseline demographics and clinical characteristics of patients with pemphigus
                                          and healthy controls.
                    Characteristic                          PV patients (N = 53)           Healthy controls (N = 38)              P
 Gender
   Female                                                        35 (66.0% )                       24 (63.2%)
                                                                                                                                0.70
   Male                                                          18 (34.0% )                       14 (36.8% )
 Age, Years
   Mean ± SD                                                    45.62 ± 12.27                      44.21 ± 13.15
                                                                                                                                0.60
   Median (range)                                                46 (21 – 72 )                    45.50 (25 – 73)
 Time until diagnosis or exacerbation, month
    Mean ± SD                                                      2.6 ±2.3                              —
 Type of pemphigus involvement
    Mucosal                                                        18 (34%)
    Cutaneous                                                     7 (13.2%)                              —
    Mucocutaneous                                                 28 (52.8%)
 ABSIS, Mean ± SD;
   Total score a                                                36.88 ± 24.92                            —
 Anti-Dsg1 Antibody (RU/ml)
   Mean ±SD                                                    238.68 ± 47.70                            —
 Anti-Dsg3 Antibody (RU/ml)
   Mean ±SD                                                    729.63 ± 99.05                            —
 IL-15 (pg/ml)
    Mean ± SD                                                     3.71 ± 1.5                        0.79 ± 1.03                < 0.001
ABSIS = Autoimmune Bullous Skin Disorder Intensity Score; Dsg = Desmoglein; IL-15 = Interleukin-15; ; SD = standard deviation.

Values are reported as numbers (%) unless otherwise specified. aTotal score is sum of objective and subjective scores.




    Approximately two decades ago, D’auria et al assessed               T-cells are survived for longer periods of time , that results in
the levels of IL-15 in the serum sample of patients affected            abnormal lymphocyte activation [14]. Furthermore IL-15 is
with three different bullous dermatoses ( 5 with bullous                also involved in the activation and proliferation of Natural
pemphigoid, 15 with PV and 15 with pemphigus erythema-                  Killer cells (NKs) [17]. Stern et al have suggested a possible
tosus) [10]. They showed a higher level of IL-15 serum in               role for NKs in the pathobiology of PV and D’auria et al
all the dermatosis as compared with healthy subjects. They              have shown that the number of circulating natural killer cells
also showed a significant correlation between the number of             is significantly correlated with the concentration of IL- 15 in
lesions and IL-15 serum levels [10]._ENREF_16 Addition-                 patients with pemphigus [10,18].
ally, Ameglio et al showed increased levels of interleukin 15                According to the mentioned role of IL-15 in the dif-
in the serum of 15 PV patients with active disease [11]. In             ferentiation and development of involved cells in immune
contrast, in a recently conducted study, Timoteo et al with             responses, the role of this cytokine has been studied in a
the evaluation of 20 PV patients and 20 healthy controls re-            number of autoimmune diseases. There are some reports
vealed a significantly lower serum level of IL-15 in patients           showing that the mean levels of IL-15 serum are significantly
with PV than in control group patients [12]. In their study             higher in Behcet disease, SLE and rheumatoid arthritis [19].
the study population consisted of non-active patients under             Active SLE patients had significantly higher levels of IL-15
pharmacologic therapy, then their results can be confounded             serum compared to healthy controls, while it was not directly
by potential suppressive effects of immunosuppressants on               associated with disease activity [20]. The levels of IL-15 in
IL-15 secretions.                                                       the serum and synovial fluid of patients with rheumatoid
    IL-15 is assumed to be a member of the immunoregu-                  arthritis, were much higher compared to the controls [21].
latory cytokines family which is primarily           produced by        Interestingly, the levels of IL-15 were related to the disease
monocytes, macrophage, dendritic cells, fibroblast, and ep-             severity and serum levels of IL-15 were strongly correlated
ithelial cells.                                                         with the levels of rheumatoid factor and anti-CCP [21].
    It is believed that IL-15 overexpression is associated with              Collectively these findings indicated that IL-15 is a key
the development of chronic inflammatory disease or autoim-              cytokine in several autoimmune diseases, and raises the pos-
mune disorders. When IL-15 is overexpressed, autoreactive               sibility that targeting IL15 with various anti-IL15 approaches



4                                                                             Original Article | Dermatol Pract Concept. 2022;12(3):e2022118
may provide a new insight for the treatment of such disor-          further clarification to establish whether inhibition of IL-15
ders [19]. For instance, in an animal model of human psoria-        action might prove valuable in the treatment of PV.
sis (xenograft mouse), the IL-15 blockade led to the psoriasis
resolution [22]. In rat models of induced arthritis, weekly
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6                                                                                Original Article | Dermatol Pract Concept. 2022;12(3):e2022118
