Cytokine and Growth Factor Reviews 45 (2019) 35–44

Contents lists available at ScienceDirect

Cytokine and Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

Emerging role of immune cell network in autoimmune skin disorders: An T

update on pemphigus, vitiligo and psoriasis
Dayasagar Dasa,1, Shamima Akhtara,1, Santosh Kurraa, Somesh Guptab, Alpana Sharmaa,
⁎

a
Department of Biochemistry, All India Institute of Medical Sciences, AIIMS, New Delhi, India
b
Department of Dermatology and Venereology, All India Institute of Medical Sciences, AIIMS, New Delhi, India

ARTICLE INFO ABSTRACT

Keywords: Autoimmune skin diseases are a group of disorders that arise due to a deregulated immune system resulting in
Autoimmune skin disease skin tissue destruction. In the majority of these conditions, either autoreactive immune cells or the auto-
Pemphigus antibodies are generated against self-antigens of the skin. Although the etiology of these diseases remains elu-
Vitiligo sive, biochemical, genetic, and environmental factors such as infectious agents, toxins damage the skin tissue
Psoriasis
leading to self-antigen generation, autoantibody attack and finally results in autoimmunity of skin. Immune
Immune cell network
Immune checkpoints
dysregulation, which involves predominantly T helper 1/17 (Th1/Th17) polarization and the inability of reg-
Tissue-resident memory cells (TRMs) ulatory T cells to regress immune response, is implicated in autoimmune skin diseases.
The emerging roles of immune cells, cytokines, and chemokines in the pathogenesis of common autoimmune
skin diseases like pemphigus, vitiligo, and psoriasis are discussed in this review. The main focus is on the
interplay between immune cell network including the innate and adaptive immune system, regulatory cells,
immune checkpoints and recently identified tissue-resident memory cells (TRMs) in disease pathogenesis and
relapse. We also attempt to highlight on the immune mechanisms common to these diseases which can be
targeted for designing novel therapeutics.

1. Introduction highest in India. The prevalence of psoriasis is 4.78%, vitiligo is

0.71%–2.64%, and Pemphigus is 4.4–7.2 per million cases [2–6].
Autoimmune skin disease pertains to dysregulation of the immune In skin resides cells of both innate and adaptive immune system which
system resulting in autoantibody formation against skin self-antigens. altogether makes it an immune organ and not just a barrier. The outermost
Although the etiology of the disease remains elusive, biochemical, ge- epidermal layer consists of mainly keratinocytes, and few melanocytes, T
netic and environmental factors act as a trigger for the autoantibody lymphocytes, and Langerhans cells (LCs). The middle dermal layer is en-
formation and disease initiation. There is a steady rise in autoimmune riched with dendritic cells (DCs), natural killer (NK) cells, macrophages,
skin diseases in recent years. Among them, psoriasis afflicts 2–3%, vi- gamma delta (γδ) T-cells, and innate lymphoid cells (ILCs) along with
tiligo affects approximately 0.5% of the population while pemphigus blood and lymph vessels. Upon pathogen attack, skin immune cells of
affects around 0.5–30 cases per million globally [1]. In the Indian different compartment work in a regulated and coordinated manner to
subcontinent, the incidences of common autoimmune skin diseases are eliminate the pathogen and maintain the barrier integrity. Nonetheless,

Abbreviations: Th, T helper; LC, langerhans cell; DC, dendritic cell; NK, natural killer cells; γδ, gamma delta; ILC, innate lymphoid cells; TRM, tissue-resident
memory cells; DSG, desmoglein; APCs, antigen presenting cells; IL, interleukin; IFN, interferon; Tfh, T follicular helper; PV, pemphigus vulgaris; PF, pemphigus
foliaceous; Tregs, regulatory T cells; TGF, transforming growth factor; TNF, tumor necrosis factor; OPN, osteopontin; CTL, cytotoxic T lymphocytes; Bregs, regulatory
B cells; 4-TBP, 4-tertiary butyl phenol; MBEH, monobenzyl ether of hydroquinone; XBP1, X-box binding protein 1; UPR, untranslated protein response; pDC,
plasmacytoid dendritic cell; iNKT, invariant NKT cells; TRP-1, tyrosinase-related protein-1; GM-CSF, granulocyte monocyte colony stimulating factor; HSP70i,
Inducible heat shock protein 70; BSA, body surface area; AHR, aryl hydrocarbon receptor; VDA, vitiligo disease activity; NB-UVB, narrowband ultraviolet; TIM, T cell
immunoglobulin- and mucin-domain-containing molecules; Gal, galectin; PD-1, programmed cell death -1; AMP, antimicrobial protein; HBD-2, human-β-defensin-2;
PBMCs, peripheral blood mononuclear cells; TLRs, toll-like receptors; NETs, neutrophil extracellular traps; MCETs, mast cell-extracellular traps; Mo-MDSCs,
monocytic myeloid-derived suppressor cells; MMP, matrix metalloproteinases; Gro, growth-related oncogene; CMKLR1, chemokine-like receptor1; PASI, psoriasis
area and severity index
⁎
Corresponding author at: Department of Biochemistry, Room no. 3015, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, 110029, India.
E-mail address: dralpanasharma@gmail.com (A. Sharma).
1
Equal contributions.

https://doi.org/10.1016/j.cytogfr.2019.01.001
Received 11 January 2019; Accepted 18 January 2019
Available online 08 February 2019
1359-6101/ © 2019 Elsevier Ltd. All rights reserved.
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

when skin immune system targets its own antigens and initiates destruc- lesional skin. In a preliminary study, co-culturing CD4+T helper (Th)
tion of the target cell, autoimmunity develops [7]. cells and CD56+CD3- NK cells from Pemphigus patients along with
In this review, new developments in the immune mechanism of DSG-3 peptides led to proliferation of CD4+ T cells indicating NK cells
common autoimmune skin disorders i.e. pemphigus, vitiligo, and acts as antigen presenting cells (APCs). NK cells stimulated CD4+ T
psoriasis are discussed. We scrutinize the literature pertaining to the cells to secrete proinflammatory cytokines interleukin (IL)-8, IL-6, and
innate, adaptive, and regulatory immune cell network, immune interferon (IFN)-γ implicating its role in pemphigus pathogenesis [10].
checkpoints as well as tissue-resident memory cells (TRMs) in these Our group recently reported that, γδ-T cells, an important player of the
diseases. innate immune system, are detected in pemphigus. High IFN-γ (Th1
type) and low IL-4 (Th2 type) secreting γδT-cells are detected in patient
circulation. Elevation of γδT-cells secreting both IFN-γ and IL-4 in
2. Pemphigus pemphigus patients indicates the plasticity of these cells to maintain
high autoantibody titers [11].
Pemphigus, an autoimmune blistering mucocutaneous disease, pro-
duces IgG autoantibodies mainly against autoantigens, Desmoglein-1 2.2. Adaptive immune system
(DSG1) and Desmoglein-3 (DSG3), even though the roles of other auto-
antigens are also implicated in different studies. The pathological hall- 2.2.1. CD4+ T helper cells
mark of pemphigus is “acantholysis” which is autoantibody driven dis- A cognate T-cell-B-cell interaction is necessary for autoantibody pro-
ruption of keratinocyte adhesion in the skin and mucosal membrane. A duction by autoreactive plasma cells. High titers of autoantibodies are de-
plethora of factors such as genetic, drugs, hormones, environment, viral tected in pemphigus patients which correlate well with the disease activity.
infections, etc. are reported to trigger autoantibody formation by initially Presence of autoreactive CD4+ T cells is well documented and reviewed
disorganizing the keratinocyte cell-cell contact and exposing the DSGs. elsewhere [12]. Before the establishment of newly discovered Th cells such
Exposed DSGs are then identified by epidermal dendritic-like LCs as as Th17, Th9, Th22, T follicular helper cells (Tfh) in immune response,
antigens which present it to T-cells (Fig. 1) [8,9]. A deregulated cell- earlier our group had investigated the Th1/Th2 cytokines in pemphigus.
mediated immune response is exhibited upon exposure to DSG’s, the Th2 (IL-10, IL-4) cytokines are elevated in Pemphigus vulgaris (PV) and
exact reason for which remains obscure. Both the arms of the immune foliaceous (PF) patients serum while Th1 (IFN-γ and IL-2) cytokines are
system i.e. innate and adaptive are involved in the above-mentioned decreased in the study [13]. Nevertheless, our group and others have es-
pathogenesis of pemphigus. Innate immune system that used to be con- tablished activation and elevation of IL17-secreting Th17 cells with con-
sidered as early and the non-specific component of immune system comitant decrease in FOXP3+ regulatory T cells (Tregs) in pemphigus
shows diversity and its involvement in pemphigus is discussed below. patients [14–18]. Besides, an involvement of Tfh cells in pemphigus is also

Fig. 1. Immunologic network underlying Pemphigus: Exposed desmogleins (DSGs) identified by epidermal LCs present the antigen to T cells leading to T cell
activation and expansion of antigen specific T cells. Elevated OPN levels helps in differentiation of activated T cells towards Th1 type while suppressing Th2 type.
Further, cytokines in the microenvironment helps differentiation of activated T cells towards T effector subsets Th1, Th17, and Tfh cells. Reduced expression of
FOXP3 and co-stimulatory molecule CD28 on Tregs leads to their decreased proliferation and differentiation. Chemokine receptor-ligand CCL22−CCR4 is decreased
in skin which reduces Treg homing to inflammation site. Bregs become defective as they are unable to suppress IFN-γ secretion from Th1 cells. Eliminating CD8 + T
cells reduces pemphigus due to less acantholysis.

2.1. Innate immune system indicated. IL-21 secreting Tfh cells were augmented in patient’s circulation
and infiltrated the lesional skin [17,18]. A single study examined all the
The function of innate immune system in pemphigus pathogenesis is subsets of Th cells and observed elevation of inflammatory cytokines IFN-γ
not much dissected probably because innate cells are rarely detected in (Th1), IL-17, and IL-23 (Th17) with simultaneous decrease in IL-10

36
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

indicating a Th1/Th17 response in Pemphigus (Fig.1). Several pro and anti- microenvironment produced by Th17 cells in lesions thus promoting in-
inflammatory cytokines (TNF-α, IL-6, IL- 1β, IL-2, IL-9, IL-12, IL-4, trans- flammation and contributing to the immunopathogenesis of pemphigus
forming growth factor (TGF)-β, and IL-33) levels remain unchanged in these (Fig.1) [14].
patients. Accordingly, chemokine CXCL8 was high while Th1/Th2 chemo- In pemphigus patients, activated B cells act as pathogenic regulators by
kine, IP-10, and CCL11 were decreased; CCL2, CCL5, and CCL3 remain secreting anti-DSG3 autoantibodies. B regulatory cells (Bregs) are able to
unchanged. In skin lesions of these patients also inflammatory cytokines IL- down regulate immune responses in mice and humans by secreting IL-10,
6 and CXCL8 were elevated and IL-2 was reduced indicating a Th1/Th17 TGF-β and expressing FOXP3 [26,27]. A high CD19+CD24hiCD38hi Bregs
response which corroborated positively with disease activity [19]. Asso- number is seen in pemphigus patients which is higher in active patients than
ciation of Th1/Th17 type with early and late-stage disease remains to be remittent. IL-10-producing Breg cells markedly increase upon stimulation in
investigated. patients and in healthy controls but only control Bregs suppressed IFN-γ
Cytokine Osteopontin (OPN), an early cytokine of Th1 type, aug- expression and Th1 immune response. Bregs from patients had 3 fold re-
ments production of IFN-γ, IL-12 and decreases IL-10 production [20]. duced suppressive function (Fig.1) [28]. Further studies in future will
Similar to other autoimmune disorders, in pemphigus also, OPN pro- evaluate the potential of these regulatory cells to control the inflammatory
duction is elevated which indicates a Th1 response, a failure of which immune response in pemphigus.
might elicit a Th2 response (Fig. 1) [21]. Taken together, activation of
Th1/Th17/Tfh and down regulation of Treg immune response in 2.2.3. Cytotoxic CD8+ T cells
pemphigus is strongly indicated. A great number of studies have shed light on CD4 + T cells role in
the pathogenesis of pemphigus while the role of CD8+ cytotoxic cell is
2.2.2. Regulatory cells less explored possibly due to the lower number of CD8+ cells in the
Regulatory T cells, predominantly CD4+FOXP3+ cells are critical skin lesions. CD8 knockout mice had reduced incidences of pemphigus
players in controlling immune responses. They suppress APC function, B-cell indicating its role in disease progression (Fig.1). The role of this small
differentiation towards plasma cell, activated CD4 + Th cells, and cytotoxic subset of T-cells needs to be further explored [29].
T lymphocyte (CTL) granule release by secreting immunomodulatory cy-
tokines such as IL-10 and TGF-β [22]. Interestingly, their numbers are re- 3. Vitiligo
duced in pemphigus which creates an imbalanced immune response
[14–16]. CD28, a co-stimulatory molecule, is necessary for Treg activation Vitiligo is an autoimmune disorder where epidermal melanocytes
and successive suppressive function [23]. Any fault in the binding of CD28 are targeted and destroyed by various ways leading to irregular de-
molecule with its ligand CD80/86 can have inversed regulatory effect. A pigmentation of the skin. Biochemical, neural, and autoimmune me-
high CD28 expression on Th cells and a low expression on Tregs implicates a chanisms partly explain the mechanisms for the degeneration of mel-
defective activation and proliferation of Tregs in the circulation of patients anocytes in vitiligo. The biochemical trigger for vitiligo is mainly
(Fig.1) [24]. In vivo expansion of Tregs considerably reduced the DSG3- oxidative stress induced by different chemicals [30]. 4-tertiary butyl
specific T-cell responses as well as DSG3-specific IgG production [25]. Our phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), the
lab had reported that chemokine receptor pair for Treg homing, CCR4- chemical triggers for vitiligo up-regulates the untranslated protein re-
CCL22 is lowered leading to homing defect at lesional sites. This defective sponse (UPR) in melanocytes (Fig. 2). Transcription factor X-box
receptor-ligand edge may have become futile to suppress the inflammatory binding protein 1 (XBP1), a UPR components, is activated which

Fig. 2. Immune mechanisms involved in vitiligo: Chemical triggers (4-TBP and MBEH) induced untranslated protein response (UPR) upregulates proinflammatory
cytokines and chemokines production in melanocytes. LCs and DCs are APCs inducing T cell activation. NKT cells binds to its receptor NKG2D to induce antigen
specific CD8 T cell proliferation which attacks melanocytes. T helper cells differentiate into Th1, Th17 and Th22 which maintains inflammatory milieu. Tregs are
unable to regulate heightened inflammation due to reduced number and defective homing. TRMs aid in disease recurrence by secreting proinflammatory cytokines
upon restimulation. Negative immune checkpoint PD-1 is upregulated in Tregs while TIM-3 is upregulated in Th1 cells contributing to inflammation.

37
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

subsequently increases production of proinflammatory cytokines IL-8 CXCL12 and CCL5 which concurred with penetration of skin with APCs
and IL-6 by the melanocytes. XBP1 inhibitors reduced IL-8 and IL-6 and T cells. In a mouse model of vitiligo, transplantation of CXCL12+
production induced by phenols [31]. Taken together, exposure to en- and CCL5+ melanocytes resulted in preferential recruitment of
vironmental stressors causes an insult to melanocytes which then pro- CD11c + APCs and CD8+ T cells to CXCL12- and CCL5-expressing
duce cytokines associated with activation of an immune response fi- melanocytes, epidermal melanocyte loss, and development of vitiligo-
nally leading to melanocyte loss and depigmentation. Autoimmune like lesions [44]. Our research group has shown that the success rate of
responses also play significant role in establishment and progression of melanocyte transplantation in patients is inversely proportional to the
vitiligo described below. number of CD8 cells and CD45RO cells in the lesion but doesn’t depends
on the number of CD4+ T cells, CD 45RA and FOXP3+ Tregs cells
3.1. Innate immune response [45]. In the essence, infiltration of the cytotoxic CD8 T cells might be
responsible for the melanocyte destruction in vitiligo.
Transcriptome analysis of vitiligo skin indicated activation of innate
immune cells [32]. CD1a + CD207+ LCs are increased in lesional skin 3.2.2. CD4+ T helper cells
with structural modifications such as increased dendrite length and Increasing number of studies has reported the role of T helper cells
number reflecting its activation. Similarly, the dermal DCs (CD1a + such as Th17 cells in the disease progression of vitiligo. Elevated Th17
CD207-) are also increased in vitiligo lesions [33]. CD11c + myeloid cell frequencies are observed in vitiligo patients [34,46–48]. RORɣt, the
dermal DCs and CD207+ LCs are enriched at the progressing interface transcription factor for Th17 cells, as well as transcription and protein
of the vitiligo biopsies. DC-LAMP + and CD1c + sub-populations of levels of Th17 cytokines, IL-17 A, IL-22, and IL-21 were increased re-
dermal DCs increased remarkably in the progressing interface and le- markably in patients [34,46–49]. Increased Th17 cell frequency posi-
sional skin. Activated inflammasomes along with increased IL-1ß tively correlated with the body surface area (BSA) of the lesion [47].
mRNA in LCs of lesional vitiligo skin, indicates the potential of LCs to Further, Th17 cells were present in the leading edge of the lesional skin
drive Th17 activation. [34]. Contradictorily, epidermal immune cell [34]. Aryl hydrocarbon receptor (AHR) transcription factor, the master
populations such as endogenous T lymphocytes, LCs, and γδ T-cells regulator of Th22 cells, was significantly elevated in vitiligo patients
were not necessary for the disease progression in a mouse model of implicating contribution of Th22 cell to abnormal immune responses
vitiligo [35]. seen in vitiligo [50]. Additionally, the numbers of Th1 cells were in-
NKT cells and plasmacytoid DCs (pDCs) play a role in vitiligo pa- creased considerably in patients [47,48]. Although IFN-γ levels are
thogenesis [32,36,37]. NKT cells (CD3-NKG2D+) with increased cy- unchanged in patients, the transcription factor for Th1 activation, T-bet
tolytic activity are elevated in vitiligo lesions [32]. In contrast, in- was increased at transcription level indicating activation of Th1 cells
variant NKT cells (iNKT), which is implicated in autoimmune disease, is [48]. Our group had shown an elevation of IL-2, a Th1 cytokine in
drastically reduced in non-segmental vitiligo suggesting a role in dis- patients [49]. In one study, Th2 cell number, their transcription factor
ease pathogenesis [38]. Further, in experimental vitiligo, contrasting GATA-3, and cytokine IL-4 were comparable between patients and
effects of two NK receptors is demonstrated in the development of self- healthy controls (Fig.2) [48]. Contrarily, a study on Indian patients
reactive CD8 + T cell response. Binding of melanocyte antigen, tyr- showed an elevated IL-4 level [49] indicating that the involvement of
osinase-related protein-1 (TRP-1) to NKG2D ligand (Rae-1e or H60) Th2 in vitiligo pathogenesis is debatable.
elicited potent CD8 + T-cell responses against TRP-1 causing develop- Natural regulatory T cells (nTregs), the suppressor CD4+ Th cells is
ment of vitiligo. Complexing of TRP-1 with the natural ligand for the decreased in vitiligo patients but increased in perilesional skin of the
NK cell receptor 2B4,CD48, leads to decreased formation of TRP-1-re- patients. Nonetheless, peripheral Tregs were impaired in their function
active CD8 + T-cell responses, thus reducing development of vitiligo as they were unable to suppress the proliferation and cytolytic capacity
(Fig.2) [37]. of autologous CD8 + T cells, ultimately leading to hyperactivation of
Keratinocytes of patients produce CXCL9 and CXCL10 which are CD8+ CTLs in vitiligo [41]. Peripheral CD4+ FOXP3+ Treg cells,
chemoattractant for DCs besides other immune cells [35]. Moreover, CCL21 (chemokine for Treg homing) and TGF-β1 were decreased in
granulocyte monocyte colony stimulating factor (GM-CSF), known to patients which correlated negatively with vitiligo disease activity
affect myeloid DC proliferation and maturation is upregulated in the (VIDA) score and BSA (Fig.2) [49,51,52]. However, one study did not
serum of vitiligo patients [36]. pDCs are IFN-γ producing cells which find any difference in Treg cells between patients and controls. Treg cell
correlated with the expression of the type I IFN-inducible ligand CXCL9 number, its transcription factor FOXP3 and cytokine TGF-β1 were
in lesional skin which correlated well with disease activity. This in turn comparable between the groups [34]. Together, it indicates that similar
correlated with the recruitment of immune cells expressing CXCR3 to pemphigus, the inflammatory Th cells are elevated in vitiligo with
[35,38]. In vitiligo-prone Pmel-1 mice, inducible Hsp70 (HSP70i), a concomitant decrease in Treg cells which became defective.
stress-related protein, accelerated depigmentation, and phenotypic Even though CD8+ CTL attack causes melanocyte loss in vitiligo,
changes in DC subpopulations [39]. Together, epidermal and peripheral will reversing the Th cell phenotype in patients decrease the melano-
DCs are associated with disease initiation probably by being APCs cyte loss is yet to be answered. Narrowband ultraviolet (NB-UVB), an
whereas NK cells regulate the disease progression. effective therapy for generalized vitiligo, is known to modulate local or
systemic immune response. The treatment down-regulates immune at-
3.2. Adaptive immune response tack against the melanocytes and simultaneously stimulates melano-
cytes to migrate to the epidermis and synthesize melanin. Using this
3.2.1. Cytotoxic CD8+ T cells treatment modality, our group has shown that IL-10 and TGF-β is in-
Peripheral expansion of melanocyte-specific CD8+ T cells occurs in creased in NB-UV treated patients while IL-13 and IL-17 A are elevated
vitiligo [40]. Accordingly, tissue infiltrate of lesion consists mainly of in untreated patients as compared to treated patients. NB-UVB mediates
cytotoxic CD8+ T cells than CD4+ Th cells [41,42]. Infiltration of its action by reducing Th17/Th1/Th2 and increasing Treg cytokines
CD8+ T cells is mainly due to cytokines and chemokines secreted by which might then suppress the cytolytic activity of CD8+ T cells [53].
the stressed keratinocyte and melanocytes. Nevertheless, the effect of the treatment on the functionality of Tregs
Chemokine CXCL16 expression is augmented in keratinocytes under and cytotoxic CD8+ cells needs to be elucidated.
oxidative stress and mediates migration of CXCR6+CD8+ T cells iso-
lated from vitiligo patients (Fig.2). Skin infiltration of CXCR6+CD8+ 3.3. Immune checkpoints
cells led to the loss of melanocyte in lesions [43]. Moreover, melano-
cytes of early lesions have considerable elevation in levels of chemokine Biologically several molecules exist in immune system that regulates

38
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

the over expressing immune response thereby maintaining the immune typical feature of psoriatic skin is high expression of innate anti-
homeostasis. These molecules are collectively known as immune microbial proteins (AMP) such as S100 A and human-β-defensin-2
checkpoints. Recently these molecules are being utilized to alter the (HBD-2) [56,57]. Koebnerisin (S100A15) and psoriasin (S100A7) over
immune response in many diseases including cancer.The T cell im- expressed in the epidermal psoriatic lesions, acts as chemoattractant for
munoglobulin- and mucin-domain-containing molecules (TIM)-1 is an immune cells (Fig. 3). These proteins induce proinflammatory cytokines
immune checkpoint, expressed on activated Th2 cells while TIM-3 is such as IL-8, IL-6, IL-1β, and TNF-α, in peripheral blood mononuclear
expressed on Th1 cells. Our group had shown that a higher percentage cells (PBMCs). Upon NB UV-B treatment, Koebnerisin levels are sup-
of circulating CD3+CD4 + TIM3+ T cells which positively associated pressed in PBMCs of psoriatic patients thus making it a therapeutic
with percentage BSA involvement in patients. Furthermore, augmented response marker in psoriasis [58].
transcription of TIM-3 and its ligand galectin (Gal)-9 as well as char-
acteristic migration pattern of TIM-3+ immune cells in lesional and
perilesional skin suggested that TIM-3+ immune cells might be in- 4.1. Innate immune response
volved in melanocyte destruction (Fig.2) [54].
Programmed cell death 1 (PD-1) is another immune checkpoint 4.1.1. Neutrophils
which inhibits immune response by binding to its ligands, PD-L1 and In psoriasis, Toll-like receptors (TLRs) bind to AMPs by which the
PD-L2. In Pmel-1 vitiligo mice treatment with PD-L1 fusion protein APCs get stimulated and secrete proinflammatory chemokine CXCL16
suppressed depigmentation as well as caused enrichment of Tregs in the [59,60]. CXCL16 mediates migration of neutrophils by decreasing
skin, spleen and in circulation suggesting PD-L1 protein therapy im- stiffness and increasing deformation facilitating transmigration through
pedes the immune response and reverses depigmentation in Pmel-1 the vessel wall. In a positive feedback loop, IL-8 enhanced CXCL16
vitiligo mice [55]. However, in spite of decreased Tregs, PD-1+Tregs production in neutrophils [60]. Upon IL-8 activation, neutrophils se-
are increased in generalized vitiligo suggesting an involvement of PD- crete neutrophil extracellular traps (NETs) which in turn upregulates
1/PD-L1 pathway in Treg exhaustion (Fig.2) [51]. Alteration in immune HBD-2 in keratinocytes, and psoriatic lesions [61]. IL-17+ neutrophils
responses using PD-1/PD-L1 blockers in vitiligo needs to be in- and mast cells are found at higher densities than IL-17+T-cells in
vestigated which can have great potential for novel therapeutics in psoriatic lesions which frequently release IL-17 in the process of
disease management in future. forming NETs and mast cell-extracellular traps (MCETs), respectively
(Fig.3). IL-23 and IL-1β can induce MCET formation and degranulation
4. Psoriasis of human mast cells [62]. IL-17 F, sharing 50% sequence homology
with IL-17 A, is also upregulated in psoriasis and produces an equal
Psoriasis is a T-cell mediated autoimmune disease characterized by intensity of inflammation as IL-17 A [63,64]. Both IL-17 A/F is highly
increased keratinocyte proliferation leading to the formation of distinct expressed by neutrophils and mast cells [63]. Neutralization of both IL-
erythematous plaques with large scaling. Although the etiology of the 17 A and IL-17 F reduces neutrophil chemotaxis and psoriasis disease
disease is unclear, genetic and environmental factors are thought to be severity more efficiently than IL-17 A alone indicating an equal con-
the reason behind abnormal immune response in psoriasis patients. A tribution of IL-17 F in the disease pathogenesis [64].

Fig. 3. Immune mechanism of Psoriasis: AMPs are over expressed in skin and circulating leucocytes in psoriasis. TLR on APCs bind to AMPSs and get stimulated and
secretes CXCL16. Neutrophils and mast cells are chemoattracted in response to chemokines and cytokines and secrete extracellular traps (ETs). ETs in turn upregulate
AMPs in keratinocytes establishing a positive feedback loop and also secrete IL-17. Macrophages are classically activated, DCs, NK cells, ILCs, γδ T cells and activated
keratinocytes secretes proinflammatory cytokines and chemokines which adds on to the inflammatory condition. Activated T cells differentiate into subtypes; Th1,
Th17, Th9 and Tfh cells. In the inflammatory state, Tregs function is altered and they behave like Th17 cells secreting IL-17. Negative immune checkpoints such as
PD-1 and are decreased in Mo MDSCs and PBMCs setting a sustained immune response. TRMS and skin resident γδ- T memory cells produce proinflammatory
cytokines upon stimulation thus contributing to disease recurrence.

39
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

4.1.2. Macrophages memory [74].

In experimental psoriasis, model skin seen to be infiltrated with
macrophages. In absence of T cells, psoriasis was enhanced with in- 4.2.2. Th1-Th2
creased inflammation and infiltration with macrophages [65]. Further, Increased activation of CD4+ T lymphocytes is observed in psor-
CD163+, RFD7+, CD68+, LAMP2+, Stabilin-1+, and MARCO + iasis. In peripheral circulation high Th1 and low Th2 cells occurs in
dermal macrophages which are “classically activated” are increased in psoriasis [81]. Remarkably higher IFN-γ, IL-2, IL-10 and lower IL-4
the psoriatic lesion and produce inflammatory molecules IL-23p19 and concentration in the serum as well as high expression of T-bet mRNA
IL-12/23p40 as well as TNF and iNOS [66,67]. Intermediate monocytes and reduced expression of GATA-3 mRNA in PBMCs of psoriatic pa-
(CD14++CD16+) with high expression of co-stimulatory molecule tients suggests the immunopathogenesis of the disease is predominantly
CD86, a marker for “classically activated” macrophage, is present in the Th1-mediated [82–84]. Accordingly, OPN is expressed in PBMCs and
skin of psoriatic patients and is associated with increased epidermal skin biopsies [85]. Psoriasis patients in the early course of disease have
proliferation and disease severity [68]. high expression of the IFN-γ, which shifted towards IL-10 secretion in
Recently, high levels of CD14+HLA-DRe/low monocytic myeloid- chronic patients suggesting a possible shift from Th1 to Th2 response as
derived suppressor cells (Mo-MDSCs) in peripheral blood psoriatic pa- an adaptation of the immune system to down regulate inflammatory
tients have been reported (Fig. 3). These cells, produce many pro-in- Th1 response (Fig.3). Further, tissue expression of both IFN-γ and IL-4
flammatory molecules such as matrix metalloproteinases (MMP)-9 and- was low in psoriasis but were similar between stable and active disease
1, IL8, growth-related oncogene (Gro), and CCL2 [69]. They suppressed which correlated weakly with psoriasis area and severity index (PASI)
CD8 T-cell proliferation less effectively than healthy control [69,70]. In scores implicating a change in cytokines levels is not related with dis-
presence of these pro-inflammatory cytokines, psoriatic Mo-MDSCs in- ease activity or severity [83].
duces aberrant Treg cell conversion from naive T effector cells, thus
affecting the immune system’s ability to correctly self-regulate [70]. 4.2.3. Th17
Th17 cells, its transcription factor RORγ and cytokines IL-17 and IL-
4.1.3. Dendritic and NK cells 22 are increased in peripheral circulation and lesions of psoriatic pa-
High expression of chemerin in psoriatic skin, a ligand for chemo- tients [81,82,86,87]. Th17 cell differentiation is mediated by activation
kine-like receptor1 (CMKLR1) expressed on pDCs leads to its selective of Notch1 signaling as inhibition of Notch1 reduced Th17 cell percen-
recruitment to lesion site (Fig. 3) [71]. CD11c+-blood dendritic cell tage, RORγ and IL-17 [88]. Unrestricted IL-36 secretion by innate im-
antigen (BDCA)-1-myeloid DCs cells are increased manifold in psoriatic mune cells signals for an increased TCR-mediated proliferation of
lesional skin and produce simultaneously IL-17 and IFN-γ [72]. Further, CD4+ T-cells as well as enhanced secretion of IL-17 A in blood and
LCs expresses chemokine CXCL9 and CXCL10, chemoattractants for T lesion of psoriasis patients [89]. IL-21 and IL-21+Th17 cells are also
cells, in psoriasis patients [73]. On the other hand, natural killer (NK) elevated in blood and lesions which had a positive correlation with
cells are present in the lesional skin of psoriasis patients and exhibited disease severity [82,87]. In vitro, IL-21 stimulation of CD4+ T-cells
reduced degranulation and produced lower levels of the pro-in- promotes their differentiation to Th17 cells [87]. Lower levels of IL-27
flammatory cytokines IFN-γ and TNF-α [74]. in blood and lesions of moderate-to-severe psoriasis patients are ob-
served. IL-27 restricts differentiation of CD4+ Th cells to Th17 cells
4.1.4. Other innate immune cells which concomitantly decreases IL-27 secretion [90].
A distinct subset of proinflammatory cutaneous lymphocyte antigen IL-17 A causes an elevation in total intracellular cholesterol in kerati-
positive (CLA+) and CCR6 + Vγ9Vδ2 T-cells in blood migrates into nocytes which is necessary for its downstream signaling. Reducing total
perturbed skin and secreteIL-17 A, IL-22 and activates keratinocytes cholesterol levels by methyl-β-cyclodextrin considerably reduced IL-17 A
upon TNF-α, IFN-γ, and IL-23 stimulation. In psoriasis, these γδT cells induced secretion of IL-8, CCL20, and S100A7 from the keratinocytes in-
are decreased in peripheral circulation with concomitant increase in dicating an association between psoriasis and dyslipidemia [91]. Further IL-
lesional skin suggesting their pathogenic role [75]. IL-23 from LC in- 17 A induces production of IL-19 in keratinocytes which is further po-
duced production of IL-17 A producing CCR6+ γδT cells as depletion of tentiated by TNF-α and IL-22. IL-19 in turn augmented the production of
LCs reduced the IL-17 A producing CCR6+ γδT cells (Fig. 3) [76]. S100A7/8/9 and moderately enhanced IL-1β, IL-20, CXCL8, and MMP-1. IL-
Innate lymphoid cells (ILCs) are lymphoid lineage cells which lack 19 strengthens IL-17 A action on keratinocytes such as induction of HBD-2,
antigen-specific receptors. An increased frequency of IL-22- and/or IL- IL-19, IL-23p19, and Th17 cell- and neutrophil-attracting chemokines [92].
17A-producing ILCs is noted in psoriatic skin and blood which corre- Additionally, in keratinocytes IL-17/CIKS signaling leads to hyperproli-
lated with disease severity [77]. A recent report mentions that ILCs are feration of the cells with attenuated differentiation and neutrophilic micro-
activated in response to IL-23 and IL-1β and are decreased following abscess formation. In non-keratinocytes, IL-17 signaling accumulates IL-17-
anti-TNFα treatment suggesting dysregulation of ILCs as a contributing producing γδ T cells in skin [93]. Besides, keratinocytes stimulated with IL-
factor to psoriasis pathogenesis (Fig. 3) [78].CXCL11 and CCL5, a 17 also upregulates chemokines which are implicated in the influx of neu-
chemoattractant for IFNγ+ immune cells, is increased in psoriatic le- trophils (CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8), dendritic cells and
sion as well as in human keratinocyte stimulated by IFNα. This increase memory T cells (CCL20). While keratinocytes stimulated with IL-22, a Th17
is mediated by the phosphorylation of STAT2 in keratinocytes [79]. cytokine, leads to down regulation of genes associated with keratinocyte
CCL19, a T-cell chemoattractant, and its receptor CCR7 are produced differentiation (Keratin 1, Filaggrin, CALML5) and epidermal modifications
locally in psoriatic keratinocytes adding to disease pathogenesis [80]. [94].

4.2. Adaptive immune response 4.2.4. Th9 and Tfh

T cells producing IL-9 are increased in psoriatic lesions indicating
4.2.1. T cells that aberrant activation of Th9 cells contributes to disease pathogen-
In psoriasis, it is hypothesized that the effector T-cells accumulate within esis. Blocking studies revealed that IL-9 is essential for production of IL-
lymph nodes from where they migrate into the skin through the blood 9, IFN-γ, IL-17, and IL-13 by skin tropic T cells to maximal level.
system. Recently, psoriatic skin is shown to be another source for in- Furthermore, a majority of the memory Th9 cells are either skin-tropic
flammatory T cells. An intra-dermal proliferation of T cells was noted in or are skin-resident [95]. In psoriasis, a higher percentage of circulating
psoriatic skin with maximal proliferation in patients with active disease than Tfh17 (CXCR3-CCR6+) cells is seen having a high correlation with
the patients in remission (Fig. 3). The number of T cells in remission patients disease severity. Expression of IL-21R on B cells was appreciably in-
was even higher than controls indicating the presence of an immunologic creased in psoriatic patients which had a strong correlation with disease

40
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

severity and frequency of Tfh17 cells [96]. On the other hand, Additionally, in psoriasis Mo-MDSCs expressed reduced levels of PD-1
CXCR5+PD-1+Tfh cells were decreased in psoriatic patients. The ab- compared to controls (Fig. 3) [70].
solute number of CXCR5+PD-1+ and CXCR5+ICOS + Tfh cells in-
creased with disease duration with no relation to disease severity [97]. 5. Tissue-resident and innate immune memory cells

4.2.5. Regulatory T cells Newly identified subclass of memory T cells, tissue-resident memory T
FOXP3+ expressing Tregs, which are known to suppress the in- (TRM) cells, are non-circulating and retain in epithelial barrier tissues, in-
flammatory immune response, are decreased in psoriasis (74, [81]). Ele- cluding skin for longer duration [103]. Involvement of resident memory T
vated levels of pro-inflammatory cytokines IL-6, IL-21, and IL-23 in the (TRM) cells is implicated in disease recurrence in the same area even after
blood of psoriatic patients leads to phosphorylation of STAT3 in Tregs completion of treatment. CD69+CD103+CD8+ TRMs were present in
[98,99]. STAT3 phosphorylation in T-cells leads to Th17 differentiation. both stable and active vitiligo perilesional skin and mainly localized in the
Accordingly, Tregs isolated from psoriatic patients could produce IFN-γ, epidermis. These TRMs also expressed CXCR3 and produced elevated levels
TNF-α, and IL-17 [96]. Further, IL-6 induced expression of IL-6Rα expres- of IFN-γ and TNF-α with moderate cytotoxic activity (Fig.2) [104]. In
sion on Treg cells which exceeded that of T effector cells [98]. Together, in psoriasis, patient in remission has enriched epidermal CD8+ TRMs ex-
high pro-inflammatory cytokine milieu, psoriatic Tregs behave like Th17 pressing CLA antigen, CCR6, CD103, and IL-23R which produced IL-17 A on
cells and are unable to suppress the T effector activation. Adding STAT3 ex vivo stimulation. Likely, epidermal CD4+ CD103+ TRMs produced IL-
inhibitor partially restores the suppressive function of Tregs and reduced the 22 on stimulation (Fig.3) [105]. Role of TRMs in pemphigus pathogenesis
expressions of IFN-γ, TNF-α and IL-17 in psoriatic patients (Fig. 3) [99]. remains to be investigated.
Besides, eliminating Treg cells in wild-type mice increased both psoriasis In experimental psoriasis model, IL-17 A/F-producing Vγ4+Vδ4+ T
and infiltrating macrophages. Adoptive transfer of FOXP3+ T cells into cells migrate and retain in the dermis for a longer duration after initial
RAG1 knockout or wild-type mice decreased development of psoriasis as stimulation. Antigen exposed Vγ4+Vδ4+ cells exhibit robust effector
well as macrophage infiltration. Thus, Treg lymphocytes impede the functions and a secondary inflammatory response indicating participation of
proinflammatory activity of macrophages [65]. “innate immune memory” in delivering fast and strong immune response
upon re-challenge [106]. Role of innate immune memory in disease re-
4.3. Immune checkpoints appearance in vitiligo and pemphigus needs to be examined.

In psoriasis, TCR+ CD3+ CD4− CD8− “double negative” (DN) T and 6. Conclusion
PD-1+cells are increased in number and infiltrate the epidermal lesions.
These cells exhibit phenotypes commonly seen in effector memory cells, Recently, significant advancement has been made in understanding
secrete IFN-γ, and fail to proliferate [100]. Accordingly, high expression the role of the immune cell network in autoimmune skin diseases. Some
of negative immune regulatory genes (CTLA4, CD69, and PD-L1) occurs common players in pemphigus, vitiligo and psoriasis pathogenesis are
in mild psoriasis compared to severe form [101]. On the contrary, ex- identified such as Th1/Th17 immune response, defective regulatory
pression of PD-1 and neuropilin-1 (NRP1) but not of human leukocyte cells, activated LCs, CD8+ T-cells and TRMs suggesting a common
antigen G (HLA-G) is reduced in PBMCs of psoriasis patients [102]. pathway for disease pathogenesis (Fig. 4). Further, different layers of

Fig. 4. Unified immune mechanism of common autoimmune skin disease: Skin self-antigens are identified by LCs and dermal DCs which acts as APCs. Antigen
binding activates LCs which secrets proinflammatory cytokines and chemokines. This in turn activates keratinocytes which also secrets proinflammatory cytokines
and chemokines, thus maintaining the inflammatory state. LCs and dermal DCs present antigen to skin resident and circulating T cells which proliferate and
differentiate into Th1, Th17 and Tfh cells. Th1 and Th17 cells maintain the inflammatory state, Tfh cells activate antigen specific B cells to proliferate and produce
autoantibodies. Tregs are decreased in circulation due to defective proliferation and in skin due to defect in homing. Tregs phenotype is altered from anti- to pro-
inflammatory. CD8 T cells attack the keratinocytes and melanocytes. Antigen specific CD4 and CD8 TRMS produce proinflammatory cytokines upon stimulation thus
contributing to disease recurrence.

41
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

regulatory cells are identified such as MoMDSCs and iNKT (innate J. Rodrigues, V. Sales-Campos, H. Oliveira, CJF, Th1/Th17-related cytokines and
regulatory cells) as well Tregs and Bregs (adaptive regulatory cells) chemokines and their implications in the pathogenesis of pemphigus vulgaris,
Mediators Inflamm. (2017) 1–9.
which needs to be investigated in PV, vitiligo, and psoriasis. Even [20] M. Inoue, M.L. Shinohara, Intracellular osteopontin (iOPN) and immunity,
though different treatment regimens have shown to increase Tregs in all Immunol. Res. 49 (2011) 160–172.
the three autoimmune skin diseases, none efficient enough to reverse [21] A. Baroni, A. De Filippis, E. Buommino, R.A. Satriano, V. Cozza, Osteopontin, a
protein with cytokine-like properties: a possible involvement in pemphigus vul-
the disease. This might be due to either role played by other regulatory garis, Arch. Dermatol. Res. 304 (2012) 237–240.
cells or phenotype change of Tregs due to their plastic behavior in in- [22] Q. Tang, J.A. Bluestone, The Foxp3+ regulatory T cell: a jack of all trades, master
flammatory microenvironment or both. A detailed knowledge of path- of regulation, Nat. Immunol. 9 (2008) 239–244.
[23] Q. Tang, K.J. Henriksen, E.K. Boden, A.J. Tooley, J. Ye, S.K. Subudhi, X.X. Zheng,
ways involved in the dysregulation of innate and adaptive regulatory T.B. Strom, J.A. Bluestone, Cutting edge: CD28 controls peripheral homeostasis of
cells is needed. Further, the role of TRMs is implicated in disease re- CD4+CD25+ regulatory T cells, J. Immunol. 171 (2003) 3348–3352.
currence after treatment completion. Novel therapeutics targeting ele- [24] M. Alecu, C. Ursaciuc, M. Surcel, G. Coman, D. Ciotaru, M. Dobre, CD28 T-cell
costimulatory molecule expression in pemphigus vulgaris, J. Eur. Acad. Dermatol.
vation of innate and adaptive regulatory cells as well as down reg-
Venereol. 23 (2009) 288–291.
ulating TRMs would be of great value in treating these diseases. In this [25] T. Schmidt, S. Willenborg, T. Hunig, C.A. Deeg, G. Sonderstrup, M. Hertl,
maiden comprehensive review, aberration in immune cell network has R. Eming, Induction of T regulatory cells by the superagonistic anti-CD28 antibody
been highlighted. The detailed understanding of this network and D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a
HLA-transgenic mouse model of pemphigus vulgaris, Exp. Dermatol. 25 (2016)
possible interventions may lead to better management of these auto- 293–298.
immune skin diseases. [26] M. Fujimoto, Regulatory B cells in skin and connective tissue diseases, J. Dermatol.
Sci. 60 (2010) 1–7.
[27] C. Mauri, A. Bosma, Immune regulatory function of B cells, Annu. Rev. Immunol.
Funding source 30 (2012) 221–241.
[28] H.Q. Zhu, R.C. Xu, Y.Y. Chen, H.J. Yuan, H. Cao, X.Q. Zhao, J. Zheng, Y. Wang,
None. M. Pan, Impaired function of CD19(+) CD24(hi) CD38(hi) regulatory B cells in
patients with pemphigus, Br. J. Dermatol. 172 (2015) 101–110.
[29] F. Giurdanella, L. Fania, M. Gnarra, P. Toto, D. Di Rollo, D.N. Sauder, C. Feliciani,
Declarations of interest A possible role for CD8+ T lymphocytes in the cell-mediated pathogenesis of
pemphigus vulgaris, Mediators Inflamm. 2013 (2013) 764290.
[30] K. Boniface, J. Seneschal, M. Picardo, A. Taieb, Vitiligo: focus on clinical aspects,
None. immunopathogenesis, and therapy, Clin. Rev. Allergy Immunol. 54 (2018) 52–67.
[31] S. Toosi, S.J. Orlow, P. Manga, Vitiligo-inducing phenols activate the unfolded
References protein response in melanocytes resulting in upregulation of IL6 and IL8, J. Invest.
Dermatol. 132 (2012) 2601–2609.
[32] R. Yu, R. Broady, Y. Huang, Y. Wang, J. Yu, M. Gao, M. Levings, S. Wei, S. Zhang,
[1] J.M. Richmond, J.E. Harris, Immunology and skin in health and disease, Cold A. Xu, M. Su, J. Dutz, X. Zhang, Y. Zhou, Transcriptome analysis reveals markers of
Spring Harb. Perspect. Med. 4 (2014) a015339. aberrantly activated innate immunity in vitiligo lesional and non-lesional skin,
[2] K.D.A. Pandey, R. Sekhri, Prevalence of psoriasis: an Indian perspective, J. Am PLoS One 7 (2012) e51040.
Acad. Dermatol. 74 (2016) AB264. [33] S. Itoi, A. Tanemura, Y. Kotobuki, M. Wataya-Kaneda, D. Tsuruta, M. Ishii,
[3] J. Reddy, A survey on the prevalence of Vitiligo in Banglore City, India, Int. J. I. Katayama, Coexistence of Langerhans cells activation and immune cells in-
Pharma Med. Biol. Sci. 3 (2014) 34–45. filtration in progressive nonsegmental vitiligo, J. Dermatol. Sci. 73 (2014) 83–85.
[4] S.O.A. Agrawal, S. Gupta, Profile of vitiligo in Kumaun region of Uttrakhand, [34] C.Q. Wang, A.E. Cruz-Inigo, J. Fuentes-Duculan, D. Moussai, N. Gulati,
India, Indian J. Dermatol. 59 (2014). M. Sullivan-Whalen, P. Gilleaudeau, J.A. Cohen, J.G. Krueger, Th17 cells and
[5] K.A. Kumar, Incidence of pemphigus in Thrissur district, south India, Indian J. activated dendritic cells are increased in vitiligo lesions, PLoS One 6 (2011)
Dermatol. Venereol. Leprol. 74 (2008) 349–351. e18907.
[6] D.P.K. Parmar, Prevalence of pemphigus incidence in the Bhuj, Kutch, Gujarat: a [35] J.M. Richmond, D.S. Bangari, K.I. Essien, S.D. Currimbhoy, J.R. Groom,
cross-sectional study, Int. J. Res. Dermatol. 3 (2017) 478–480. A.G. Pandya, M.E. Youd, A.D. Luster, J.E. Harris, Keratinocyte-derived chemokines
[7] F. Abdallah, L. Mijouin, C. Pichon, Skin immune landscape: inside and outside the orchestrate T-Cell positioning in the Epidermis during vitiligo and may serve as
organism, Mediators Inflamm. 2017 (2017) 5095293. biomarkers of disease, J. Invest. Dermatol. 137 (2017) 350–358.
[8] M. Kasperkiewicz, C.T. Ellebrecht, H. Takahashi, J. Yamagami, D. Zillikens, [36] A.A. Abdellatif, A.M. Zaki, H.M. Abdo, D.G. Aly, T.A. Emara, S. El-Toukhy,
A.S. Payne, M. Amagai, Pemphigus, Nat. Rev. Dis. Primers 3 (2017) 17026. H.M. Emam, M.S. Abdelwahab, Assessment of serum levels of granulocyte-mac-
[9] R. Pollmann, T. Schmidt, R. Eming, M. Hertl, Pemphigus: a comprehensive review rophage colony-stimulating factor (GM-CSF) among non-segmental vitiligo pa-
on pathogenesis, clinical presentation and novel therapeutic approaches, Clin. tients: a pilot study, Acta Dermatovenerol. Alp. Pannonica Adriat. 24 (2015)
Rev. Allergy Immunol. 54 (2018) 1–25. 43–45.
[10] J.N. Stern, D.B. Keskin, N. Barteneva, J. Zuniga, E.J. Yunis, A.R. Ahmed, Possible [37] A. Zloza, G.E. Lyons, L.K. Chlewicki, F.J. Kohlhapp, J.A. O’Sullivan, A.T. Lacek,
role of natural killer cells in pemphigus vulgaris - preliminary observations, Clin. T.V. Moore, M.C. Jagoda, V. Kumar, J.A. Guevara-Patino, Engagement of NK re-
Exp. Immunol. 152 (2008) 472–481. ceptor NKG2D, but not 2B4, results in self-reactive CD8+ T cells and autoimmune
[11] D. Das, V. Anand, S. Khandpur, V.K. Sharma, A. Sharma, T helper type 1 polarizing vitiligo, Autoimmunity 44 (2011) 599–606.
gammadelta T cells and Scavenger receptors contribute to the pathogenesis of [38] A. Bertolotti, K. Boniface, B. Vergier, D. Mossalayi, A. Taieb, K. Ezzedine,
Pemphigus vulgaris, Immunology 153 (2017) 97–104. J. Seneschal, Type I interferon signature in the initiation of the immune response
[12] K. Amber, P. Staropoli, M.I. Shiman, G.W. Elgart, M. Hertl, Autoreactive T cells in in vitiligo, Pigm. Cell Melanoma Res. 27 (2019) 398–407.
the immune pathogenesis of pemphigus vulgaris, Exp. Dermatol. 22 (2013) [39] J. Mosenson, A. Zloza, J. Klarquist, A.J. Barfuss, J.A. Guevara-Patino, I.C. Le Pool,
699–704. HSP70i is a critical component of the immune response leading to vitiligo, Pigm.
[13] A. Satyam, S. Khandpur, V.K. Sharma, A. Sharma, Involvement of T(H)1/T(H)2 Cell Melanoma Res. 25 (2012) 88–98.
cytokines in the pathogenesis of autoimmune skin disease-Pemphigus vulgaris, [40] L. Zhou, K. Li, Y.L. Shi, I. Hamzavi, T.W. Gao, M. Henderson, R.H. Huggins,
Immunol. Invest. 38 (2009) 498–509. O. Agbai, B. Mahmoud, X. Mi, H.W. Lim, Q.S. Mi, Systemic analyses of im-
[14] R. Asothai, V. Anand, D. Das, P.S. Antil, S. Khandpur, V.K. Sharma, A. Sharma, munophenotypes of peripheral T cells in non-segmental vitiligo: implication of
Distinctive Treg associated CCR4-CCL22 expression profile with altered frequency defective natural killer T cells, Pigm. Cell Melanoma Res. 25 (2012) 602–611.
of Th17/Treg cell in the immunopathogenesis of Pemphigus Vulgaris, [41] Y. Lili, W. Yi, Y. Ji, S. Yue, S. Weimin, L. Ming, Global activation of CD8+ cy-
Immunobiology 220 (2015) 1129–1135. totoxic T lymphocytes correlates with an impairment in regulatory T cells in pa-
[15] N. Joshi, R.W. Minz, S. Anand, N.V. Parmar, A.J. Kanwar, Vitamin D deficiency tients with generalized vitiligo, PLoS One 7 (2012) e37513.
and lower TGF-β/IL-17 ratio in a North Indian cohort of pemphigus vulgaris, BMC [42] R. Pichler, K. Sfetsos, B. Badics, S. Gutenbrunner, J. Berg, J. Auböck, Lymphocyte
Res. Notes 7 (2014) 536. imbalance in vitiligo patients indicated by elevated CD4C/CD8C T-cell ratio,
[16] R.C. Xu, H.Q. Zhu, W.P. Li, X.Q. Zhao, H.J. Yuan, J. Zheng, M. Pan, The imbalance Wien. Med. Wochenschr. 159 (2009) 337–341.
of Th17 and regulatory T cells in pemphigus patients, Eur. J. Dermatol. 23 (2013) [43] S. Li, G. Zhu, Y. Yang, Z. Jian, S. Guo, W. Dai, Q. Shi, R. Ge, J. Ma, L. Liu, K. Li,
795–802. Q. Luan, G. Wang, T. Gao, C. Li, Oxidative stress drives CD8(+) T-cell skin traf-
[17] T. Hennerici, R. Pollmann, T. Schmidt, M. Seipelt, B. Tackenberg, C. Mobs, ficking in patients with vitiligo through CXCL16 upregulation by activating the
K. Ghoreschi, M. Hertl, R. Eming, Increased frequency of t follicular helper cells unfolded protein response in keratinocytes, J. Allergy Clin. Immunol. 140 (2017)
and elevated Interleukin-27 plasma levels in patients with pemphigus, PLoS One 177–189 e179.
11 (2016) e0148919. [44] A. Rezk, D.M. Kemp, M. El-Domyati, W.H. El-Din, J.B. Lee, J. Uitto, O. Igoucheva,
[18] H. Yuan, S. Zhou, Z. Liu, W. Cong, X. Fei, W. Zeng, H. Zhu, R. Xu, Y. Wang, V. Alexeev, Misbalanced CXCL12 and CCL5 chemotactic signals in vitiligo onset
J. Zheng, M. Pan, Pivotal role of Lesional and perilesional T/B lymphocytes in and progression, J. Invest Dermatol. 137 (2017) 1126–1134.
pemphigus pathogenesis, J. Invest. Dermatol. 137 (2017) 2362–2370. [45] A. Rao, S. Gupta, A.K. Dinda, A. Sharma, V.K. Sharma, G. Kumar, D.K. Mitra,
[19] R. Timoteo, Vinicius da Silva, M. Miguel, C.B. Silva, D.A. Da Silva Catarino, C.K. Prashant, G. Singh, Study of clinical, biochemical and immunological factors

42
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

determining stability of disease in patients with generalized vitiligo undergoing HLA-DR(-/low) myeloid-derived suppressor cells in psoriasis: a mechanism of
melanocyte transplantation, Br. J. Dermatol. 166 (2012) 1230–1236. dysregulated t cells, J. Invest. Dermatol. 136 (2016) 798–808.
[46] F. Behfarjam, P. Mansouri, Z. Jadali, Imbalance of peripheral blood t helper type [71] J. Skrzeczynska-Moncznik, K. Wawro, A. Stefanska, E. Oleszycka, P. Kulig,
17 responses in patients with vitiligo, Iran. J. Allergy Asthma Immunol. 17 (2018) B.A. Zabel, M. Sulkowski, M. Kapinska-Mrowiecka, M. Czubak-Macugowska,
171–178. E.C. Butcher, J. Cichy, Potential role of chemerin in recruitment of plasmacytoid
[47] Zhou Li, Y.L. Shi, Kai Li, Iltefat Hamzavi, Tian-Wen Gao, Richard H. Huggins, dendritic cells to diseased skin, Biochem. Biophys. Res. Commun. 380 (2009)
Henry W. Lim, Qing-Sheng Mi, Increased circulating Th17 cells and elevated 323–327.
serumlevels of TGF-beta and IL-21 are correlated with humannon-segmental vi- [72] L.C. Zaba, J. Fuentes-Duculan, N.J. Eungdamrong, M.V. Abello, I. Novitskaya,
tiligo development, Pigment Cell Melanoma Res. 28 (2015) 324–329. K.C. Pierson, J. Gonzalez, J.G. Krueger, M.A. Lowes, Psoriasis is characterized by
[48] Y. Zhen, L. Yao, S. Zhong, Y. Song, Y. Cui, S. Li, Enhanced Th1 and Th17 responses accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid den-
in peripheral blood in active non-segmental vitiligo, Arch. Dermatol. Res. 308 dritic cells, J. Invest. Dermatol. 129 (2009) 79–88.
(2016) 703–710. [73] H. Fujita, A. Shemer, M. Suarez-Farinas, L.M. Johnson-Huang, S. Tintle,
[49] R. Khan, S. Gupta, A. Sharma, Circulatory levels of T-cell cytokines (interleukin I. Cardinale, J. Fuentes-Duculan, I. Novitskaya, J.A. Carucci, J.G. Krueger,
[IL]-2, IL-4, IL-17, and transforming growth factor-beta) in patients with vitiligo, E. Guttman-Yassky, Lesional dendritic cells in patients with chronic atopic der-
J. Am. Acad. Dermatol. 66 (2019) 510–511. matitis and psoriasis exhibit parallel ability to activate T-cell subsets, J. Allergy
[50] F. Behfarjam, Z. Jadali, Vitiligo patients show significant up-regulation of aryl Clin. Immunol. 128 (2011) 574–582 e571-512.
hydrocarbon receptor transcription factor, An. Bras. Dermatol. 93 (2018) [74] S.E. Dunphy, C.M. Sweeney, G. Kelly, A.M. Tobin, B. Kirby, C.M. Gardiner, Natural
302–303. killer cells from psoriasis vulgaris patients have reduced levels of cytotoxicity
[51] M. Tembhre, A.S. Parihar, V.K. Sharma, A. Sharma, P. Chattopadhyay, S. Gupta, associated degranulation and cytokine production, Clin. Immunol. 177 (2015)
Alteration in regulatory T cells and programmed death (PD)1 expressing reg- 43–49.
ulatory T cells in active generalized vitiligo and their clinical correlation, Br. J. [75] U. Laggner, P. Di Meglio, G.K. Perera, C. Hundhausen, K.E. Lacy, N. Ali,
Dermatol. Syph. 172 (2015) 940–950. C.H. Smith, A.C. Hayday, B.J. Nickoloff, F.O. Nestle, Identification of a novel
[52] D.S. Hegab, M.A. Attia, Decreased circulating t regulatory cells in egyptian pa- proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a po-
tients with nonsegmental vitiligo: correlation with disease activity, Dermatol. Res. tential role in psoriasis, J. Immunol. 187 (2011) 2783–2793.
Pract. 2015 (2015) 145409. [76] R. Yoshiki, K. Kabashima, T. Honda, S. Nakamizo, Y. Sawada, K. Sugita,
[53] M.K. Tembhre, V.K. Sharma, A. Sharma, P. Chattopadhyay, S. Gupta, T helper and H. Yoshioka, S. Ohmori, B. Malissen, Y. Tokura, M. Nakamura, IL-23 from
regulatory T cell cytokine profile in active, stable and narrow band ultraviolet B Langerhans cells is required for the development of imiquimod-induced psoriasis-
treated generalized vitiligo, Clin. Chim. Acta 424 (2013) 27–32. like dermatitis by induction of IL-17A-producing gammadelta T cells, J. Invest.
[54] M.K. Tembhre, A.S. Parihar, A. Sharma, S. Gupta, P. Chattopadhyay, V.K. Sharma, Dermatol. 134 (2014) 1912–1921.
Participation of T cell immunoglobulin and mucin domain-3 (TIM-3) and its ligand [77] N.L. Ward, D.T. Umetsu, A new player on the psoriasis block: IL-17A- and IL-22-
(galectin-9) in the pathogenesis of active generalized vitiligo, Immunol. Res. 62 producing innate lymphoid cells, J. Invest. Dermatol. 134 (2014) 2305–2307.
(2015) 23–34. [78] V.R. Khairutdinov, A.F. Mikhailichenko, I.E. Belousova, E.S. Kuligina,
[55] X. Miao, R. Xu, B. Fan, J. Chen, X. Li, W. Mao, S. Hua, B. Li, PD-L1 reverses A.V. Samtsov, E.N. Imyanitov, The role of intradermal proliferation of T-cells in
depigmentation in Pmel-1 vitiligo mice by increasing the abundance of Tregs in the pathogenesis of psoriasis, An. Bras. Dermatol. 92 (2017) 41–44.
the skin, Sci. Rep. 8 (2018) 1–6. [79] C. Johansen, A.H. Rittig, M. Mose, T. Bertelsen, I. Weimar, J. Nielsen, T. Andersen,
[56] A. Batycka-Baran, J. Maj, R. Wolf, J.C. Szepietowski, The new insight into the role T.K. Rasmussen, B. Deleuran, L. Iversen, STAT2 is involved in the pathogenesis of
of antimicrobial proteins-alarmins in the immunopathogenesis of psoriasis, J. psoriasis by promoting CXCL11 and CCL5 production by keratinocytes, PLoS One
Immunol. Res. 2014 (2014) 628289. 12 (2017) e0176994.
[57] S. Morizane, R.L. Gallo, Antimicrobial peptides in the pathogenesis of psoriasis, J. [80] H. Mitsui, M. Suarez-Farinas, D.A. Belkin, N. Levenkova, J. Fuentes-Duculan,
Dermatol. 39 (2012) 225–230. I. Coats, H. Fujita, J.G. Krueger, Combined use of laser capture microdissection
[58] A. Batycka-Baran, E. Hattinger, S. Zwicker, B. Summer, O.M. Zack Howard, and cDNA microarray analysis identifies locally expressed disease-related genes in
P. Thomas, J.C. Szepietowski, T. Ruzicka, J.C. Prinz, R. Wolf, Leukocyte-derived focal regions of psoriasis vulgaris skin lesions, J. Invest. Dermatol. 132 (2012)
koebnerisin (S100A15) and psoriasin (S100A7) are systemic mediators of in- 1615–1626.
flammation in psoriasis, J. Dermatol. Sci. 79 (2015) 214–221. [81] M. Priyadarssini, D. Divya Priya, S. Indhumathi, M. Rajappa, L. Chandrashekar,
[59] S.T. Oh, A. Schramme, W. Tilgen, P. Gutwein, J. Reichrath, Overexpression of D.M. Thappa, Immunophenotyping of T cells in the peripheral circulation in
CXCL16 in lesional psoriatic skin, Dermatoendocrinology 1 (2009) 114–118. psoriasis, Br. J. Biomed. Sci. 73 (2016) 174–179.
[60] S. Steffen, S. Abraham, M. Herbig, F. Schmidt, K. Blau, S. Meisterfeld, S. Beissert, [82] S. Jain, I.R. Kaur, S. Das, S.N. Bhattacharya, A. Singh, T helper 1 to T helper 2 shift
J. Guck, C. Gunther, Toll-like receptor-mediated upregulation of CXCL16 in in cytokine expression: an autoregulatory process in superantigen-associated
psoriasis orchestrates neutrophil activation, J. Invest. Dermatol. 138 (2018) psoriasis progression? J. Med. Microbiol. 58 (2009) 180–184.
344–354. [83] S.G.V. Khandpur, D. Das, A. Sharma, Is there a correlation of serum and tissue T
[61] S.Y. Hu, Yen H, Lin F, Chen C, Lan G, CE, Neutrophil extracellular trap formation is helper-1 and -2 cytokine profiles with psoriasis activity and severity? A cross-
increased in psoriasis and induces human β-defensin-2 production in epidermal sectional study, Indian J. Dermatol. Venereol. Leprol. 84 (2018) 414–418.
keratinocytes, Sci. Rep. 6 (2016). [84] K. Zhu, J. Ye, M. Wu, H. Cheng, Expression of Th1 and Th2 cytokine-associated
[62] A. Lin, C.J. Rubin, R. Khandpur, J.Y. Wang, M.B. Riblett, S. Yalavarthi, transcription factors, T-bet and GATA-3, in peripheral blood mononuclear cells
E.C. Villanueva, P. Shah, M.J. Kaplan, A.T. Bruce, Mast cells and neutrophils re- and skin lesions of patients with psoriasis vulgaris, Arch. Dermatol. Res. 302
lease IL-17 through extracellular trap formation in psoriasis, J. Immunol. 187 (2010) 517–523.
(2011) 490–500. [85] E. Buommino, M.A. Tufano, N. Balato, N. Canozo, M. Donnarumma, L. Gallo,
[63] M. Kakeda, C. Schlapbach, G. Danelon, M.M. Tang, V. Cecchinato, N. Yawalkar, A. Balato, F. Ayala, Osteopontin: a new emerging role in psoriasis, Arch. Dermatol.
M. Uguccioni, Innate immune cells express IL-17A/F in acute generalized ex- Res. 301 (2009) 397–404.
anthematous pustulosis and generalized pustular psoriasis, Arch. Dermatol. Res. [86] M. Mansouri, P. Mansouri, A.A. Raze, Z. Jadali, The potential role of Th17 lym-
306 (2014) 933–938. phocytes in patients with psoriasis, An. Bras. Dermatol. 93 (2018) 63–66.
[64] S. Glatt, D. Baeten, T. Baker, M. Griffiths, L. Ionescu, A.D.G. Lawson, A. Maroof, [87] L.-L.W. Ying Wang, Hao-Yu Yang, Fei-Fei Wang, Xue-Xiu Zhang, Yan-Ping Bai,
R. Oliver, S. Popa, F. Strimenopoulou, P. Vajjah, M. Watling, N. Yeremenko, Interleukin-21 is associated with the severity of psoriasis vulgaris through pro-
P. Miossec, S. Shaw, Dual IL-17A and IL-17F neutralisation by bimekizumab in moting CD4+ T cells to differentiate into Th17 cells, Am. J. Transl. Res. 8 (2016)
psoriatic arthritis: evidence from preclinical experiments and a randomised pla- 3188–3196.
cebo-controlled clinical trial that IL-17F contributes to human chronic tissue in- [88] L. Ma, H. Xue, T. Gao, M. Gao, Y. Zhang, Notch1 signaling regulates the Th17/Treg
flammation, Ann. Rheum. Dis. 77 (2018) 523–532. immune imbalance in patients with psoriasis vulgaris, Mediators Inflamm. (2018)
[65] R. Leite Dantas, D. Masemann, T. Schied, V. Bergmeier, T. Vogl, K. Loser, 1–10.
B. Brachvogel, G. Varga, S. Ludwig, V. Wixler, Macrophage-mediated psoriasis can [89] A. Arakawa, S. Vollmer, P. Besgen, A. Galinski, B. Summer, Y. Kawakami,
be suppressed by regulatory T lymphocytes, J. Pathol. 240 (2016) 366–377. A. Wollenberg, K. Dornmair, M. Spannagl, T. Ruzicka, T. Thomas, J.C. Prinz,
[66] J. Fuentes-Duculan, M. Suarez-Farinas, L.C. Zaba, K.E. Nograles, K.C. Pierson, Unopposed IL-36 activity promotes clonal CD4+ T-cell responses with IL-17A
H. Mitsui, C.A. Pensabene, J. Kzhyshkowska, J.G. Krueger, M.A. Lowes, A sub- production in generalized pustular psoriasis, J. Invest. Dermatol. 138 (2018)
population of CD163-positive macrophages is classically activated in psoriasis, J. 1338–1347.
Invest. Dermatol. 130 (2010) 2412–2422. [90] W. Chen, Y. Gong, X. Zhang, Y. Tong, X. Wang, C. Fei, H. Xu, Q. Yu, Y. Wang,
[67] N. Yawalkar, G.G. Tscharner, R.E. Hunger, A.S. Hassan, Increased expression of IL- Y. Shi, Decreased expression of IL-27 in moderate-to-severe psoriasis and its anti-
12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque inflammation role in imiquimod-induced psoriasis-like mouse model, J. Dermatol.
psoriasis, J. Dermatol. Sci. 54 (2009) 99–105. Sci. 85 (2017) 115–123.
[68] C.T.H. Nguyen, N. Kambe, F. Yamazaki, I. Ueda-Hayakawa, I. Kishimoto, [91] P. Varshney, N. Saini, PI3K/AKT/mTOR activation and autophagy inhibition plays
H. Okamoto, Up-regulated expression of CD86 on circulating intermediate a key role in increased cholesterol during IL-17A mediated inflammatory response
monocytes correlated with disease severity in psoriasis, J. Dermatol. Sci. 90 (2018) in psoriasis, Biochim. Biophys. Acta Mol. Basis Dis. 1864 (2016) 1795–1803.
135–143. [92] E. Witte, G. Kokolakis, K. Witte, S. Philipp, W. Doecke, N. Babel, B.M. Wittig,
[69] D. Ilkovitch, L.K. Ferris, Myeloid-derived suppressor cells are elevated in patients K. Warszawska, A. Kurek, M. Erdmann-Keding, S. Kunz, K. Asadullah, M.E. Kadin,
with psoriasis and produce various molecules, Mol. Med. Rep. 14 (2016) H.D. Volk, W. Sterry, K. Wolk, R. Saba, IL-19 is a component of the pathogenetic
3935–3940. IL-23/IL-17 cascade in psoriasis, J. Invest. Dermatol. 134 (2014) 2757–2767.
[70] D.C. Soler, A.B. Young, L. Fiessinger, F. Galimberti, S. Debanne, S. Groft, [93] H.L. Ha, H. Wang, P. Pisitkun, J.C. Kim, I. Tassi, W. Tang, M.I. Morasso,
T.S. McCormick, K.D. Cooper, Increased, but functionally impaired, CD14(+) M.C. Udey, U. Siebenlist, IL-17 drives psoriatic inflammation via distinct, target

43
D. Das, et al. Cytokine and Growth Factor Reviews 45 (2019) 35–44

cell-specific mechanisms, Proc. Natl. Acad. Sci. U. S. A. 111 (2014) E3422–3431. Dr. Shamima Akhtar has graduated her PhD from Institute
[94] K.E. Nograles, L.C. Zaba, E. Guttman-Yassky, J. Fuentes-Duculan, M. Suarez- of Molecular Cardiovascular Research (IMCAR, University
Farinas, I. Cardinale, A. Khatcherian, J. Gonzalez, K.C. Pierson, T.R. White, Hospital), Aachen, Germany. She received DAAD-Siemens
C. Pensabene, I. Coats, I. Novitskaya, M.A. Lowes, J.G. Krueger, Th17 cytokines scholarship to persue her PhD from 2009-2013. Her PhD
interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte- research focused on stabilizing atherosclerotic plaques by
response pathways, Br. J. Dermatol. 159 (2008) 1092–1102. CXCL12 treatment and studying the role of HIF-1α in
[95] C. Schlapbach, A. Gehad, C. Yang, R. Watanabe, E. Guenova, J.E. Teague, atherosclerosis. Presently, she is a post-doctoral fellow in
L. Campbell, N. Yawalkar, T.S. Kupper, R.A. Clark, Human TH9 cells are skin- Dr. Alpana Sharma’s Lab at Department of Biochemistry, All
tropic and have autocrine and paracrine proinflammatory capacity, Sci. Transl. India Institute of Medical Sciences (AIIMS), New Delhi,
Med. 6 (2014) 219ra218. India. She received competitive National Post-Doctoral
[96] Y. Wang, L. Wang, H. Yang, W. Yuan, J. Ren, Y. Bai, Activated circulating t fol- Fellowship from Department of Science and Technology
licular helper cells are associated with disease severity in patients with psoriasis, J. (DST) India for her current position. Her post-doctoral work
Immunol. Res. 2016 (2016) 7346030. focuses on stratifying different stages of endothelial dys-
[97] D. Shin, D.S. Kim, S.H. Kim, J.H. Je, H.J. Kim, D. Young Kim, S.M. Kim, M.G. Lee, function and validating them in cardiovascular patients.
Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis,
Arch. Dermatol. Res. 308 (2016) 593–599.
[98] W.A. Goodman, A.D. Levine, J.V. Massari, H. Sugiyama, T.S. McCormick, Santosh Kurra has obtained his Master in Science from
K.D. Cooper, IL-6 signaling in psoriasis prevents immune suppression by reg- GITAM University, India. Presently, is a PhD Student at Dr.
ulatory T cells, J. Immunol. 183 (2009) 3170–3176. Alpana Sharma’s Lab at Department of Biochemistry,
[99] L. Yang, B. Li, E. Dang, L. Jin, X. Fan, G. Wang, Impaired function of regulatory T AIIMS, New Delhi, India. The focus of his PhD is studying
cells in patients with psoriasis is mediated by phosphorylation of STAT3, J. the role of gamma delta T cells in the pathogenesis of
Dermatol. Sci. 81 (2015) 85–92. Vitiligo.
[100] D. Brandt, M. Sergon, S. Abraham, K. Mabert, C.M. Hedrich, TCR
(+)CD3(+)CD4(-)CD8(-) effector T cells in psoriasis, Clin. Immunol. 181 (2017)
51–59.
[101] J. Kim, R. Bissonnette, J. Lee, J. Correa da Rosa, M. Suarez-Farinas, M.A. Lowes,
J.G. Krueger, The Spectrum of mild to severe psoriasis vulgaris is defined by a
common activation of IL-17 pathway genes, but with key differences in immune
regulatory genes, J. Invest. Dermatol. 136 (2016) 2173–2182.
[102] J. Bartosinska, J. Purkot, M. Kowal, A. Michalak-Stoma, D. Krasowska,
G. Chodorowska, K. Giannopoulos, The expression of selected molecular markers
Dr. Somesh Gupta, is a professor and practicing clinician
of immune tolerance in psoriatic patients, Adv. Clin. Exp. Med. 27 (2018)
at Department of Dermatology and Venerology at All India
721–725.
Institute of Medical Sciences (AIIMS), New Delhi, India. He
[103] H. Wu, W. Liao, Q. Li, H. Long, H. Yin, M. Zhao, V. Chan, C.S. Lau, Q. Lu,
obtained his MD in Dermatology and Venerology from
Pathogenic role of tissue-resident memory T cells in autoimmune diseases,
Government Medical College, Jabalpur, MP, India in 1997.
Autoimmun. Rev. 17 (2018) 906–911.
His main focus of research is on Vitiligo and Psoriasis. He is
[104] K. Boniface, C. Jacquemin, A.S. Darrigade, B. Dessarthe, C. Martins,
the recipient of many national awards such as, Dermatology
N. Boukhedouni, C. Vernisse, A. Grasseau, D. Thiolat, J. Rambert, F. Lucchese,
Excellence Award (2003–2004) Vishnu Priya Devi IADVL
A. Bertolotti, K. Ezzedine, A. Taieb, J. Seneschal, Vitiligo skin is imprinted with
Award Appreciation Award by IADVL Dr. P.S. Ranganathan
resident memory CD8 t cells expressing CXCR3, J. Invest. Dermatol. 138 (2018)
Memorial Award Dr. V. Govindan Nair Memorial Prize To
355–364.
date, he has authored more than 200 peer-reviewed papers.
[105] S. Cheuk, M. Wiken, L. Blomqvist, S. Nylen, T. Talme, M. Stahle, L. Eidsmo,
Epidermal Th22 and Tc17 cells form a localized disease memory in clinically
healed psoriasis, J. Immunol. 192 (2014) 3111–3120.
[106] T. Hartwig, S. Pantelyushin, A.L. Croxford, P. Kulig, B. Becher, Dermal IL-17-
producing gammadelta T cells establish long-lived memory in the skin, Eur. J. Dr. Alpana Sharma is a professor at Department of
Immunol. 45 (2015) 3022–3033. Biochemistry, AIIMS, New Delhi, India. She received her
PhD and MPhil in Biochemistry from JN Medical College,
Aligarh Muslim University, India. Her broad area of re-
Dayasagar Das has graduated his Master in Science in search interest includes immunopathogenesis of auto-
Microbiology from Kasturba Medical College, Manipal
immune skin diseases such as pemphigus, vitiligo and
University, India. He is currently a PhD student at Dr. psoriasis. She is a recipient of many national and interna-
Alpana Sharma’s Lab at Department of Biochemistry, All
tional awards e.g. Indo-French Fellowship, and ACR-NCI
India Institute of Medical Sciences (AIIMS), New Delhi,
International Investigator award (USA), AIIMS Excellence
India. His doctoral thesis is focused on “exploring the Research Award etc. She is member of National Academy of
plasticity of gamma delta T cell in autoimmune blistering
Medical Sciences, National Academy of Sciences, and
skin disease, Pemphigus vulgaris”. He has received GP Indian Immunological Society. She is Treasurer of Indian
Talwar Young Scientist award during his PhD. He has also
Immunology Society. She is guiding many pH.D., M.D. and
availed many International Travel grants to attend the M.Sc. students for their dissertation. Her research work is funded by various national
conferences.
funding agencies such as Department of Biotechnology (DBT), Indian Council of Medical
Research (ICMR), Council of Scientific and Industrial Research (CSIR), etc. She has
written two books, contributed 23 chapters in various textbooks and published more than
110 research articles in peer-reviewed Journals.

44