Natural Killer Cells in Atopic Dermatitis Opening Doors to New Treatments

Abstract

Longitudinal studies have indicated the multifaceted regimens for atopic dermatitis (AD) administration, including ultraviolet phototherapy, oral JAK inhibitors, and the concomitant adjunctive therapies according to the American Academy of Dermatology published Guidelines of Care for the Management of Atopic Dermatitis. As a disease with typical characteristics of relapsing pruritus and chronic inflammation, AD has caused heavy burden on children and adults, as well as healthcare providers and family members. As a multi-factorial disease, AD has been considered primarily derived by Th2 dysfunction, with clinical and molecular heterogeneity. The current therapeutic regimens are various and largely due to the diversity in the wide spectrum of the clinical phenotypes based on epidermal barrier disruption, genetic predisposition, and dysregulation of patients’ immune system. Meanwhile there’s an urgent need for developing safer and long-term agents to efficiently control moderate to severe AD. In this book chapter, we mainly summarized the fundamental concept, clinical manifestation, pathophysiology and molecular mechanisms of AD, and in particular, the biofunction and modulation of natural killer (NK) cells for AD. Collectively, the contents in this chapter will help further understand the landscape of this disease and the rationale behind new emerging therapies.

1. Introduction

As an extremely heterogeneous disease with varying phenotypes, AD has caused overwhelming pain to the patients and the guardians physically and mentally as well as significant incidence and healthcare costs [1, 2, 3, 4]. For decades, AD has been proved with the occurrence in childhood and the increased incidence rate with age, which also increases the risk of allergic rhinitis, food allergy, and asthma later in life as well [5]. For example, patients with AD should continuously suffer xerosis (dry skin) and the intensely pruritic lesions spread all over the body [6]. As reviewed by Napolitano and the colleagues, AD in adults and adolescents can be divided into several subtypes, including the head and neck eczema, the flexural eczema, the hand eczema, erythrodermia (0.7%), diffuse eczema (6.5%), portrait-like dermatitis (20.1%), prurigo nodularis-like dermatitis (2.1%), and eczema nummulare-like dermatitis (5.8%) [7]. On the one hand, the criteria for clinical diagnosis of AD mainly contain the albeit with age-related differences and the typically distributed eczematous lesions in AD patients [7]. On the other hand, the most effective options of AD administration are aiming to decrease inflammation and restore the skin barrier [5].

State-of-the-art renewal has indicated the involvement of T lymphocytes, natural killer (NK) cells and dendritic cells (DCs) as well as invariant natural killer T (iNKT) cells for the pathogenesis of the complex inflammatory cutaneous disorder via mediating the inflammatory reaction and the epidermal barrier dysfunction as well [8, 9, 10, 11, 12, 13]. For example, the genetic predisposition of atopics in AD patients is caused by the expansion of Th2 cells and mast cells as well as the release of eosinophilia-associated cytokines (e.g., IL-3, IL-4, IL-5, and IL-13) and IgE [14, 15]. Meanwhile, Ilhan et al. verified that AD patients revealed decline in the proportion of Valpha24⁺CD161⁺ NKT cell subtypes compared with the corresponding healthy individuals, whereas no differ was observed in the CD3⁺CD16⁺CD56⁺ NKT cell counterpart [16]. As reviewed by von Bubnoff and the colleagues, NK cells have been considered as the known immune deviation for AD via contributing the production of Th2 cytokines (e.g., IFN-gamma), whereas Luci et al reported the qualitative and quantitative alterations of peripheral NK cells in AD patients [17, 18].

For the purpose, in this book chapter, we mainly focus on the rudimentary knowledge of AD from the aspects of clinical diagnosis, pathophysiology, molecular mechanisms, and systemic therapy of AD, which will benefit the further understanding of the pathogenesis of AD and the concomitant dysfunction of NK cells for the common chronic inflammatory skin disease and facilitating the personalized and targeted therapy in future.

2. Atopic dermatitis

Atopic dermatitis (AD), also known as atopic eczema, has been recognized as a global health issue with pruritus as the primary lesion [19, 20]. For decades, AD has caused extensive burden on children and adults, whereas the extent and appearance of lesions vary with race and age [21]. Currently, AD patients are considered with a family or personal history of atopic disease, which occupy a percentage of approximately 75–80% of the total AD cases [22]. Meanwhile, AD is commonly complicated by allergic rhinitis, asthma, and food allergies as well, which further aggravates the complexity and the difficulty of treatment upon AD [3].

Worse still, the dermatologic manifestations of AD are also diverse in clinical presentations, which are detrimental to disease diagnosis in clinical practice. Generally, the clinical manifestations of AD contain atopy and pruritus, which is triggered by a variety of irritants including Soaps, detergents, disinfectants, occupational chemicals, fumes, Juices from fresh fruits, meats, vegetables, house dust mites, pets (e.g., cats, dogs, birds), pollens (seasonal), molds, human dander, Staph Aureus, viral infections, mycologic pityrosporum, candida, dermatophytes, temperature/climate, foods (e.g., irritant, vasodilators, allergen), psyche, and hormones [14]. In brief, as summarized by Beltrani et al., AD and the concomitant clinical presentations and course were considered as a syndrome constituted by an identifiable group of symptoms and signs representing the multidimensional dermatological manifestation of atopic diathesis [14]. For decades, we and other investigators in the field are dedicating to verify the pathophysiology and the underlying pathogenesis of AD to incorporate novel treatments in both preclinical and clinical practice. Meanwhile, a range of academic organizations have also published a number of guidelines for AD diagnosis and treatment, such as “Guidelines of Care for the Management of Atopic Dermatitis” published by the American Academy of Dermatology and the document entitled “Japanese guidelines for atopic dermatitis 2017” released by the Japanese Society of Allergology [23, 24].

2.1 Pathophysiology of atopic dermatitis

Despite the incompletely understood of the etiology due to the complicated and multifactorial pathogenesis of AD, the pathophysiology of AD is continuously explored and uncovered, and in particular, the interaction among immune dysfunction, genetic predisposition, and the environmental provocation factors for AD development [4, 25]. In details, the pathophysiology of AD is multifactorial and complex, including the alterations in cell mediated immune responses, dehydration, the elements of barrier dysfunction, environmental factors, pH alterations, increase in the trans-epidermal water loss, and the IgE mediated hypersensitivity [26, 27]. For example, the environmental pollutants and the concomitant diverse environmental factors appear to accelerate the occurrence of AD via triggering responses from both the adaptive and innate immune pathways, such as harsh detergents, airborne formaldehyde, preservatives, and fragrances. To date, a variety of molecular biomarkers have been identified to play a role in different ways, such as measuring treatment response, predicting clinical prognosis, and gauging disease severity [1]. Currently, phototherapy is the major and effective therapeutic modality for various skin diseases, including AD, eczema, photodermatitis, vitiligo, parapsoriasis, and psoriasis, yet the outcomes of AD patients are not satisfactory and persistent [28]. Therefore, based on the indicated biomarkers, novel therapeutic options are hopefully developed for AD patients, and in particular, the targeted and individualized immunomodulators for AD administration.

At the meantime, current advances in the aforementioned pathophysiology of AD are facilitating the stratification of different AD phenotypes, which thus would potentially convert to the development of targeted-specific, personalized regimens of AD in future [29, 30]. State-of-the-art literatures have indicated the feasibility of effective strategies for the improvement of AD, including detailed countermeasures and investigation of the potential causes and the exacerbating factors, correction of skin dysfunctions in AD patients, and the concomitant pharmacotherapy [19, 24].

2.2 Molecular mechanisms of atopic dermatitis

To date, a variety of elements have been considered to play a role during the development of AD [31]. For example, the imbalance of Th1 and Th2 is adequate to increase alterations in cell mediated immune responses and thus facilitate IgE-mediated hypersensitivity [26]. For example, T lymphocytes have been supposed to be the principal effector cells of various eczematous conditions, yet a number of infiltration patterns of T-cell subsets with significant differences are also noted in AD, and in particular, the ratio of CD4⁺ T helper cells and the CD8⁺ T suppressor cells is higher in the papillary dermal infiltrate but lower in the epidermal infiltration [14]. Meanwhile, Jensen et al. found that patients with moderate to severe atopic dermatitis revealed reduced NK cell activity and enhanced effect of IFN-γ [32]. Therewith, verification of the numerous and complex changes of the innate and adaptive immunity at both the phenotypic level and the genetic level will collectively provide the basis for dissecting the various endotypes and phenotypes of AD and developing novel systemic intervention [33].

Overall, AD has been considered with association with the NK cell-mediated immune dysregulation attributes to the direct interaction of NK cells with the polymorphic HLA class I (HLA-I) ligand variants via the killer cell Ig-like receptors (KIRs, such as KIR2DL5, KIR2DS5, and KIR2DS1), [34, 35, 36, 37]. Taken together, systematic and detailed verification of the molecular mechanisms of AD via underpinning the epidermal barrier dysfunction will resultant in a better comprehension of the pathophysiological mechanisms of AD and the complications [3].

3. Natural killer (NK) cells

Natural killer (NK) cells are heterogeneous lymphocytes generated from hematopoietic stem cells (HSCs), which is firstly identified by Kiessling et al. in the 1970s [38, 39]. NK cells belong to the third type of lymphocytes, which are distinguish from the T lymphocytes and B lymphocytes [18, 40, 41, 42]. For example, NK cells play a critical role in both innate immune and adaptive immune dispense with the requirement of prior sensitization as well as the recognition of peptide antigens. Compared with the chimeric antigen receptor-transduced T (CAR-T) cells, NK cells display excellent cytotoxic effect via both the receptor-dependent and receptor-independent signaling cascades by orchestrating the molecular mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), paracrine effects (e.g., TNF-α, IFN-γ, GM-CSF), direct cytolytic effect, and the manipulation of relative immune contextures [39, 43, 44, 45, 46]. Meanwhile, the potent adverse reaction and immune-related adverse events (irAEs) of CAR-T cells can be efficiently avoided in NK cell-based immunotherapy, such as acute graft-versus-host disease (aGvHD), cytokine release syndrome (CRS), and immune cell- associated neurotoxicity syndrome (iCANS) [39, 47, 48, 49].

Generally, NK cells can be enriched from a variety of sources, such as peripheral blood, umbilical cord blood, placental blood, NK cell lines (e.g., NK-92MI, YT), and stem cells including hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) [39, 50, 51, 52]. For example, in peripheral blood, NK cells occupy a percentage of 5–20% of leukocytes, including the CD56^dimCD16^high subpopulation and the CD56^brightCD16^low/neg counterpart [39, 53]. NK cells are acknowledged for the unique ability to recognize and kill tumor cells via the secretion of cytokines and direct interaction. NK cells exert cytotoxicity against pathogenic microorganism, tumor cells, infected cells and aging cells [54]. Meanwhile, NK cells are adequate to modulate the biofunction of relative immune cells via direct cell-cell contact-dependent mode and secretion of chemokines, cytokines, granuloenzyme and perforin [40, 55].

Nowadays, circulating NK cells in the peripheral blood have been considered with altered function and reduced frequency in individuals with moderate-to-severe AD, which suggests the potential feasibility of the immunotherapy strategy for AD administration [18, 56, 57]. Interestingly, the overactivation of NK cells has been found in patients with pemphigus vulgaris and alopecia areata as well as AD [18]. For example, NK cells are adequate to collaborate with type 2 immune cells for the modulation of the pathogenesis of AD [58]. Because interferon-γ (IFN-γ) generated by NK cells and the relative immune cell types is considered as a prominent modulator for negative regulation of the aforementioned type 2 immunity. Notably, Alkon and the colleagues took advantage of the single-cell RNA-SEQ analysis and identified the innate lymphoid cell (ILC) lineage infidelity in AD. In details, they found that the majority of cutaneous ILCs between AD and normal human skin (NHS) belonged to the CRTH2⁺ subpopulation and these cells resided in the upper skin layers [59]. Instead, Min verified that the CD1d^hiPD-L1^hiCD27⁺ regulatory NK cell subset could efficiently suppress AD via significantly inhibiting the numbers of ILC2s and Th2 cells, which collectively suggested the biofunction and association of TGF-β-producing NK cells with the severity of AD [60].

According to the ClinicalTrials.gov (https://www.clinicaltrials.gov/) website, there are a total number of 5 trials upon NK cells and AD, including 3 observational trials (NCT04354207, NCT01429311, NCT03581747) and 2 interventional trials (NCT00824889, NCT02564055), which is distributed in Lithuania, United States, France, Switzerland (Figure 1, Table 1). As mentioned above, the detailed information of NK cells in the pathogenesis and therapy of AD is still far from satisfactory.

Figure 1.

The map of clinical trials upon AD and NK cells.

NCT Number	Study Type	Enrollment	Locations
NCT04354207	Observational	500	Lithuania
NCT01429311	Observational	84	United States
NCT00824889	Interventional	28	France
NCT03581747	Observational	1000	Switzerland
NCT02564055	Interventional	247	United States

Table 1.

Clinical trials of NK cells for AD.

4. Discussion and conclusions

AD has caused unbearable pain to numerous patients and their companions, and there’s an urgent demand for the development of effective, well tolerated, and personalized treatment regimens in the near future. Natural killer (NK) cells are lymphocytes involved in both innate immune response and adaptive immune response, which are also considered with pathogenicity during AD and thus provide novel candidates for establishing the aforementioned well tolerated and personalized therapeutic schedules of atopic dermatitis in future.

Acknowledgments

The coauthors thank the members in NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor & Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Hefei Institute of Physical Science in Chinese Academy of Sciences, The First Affiliated Hospital of Shandong First Medical University, and Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., and Jiangxi Health-Biotech Stem Cell Technology Co., Ltd. for their technical support. This work was supported by grants from the National Natural Science Foundation of China (No. 82260031), the project Youth Fund supported by Shandong Provincial Natural Science Foundation (ZR2020QC097), Natural Science Foundation of Jiangxi Province (20224BAB206077, 20212BAB216073), Key Project funded by Department of Science and Technology of Shangrao City (2020AB002, 2022AB003, 2022A001), Fujian Provincial Ministerial Finance Special Project (2021XH018), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Medical Innovation Project of Fujian Provincial Health and Health Commission (2019-CX-21), Natural Science Foundation of Jiangxi Province (20212BAB216073), Key project funded by Department of Science and Technology of Shangrao City (2020 K003, 2021F013), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao City (2020G002), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), Horizontal Project upon Retrospective Analyses of COVID-19 (2020XH001), Double Thousand Plan of Jiangxi Province (2022 to LSZ).

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

Not applicable.

Appendices and nomenclature

ADCC	antibody-dependent cell-mediated cytotoxicity
hPSCs	human pluripotent stem cells
NK	natural killer
hESCs	human embryonic stem cells
hiPSCs	human inducible pluripotent stem cells
UCB	umbilical cord blood
PB	peripheral blood
PBMCs	peripheral blood-derived mononuclear cells
PB-NK	peripheral blood-derived NK
IFN-γ	interferon-γ
AD	atopic dermatitis
aGvHD	acute graft-versus-host disease
irAEs	immune-related adverse events
HSCs	hematopoietic stem cells
CRS	cytokine release syndrome
aGvHD	acute graft-versus-host disease
iCANS	immune cell-associated neurotoxicity syndrome
CAR-T	chimeric antigen receptor-transduced T
NK	natural killer
ADCC	antibody-dependent cell-mediated cytotoxicity
DCs	dendritic cells
iNKT	invariant natural killer T