10.5826/dpc.1201a152
Translational research has changed the understanding of AD pathogenesis beyond basic mechanisms of immunology. The study in patients of rational therapies based on targeted therapies (biologicals) provides valuable information from the patient and provides lessons of clinical immunology on clinically relevant mechanism of AD pathogenesis. AD features such as skin barrier defect, skin dysbiosis, and pruritus share a common abnormal adaptive immune response process. Skin related skin-homing CLA+CD4+ memory T cells produce IL-4, IL-13, and IL-31 which are key mediators in AD pathogenesis. Lessons learned from AD is that translation immunology allows generating rational therapies for AD and learning the immunopathogenesis in the patient
text/xml
2160-9381
2300
en
Luis Santamaria-Babi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Atopic Dermatitis Pathogenesis: Lessons From Immunology
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-02-02
2022-01-07
2022-02-02
2022-02-09
e2022152
Dermatol Pract Concept
Translational research has changed the understanding of AD pathogenesis beyond basic mechanisms of immunology. The study in patients of rational therapies based on targeted therapies (biologicals) provides valuable information from the patient and provides lessons of clinical immunology on clinically relevant mechanism of AD pathogenesis. AD features such as skin barrier defect, skin dysbiosis, and pruritus share a common abnormal adaptive immune response process. Skin related skin-homing CLA+CD4+ memory T cells produce IL-4, IL-13, and IL-31 which are key mediators in AD pathogenesis. Lessons learned from AD is that translation immunology allows generating rational therapies for AD and learning the immunopathogenesis in the patient
Luis Santamaria-Babi
2022/02/02
10.5826/dpc.1201a152
e2022152
Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Parc Científic de Barcelona, Barcelona, Spain
2160-9381
en
e2022152
Atopic Dermatitis Pathogenesis: Lessons From Immunology
https://dpcj.org/index.php/dpc/article/download/2300/1497
        Atopic Dermatitis Pathogenesis: Lessons From
                        Immunology
                                                            Luis F Santamaria-Babí1


1 Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona,
  Parc Científic de Barcelona, Barcelona, Spain



Key words: atopic dermatitis, translational research, homing, CLA
Abbreviations: CLA: Cutaneous Lymphocyte-Associated Antigen; Sa: Staphylococcus aureus; AD: atopic dermatitis
Citation: Santamaria-Babí L.F. Atopic dermatitis pathogenesis: lessons from immunology. Dermatol Pract Concept. 2022;12(1):e2022152.
DOI: https://doi.org/10.5826/dpc.1201a152
Accepted: December 14, 2021; Published: January 2022
Copyright: ©2022 Santamaria-Babi. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Corresponding author: Luis F Santamaria-Babí, PhD, Professor of Clinical and Translational Immunology. Translational Immunology.
Parc Científic de Barcelona, Barcelona, Spain. E-mail: Luis.santamaria@ub.edu




   This article is part of a series of reviews dedicated to Atopic Dermatitis, guest edited by Prof Anna Balato.
   Guest Editor

   Prof. Anna Balato, MD, PhD

   Associate Professor of Dermatology, Dermatology Unit, University of Campania, Naples, Italy




  ABSTRACT                 Translational research has changed the understanding of atopic dermatitis (AD) pathogenesis beyond
                           the basic mechanisms of immunology. The study in patients of rational therapies based on targeted
                           therapies (biologicals) provides valuable information from the patient and provides lessons of clinical
                           immunology on clinically relevant mechanism of AD pathogenesis. AD features such as skin barrier
                           defect, skin dysbiosis, and pruritus share a common abnormal adaptive immune response process.
                           Skin-homing CLA+CD4+ memory T-cells produce IL-4, IL-13, and IL-31 which are key mediators in
                           AD pathogenesis. Lessons learned from AD show that translational immunology allows generating
                           rational therapies for AD and learning its immunopathogenesis in the patient.




Review | Dermatol Pract Concept. 2022;12(1):e2022152                                                                                  1
Introduction                                                          includes adaptive and innate mechanisms. The adaptive
                                                                      response is based on the capture of allergens, antigens, and
Atopic dermatitis (AD) is a chronic inflammatory skin disease         superantigens by antigen presenting cells and presentation to
characterized by a defective epidermal barrier, cutaneous dys-        specific CD4 memory T-cells that are activated and secrete
biosis, pruritus, in a context of abnormal immune response            IL-13, IL-4, IL-31, and IL-22 (Figure 1). On the other hand,
[1]. The translational research model, originally applied to          the innate response is based on ILC2 cells that are tissue-res-
plaque psoriasis, has revolutionized the concepts of moderate         ident and produce IL-5 and IL-13. To secrete cytokines, ILC2
to severe AD pathogenesis and has provided relevant clinical          lymphocytes need to be activated by epithelial cytokines, also
information on the important immunological mechanisms of              termed alarmins, produced by keratinocytes. The best char-
AD [2]. Translational research allows validating in the patient       acterized alarmins are TLSP (thymic stromal lymphopoietin,
new pathological mechanisms proposed in basic research.               IL-25, IL-33, and IL-1α [1]. They have been very well studied
The use of targeted therapies such as humanized monoclonal            also in AD [5,6].
antibodies directed to human targets (cytokines, receptors,
cells. . .) in clinical trials, together with advanced technologies   Th2 Response and Translational Research in AD
analyzing molecular mechanisms in patients (transcriptom-             IL-13 and IL4 have been demonstrated to be clinically rele-
ics, proteomics. . .), has demonstrated that AD is a complex          vant in AD by targeted therapeutic strategies since neutraliza-
and heterogeneous condition that can now be treated more              tion of IL-4Rα and IL-13 clearly improved AD by inhibiting
effectively with rational therapies directed to the pathogenic        IL4/IL-13 and IL-13 biological activities, respectively [7]. In
basis of the disease. The “omics” revolution facilitated the          recent years, several clinical trials with biological therapies
understanding of AD pathogenesis at molecular lever beyond            have sought to explore the relevance of Thymic stromal
clinical scores. Now all clinical studies with innovative drug        lymphoietin (TSLP), IL-25, IL-33 as possible new therapeutic
therapies incorporate this molecular phenotyping of patients          targets for AD since they induce T2 response in ILC2. Les-
[3]. This review highlights, from a translational immunology          sons from these clinical trials that explore the roles of those
perspective, recently identified immunological mechanisms             alarmins in AD patients indicate that the neutralization of
involved in moderate to severe AD pathogenesis that are               TSLP, IL-25 and IL-33 is not effective in improving disease
clinically relevant (Table 1).                                        [8]. In contrast to AD, in asthma the clinical importance of
                                                                      IL-33 and TSLP is well demonstrated [9]. Since T2 cytokines
Type 2 (T2) Immune Response in AD                                     can also be produced by CD4+ memory T-cells, at the present
Many AD patients exhibit an exaggerated immune T2                     time, clinical efficacy in patients supports more strongly the
response that leads to increased IgE levels. The T2 immune            relevance of the adaptive immune response in contrast to the
response consists of the production of IL-4, IL-13, and IL-5 by       innate response. In fact, CD4+ memory Th2 cells are the most
memory CD4+ Th2 cells, type-2 innate lymphoid cells (ILC2),           abundant in inflamed lesions and considered the most import-
mast cells, and basophils [4]. Thus, T2 immune response               ant [1]. Interestingly, blockage of antigen presentation to



                     Table 1. Targeted Therapies in Moderate-to-Severe Atopic Dermatitis.
    Target                       Mechanism                                         Therapy                Clinical evidence in AD
 IL-4RA      Th2 (IL-4, IL-13)                                        Anti-IL-4Rα                                      +
 IL-13       IL-13                                                    Anti-IL-13                                       +
 IL-31       IL-31                                                    Anti-IL-31RA                                     +
 IL-22       IL-22                                                    Anti-IL-22                                       +
 OX40L       Antigen presentation                                     Anti-OX40L                                       +
 CCR4        CCR4 mediated CLA+ T-cell chemotaxis by                  CCR4 antagonist small                            +
             CCL17 and CCL22                                          molecule
 IL-17A      IL-17A                                                   Anti-IL-17A                                      -
 IL-5        Eosinophil biology                                       Anti-IL-5                                        -
 TSLP        Innate T2 response. TSLP activation of ILC2              Anti-TSLP                                        -
 IL-33       Innate T2 response. IL-33 activation of ILC2             Anti-IL-33                                       -
 IL-25       Innate T2 response. IL-25 activation of ILC2             Anti-IL-25                                       -
 IL-23       IL-23/Th17 axis                                          Anti-IL-23p19                                    -

TSLP = Thymic stromal lymphopoietin.



2                                                                                  Review | Dermatol Pract Concept. 2022;12(1):e2022152
Figure 1. Lesson learned from translational immunology in atopic dermatitis (AD). The skin barrier abnormality, together with the itch-scratch-
ing cycle in AD, facilitate skin entry of allergens and Staphylococcus aureus that active pathogenic skin-homing CLA+ CD4+CCR4+ memory
T-cells leading to production of IL-13, IL-4, IL-31, and IL-22. Th2 cytokines further alter the skin barrier, decreasing natural antimicrobial
peptides that promote Staphylococcus aureus colonization. Cytokines IL-4, IL-13, and IL-31 bind to their respective receptors present in
sensitive neurons in the skin that transmit pruritus to the central nervous system. Inflammation is amplified by IL-13-mediated infiltration of
CLA+CD4+CCR4+ T cells attracted by IL-13-induced CCL17 production by keratinocytes.


CD4+ memory T-cells by a humanized monoclonal antibody                   on their surface [1,13]. IL-13 and CCR4 are closely related
that inhibits the OX-OX40L interaction has demonstrated                  in AD inflammation. The CCR4 is a chemokine receptor
to be effective in the clinic (Figure 1) [10]). IL-5 constitutes         preferentially expressed by CLA+CD4+ T-cells [14] whose
another T2 cytokine that regulates eosinophil generation and             ligands are CCL17 and CCL22 and are induced in keratino-
survival. In AD, neutralization of IL-5 has not provided clini-          cytes upon IL-13 activation and preferentially attract CLA+
cal improvement in patients, whereas in asthma, it constitutes           CD4+ lymphocytes [15]. Interestingly, CCL17 is considered a
a biological therapy already approved [8].                               relevant biomarker for AD [16] and a recent study has shown
                                                                         that a small molecule antagonist of the CCR4 receptor can
Novel Insights on IL-13 Relevance in AD
                                                                         improve AD [17].
IL-4 and IL-13 represent the best clinically validated cytokines
in AD due to the efficacy of biologicals targeting IL-4RA and            IL-13 and IL-4 Affect the Skin Barrier Function
IL-13. Recent studies in AD lesional skin indicate that IL-13            and the Microbial Cutaneous Colonization by
may have more relevance in the inflammatory processes that               Staphyloccocus Aureus in AD
take place in the skin than IL-4 [7]. IL-13 receptors, IL-13RA1          The skin barrier integrity is damaged in AD cutaneous
and IL-13RA2, are preferentially found in non-hematopoietic              lesions making the stratum corneum permeable to allergens,
cells such as keratinocytes and fibroblasts. In addition, IL-13          microbes, and their toxins. Besides genetic structural defects,
it is expressed in higher level in AD lesions compared to IL-4,          such as filaggrin mutations, which are present in some AD
and transcriptomic analyses have demonstrated a dominant                 patients, IL-13 and IL-4 reduce the expression of relevant
IL-13 molecular signature [11]. Interestingly, JAK1 is the               skin elements involved in the skin barrier such as filaggrin,
most highly expressed member of the JAK family in lesional               loricrin, involucrin and important lipid components [18,19].
AD biopsies and is involved in IL-13 signal transduction [12].           By far, Staphylococcus aureus (Sa) is the best characterized
Besides this, IL-13 also plays a relevant role in the recruitment        microorganism in AD because it is present on the skin of AD
of pathogenic skin-homing memory T-cells that express the                patients [20]. In fact, Sa skin-colonized AD patients have been
cutaneous lymphocyte-associated antigen (CLA) positive                   recently shown to present a more severe form of disease than



Review | Dermatol Pract Concept. 2022;12(1):e2022152                                                                                         3
non-colonized ones [21]. Th2 cytokines have been shown             baseline [27]. Current efforts to demonstrate the clinical
to facilitate skin colonization by Sa since they reduce the        relevance of IL-17A and IL-23 have failed since neutral-
expression of natural antimicrobial peptides, thus reducing        ization of those cytokines in patients has not provided any
defenses against Sa infection, favoring Sa skin adherence by       clinical benefit [8]. In relation to the immune response,
promoting fibronectin production [20].                             new technologies in simultaneous quantification of serum
                                                                   biomarkers of immune response have allowed to classify
Immunological Mechanisms of Pruritus                               moderate to severe AD patients into 4 endotypes which
Itch is probably the symptom that most affects the quality of      demonstrate patients heterogeneity. These are IL-1R1 and
life of AD patients, and it is part of the itch-scratching cycle   skin-homing tropism, dominant Th1/Th2/Th17 response,
that most patients suffer from [22]. The adaptive immune           Th2/Th22/CCl18 response, and low levels of Th2 cytokines
response is responsible to a great extent of the pruritus pres-    and eosinophilia [28].
ent in AD as demonstrated by biological therapies and small
molecules that inhibit key signaling pathways involved in          Circulating CLA+ Memory T Cells and AD
pruritus. There are 2 different immunological mechanisms           Circulating T-cells expressing the CLA antigen represent a
behind the adaptive immune response and signal transduction        subset of memory T-cells that reflect cutaneous immunologi-
of itch by sensitive nervous fibers in the skin. CD4+ Th2 cells    cal abnormalities taking place in the skin [29]. They are used
producing IL-4 and IL-13, and the Th2 related IL-31. These         to understand atopic dermatitis phenotypes as possible cell
3 cytokines stimulate sensitive cutaneous fibers that express      biomarkers of disease [30,31]. The translational relevance
their specific receptors to transmit pruritus to the central       of this subset in AD, which also exists in human circulation
nervous system through JAK1 kinase signaling [23]. The             as resident memory Th2 cells, as well as in the skin [32],
relevance of IL-4 and IL-13 in pruritus is supported by the        has been further studied during dupilumab treatment of
important release of itch by neutralizing antibodies to IL-4RA     moderate to severe AD patients. At week 4 of treatment,
and IL-13 in moderate to severe patients. In addition, small       dupilumab decreased IL-4, IL-13 and IL-22 production
molecules that act as JAK inhibitors and block JAK1 signaling      in CLA+CD4+CCR4+, but not in the CLA- memory T
of IL-4 and IL-13 receptors, are also potent therapies that act    cells subset [33,34]. These results indicate that circulating
on immune-mediated itch. IL-31 is a unique cytokine since it       skin homing lymphocytes preferentially respond to IL4RA
is mainly involved in pruritus generation. CLA+CD4+ mem-           blockage in AD patients and are in line with the relevance
ory T-cells constitute the main source of IL-31 [24]. IL-31        of adaptive immune response in AD in the current model
binds to the IL-31RA that it is expressed in cutaneous sensi-      of AD [1].
tive neurons and transduces signaling through JAk1 signaling.
The relevance of IL-31 in itch in AD patients is supported by
the antipruritic activity of anti-IL-31RA which is currently in    Conclusions
phase III trials [25].
                                                                   Current translational immunology results support a simpli-
                                                                   fied model of AD pathogenesis (Figure 1), where patients
Immunological Response In AD: Beyond                               carry an abnormal immune response that reacts to agents
Th2 and Th1                                                        accessing the skin trough a permeable skin barrier, in the
The classical model of AD pathogenesis where the acute             context of the itch-scratching circle. Circulating CLA+C-
phase is Th2 and the chronic stage is Th1 has evolved to           D4+CCR4+ memory T-cells infiltrate non-lesional skin and
more a complex scenario including Th1, Th2, Th17, and              become activated by antigen presenting cells and secrete IL-4,
Th22 cytokines [26]. However, the presence of all those            IL-13, and IL-31 among other cytokines. IL-4 and IL-13, and
T-cell subtypes in AD does not imply they are clinically rel-      in particular IL-13 due to the presence of the IL-13 receptor
evant players. At present, translational research has demon-       in the skin and greater amount of IL-13 than IL-4, alter
strated that only some of them are important, although             skin barrier function. In addition, IL-13 would promote Sa
it cannot be discarded that in different AD phenotypes,            colonization by decreasing natural antimicrobial peptides
endotypes, or ethnicities these cytokines may be relevant.         and adherence through increased production of fibronec-
IL-22, IL-17A and IL-23 are well characterized mediators           tin. Those 3 cytokines mediate pruritus by binding to their
of inflammation in psoriasis; however, they are also present       specific receptors in sensitive neurons that transmit pruritus
in AD inflammation. The study of specific antibodies for           to central nervous system. IL-13 would promote inflamma-
these cytokines in AD patients has clarified their role in this    tion by the recruitment of skin-homing CLA+CD4+CCR4+
disease. Neutralization of IL-22 improved AD preferentially        that are attracted by IL-13-activated keratinocytes that
in patients with increased lesional expression of IL-22 at         produce CCL17.



4                                                                               Review | Dermatol Pract Concept. 2022;12(1):e2022152
References                                                                     dermatitis skin. J Invest Dermatol. 2000;115(4):640-646. DOI:
                                                                               10.1046/j.1523-1747.2000.00115.x. PMID: 10998136.
 1. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lan-           16.   Renert-Yuval Y, Thyssen JP, Bissonnette R, et al. Biomarkers in
    cet. 2020;396(10247):345-360. DOI: 10.1016/S0140-                          atopic dermatitis—a review on behalf of the International Eczema
    6736(20)31286-1. PMID: 32738956.                                           Council. J Allergy Clin Immunol. 2021;147(4):1174-1190.e1.
 2. Noda S, Krueger JG, Guttman-Yassky E. The translational rev-               DOI: 10.1016/j.jaci.2021.01.013. PMID: 33516871.
    olution and use of biologics in patients with inflammatory skin      17.   Bissonnette R, Rulloda J, Nadine Lee N, et al. RPT193, an oral
    diseases. J Allergy Clin Immunol. 2015;135(2):324-336. DOI:                CCR4 inhibitor: Efficacy results from a randomized, placebo-con-
    10.1016/j.jaci.2014.11.015. PMID: 25541257.                                trolled Phase 1b monotherapy trial in patients with moderate-to-
 3. Oliva M, Renert-Yuval Y, Guttman-Yassky E. The “omics” rev-                severe atopic dermatitis. ISDS 2021. Abstract 88.
    olution: Redefining the understanding and treatment of allergic      18.   Kim BE, Leung DYM, Boguniewicz M, Howell MD. Loricrin and
    skin diseases. Curr Opin Allergy Clin Immunol. 2016;16(5):469-             involucrin expression is down-regulated by Th2 cytokines through
    476. DOI: 10.1097/ACI.0000000000000306. PMID: 27490125.                    STAT-6. Clin Immunol. 2008;126(3):332-337. DOI: 10.1016/j.
 4. Lloyd CM, Snelgrove RJ. Type 2 immunity: Expanding our view.               clim.2007.11.006. PMID: 18166499: PMCID: PMC2275206.
    Sci Immunol. 2018 ;3(25):eaat1604. DOI: 10.1126/sciimmunol.          19.   Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic
    aat1604. PMID: 29980619.                                                   dermatitis filaggrin skin expression. J Allergy Clin Immunol.
 5. Saunders SP, Moran T, Floudas A, et al. Spontaneous atopic der-            2009;124(3 Suppl 2):R7-R12. DOI: 10.1016/j.jaci.2009.07.012.
    matitis is mediated by innate immunity, with the secondary lung            PMID: 19720210.
    inflammation of the atopic march requiring adaptive immunity.        20.   Kim J, Kim BE, Ahn K, Leung DYM. Interactions between atopic
    J Allergy Clin Immunol. 2016;137(2):482-491. DOI: 10.1016/j.               dermatitis and staphylococcus aureus infection: Clinical impli-
    jaci.2015.06.045. PMID: 26299987. PMCID: PMC4735016.                       cations. Allergy Asthma Immunol Res. 2019;11(5):593-603.
 6. Salimi M, Barlow JL, Saunders SP, et al. A role for IL-25 and IL-          DOI: 10.4168/aair.2019.11.5.593. PMID: 31332972. PMCID:
    33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp         PMC6658404.
    Med. 2013;210(13):2939-2950. DOI: 10.1084/jem.20130351.              21.   Simpson EL, Villarreal M, Jepson B, et al. Patients with Atopic
    PMID: 24323357. PMCID: PMC3865470.                                         Dermatitis Colonized with Staphylococcus aureus Have a Distinct
 7. Bieber T. Interleukin-13: Targeting an underestimated cytokine             Phenotype and Endotype. J Invest Dermatol. 2018;138(10):2224-
    in atopic dermatitis. Allergy. 2020;75(1):54-62. DOI: 10.1111/             2233. DOI: 10.1016/j.jid.2018.03.1517. PMID: 29604251.
    all.13954. PMID: 31230370.                                                 PMCID: PMC6153055.
 8. Bieber T. Atopic dermatitis: an expanding therapeutic pipeline       22.   Mack MR, Kim BS. The Itch-Scratch Cycle: A Neuroimmune Per-
    for a complex disease. Nat Rev Drug Discov. 2022;21(1):21-40.              spective. Trends Immunol. 2018;39(12):980-991. DOI: 10.1016/j.
    DOI: 10.1038/s41573-021-00266-6. PMID: 34417579. PMCID:                    it.2018.10.001. PMID: 30471983.
    PMC8377708.                                                          23.   Oetjen LK, Mack MR, Feng J, et al. Sensory Neurons Co-opt Clas-
 9. Tamari M, Trier AM, Kim BS. Emerging targeted therapeutics un-             sical Immune Signaling Pathways to Mediate Chronic Itch. Cell.
    derscore immunologic heterogeneity of asthma. J Allergy Clin Im-           2017;171(1):217-228.e13. DOI: 10.1016/j.cell.2017.08.006.
    munol. 2021;148(3):719-721. DOI: 10.1016/j.jaci.2021.07.008.               PMID: 28890086. PMCID: PMC5658016.
    PMID: 34310926.                                                      24.   Bilsborough J, Leung DYM, Maurer M, et al. IL-31 is associated
10. Guttman-Yassky E, Pavel AB, Zhou L, et al. GBR 830, an an-                 with cutaneous lymphocyte antigen-positive skin homing T
    ti-OX40, improves skin gene signatures and clinical scores                 cells in patients with atopic dermatitis. J Allergy Clin Immunol.
    in patients with atopic dermatitis. J Allergy Clin Immunol.                2006;117(2):418-425. DOI: 10.1016/j.jaci.2005.10.046. PMID:
    2019;144(2):482-493.e7. DOI: 10.1016/j.jaci.2018.11.053.                   16461143.
    PMID: 30738171.                                                      25.   Silverberg JI, Pinter A, Alavi A, et al. Nemolizumab is associated
11. Tsoi LC, Rodriguez E, Degenhardt F, et al. Atopic Dermatitis Is an         with a rapid improvement in atopic dermatitis signs and symp-
    IL-13–Dominant Disease with Greater Molecular Heterogeneity                toms: subpopulation (EASI ≥ 16) analysis of randomized phase
    Compared to Psoriasis. J Invest Dermatol. 2019;139(7):1480-                2B study. J Eur Acad Dermatol Venereol. 2021;35(7):1562-1568.
    1489. DOI: 10.1016/j.jid.2018.12.018. PMID: 30641038: PM-                  DOI: 10.1111/jdv.17218. PMID: 33711179.
    CID: PMC6711380.                                                     26.   Gittler JK, Shemer A, Suárez-Fariñas M, et al. Progressive ac-
12. Möbus L, Rodriguez E, Harder I, et al. Atopic dermatitis dis-              tivation of TH2/TH22 cytokines and selective epidermal pro-
    plays stable and dynamic skin transcriptome signatures. J Al-              teins characterizes acute and chronic atopic dermatitis. J Al-
    lergy Clin Immunol. 2021;147(1):213-223. DOI: 10.1016/j.                   lergy Clin Immunol. 2012;130(6):1344-1354. DOI: 10.1016/j.
    jaci.2020.06.012. PMID: 32615169.                                          jaci.2012.07.012. PMID: 22951056. PMCID: PMC3991245.
13. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic       27.   Brunner PM, Pavel AB, Khattri S, et al. Baseline IL-22 expression
    dermatitis. Nat Rev Dis Primers. 2018;4(1):1. DOI: 10.1038/                in patients with atopic dermatitis stratifies tissue responses to
    s41572-018-0001-z. PMID: 29930242.                                         fezakinumab. J Allergy Clin Immunol. 2019;143(1):142-154.
14. Campbell JJ, Haraldsen G, Pan J, et al. The chemokine receptor             DOI: 10.1016/j.jaci.2018.07.028. PMID: 30121291.
    CCR4 in vascular recognition by cutaneous but not intesti-           28.   Bakker DS, Nierkens S, Knol EF, et al. Confirmation of multiple
    nal memory T cells. Nature. 1999;400(6746):776-780. DOI:                   endotypes in atopic dermatitis based on serum biomarkers. J
    10.1038/23495. PMID: 10466728.                                             Allergy Clin Immunol. 2021;147(1):189-198. DOI: 10.1016/j.
15. Vestergaard C, Bang K, Gesser B, Yoneyama H, Matsushima K,                 jaci.2020.04.062. PMID: 32526312.
    Larsen CG. A Th2 chemokine, TARC, produced by keratinocytes          29.   de Jesús-Gil C, Sans-de SanNicolàs L, García-Jiménez I, et al.
    may recruit CLA+CCR4+ lymphocytes into lesional atopic                     The Translational Relevance of Human Circulating Memory




Review | Dermatol Pract Concept. 2022;12(1):e2022152                                                                                          5
    Cutaneous Lymphocyte-Associated Antigen Positive T Cells in            tion. J Exp Med. 2021;218(11):e20210417. DOI: 10.1084/
    Inflammatory Skin Disorders. Front Immunol. 2021;12:652613.            jem.20210417. PMID: 34643646. PMCID: PMC8563284.
    DOI: 10.3389/fimmu.2021.652613. PMID: 33833765. PMCID:             33. Bakker DS, van der Wal MM, Heeb LEM, et al. Early and Long-
    PMC8021783.                                                            Term Effects of Dupilumab Treatment on Circulating T-Cell
30. Ferran M, Santamaria-Babi LF. Pathological mechanisms of               Functions in Patients with Moderate-to-Severe Atopic Dermatitis.
    skin homing T cells in atopic dermatitis. World Allergy Organ          J Invest Dermatol. 2021;141(8):1943-1953.e13. DOI: 10.1016/j.
    J. 2010;3(3):44-47. DOI: 10.1097/WOX.0b013e3181d675f8.                 jid.2021.01.022. PMID: 33610558.
    PMID: 23282416. PMCID: PMC3651146.                                 34. Roesner LM, Bridgewood C, McGonagle D, Wittmann M. Dup-
31. Czarnowicki T, Santamaria-Babí LF, Guttman-Yassky E. Circu-            ilumab: An Opportunity to Unravel In Vivo Actions of IL-4 and
    lating CLA+ T cells in atopic dermatitis and their possible role       IL-13 in Humans. J Invest Dermatol. 2021;141(8):1879-1881.
    as peripheral biomarkers. Allergy. 2017;72(3):366-372. DOI:            DOI: 10.1016/j.jid.2021.02.007. PMID: 34303467.
    10.1111/all.13080. PMID: 27861978.
32. Strobl J, Gail L, Kleissl L, et al. Human resident memory T
    cells exit the skin and mediate systemic Th2-driven inflamma-




6                                                                                  Review | Dermatol Pract Concept. 2022;12(1):e2022152
