Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

doi:10.1016/j.jaci.2016.06.010

Journal of Allergy and Clinical Immunology

Volume 138, Issue 2, August 2016, Pages 336-349

https://doi.org/10.1016/j.jaci.2016.06.010 Get rights and content

Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.

Section snippets

Is AD limited to the skin or is it a systemic disease?

The question of whether AD is a systemic disease can be answered by using epidemiologic data and systemic biomarkers of the disease. Concerning epidemiology, it is broadly accepted that AD is associated with other atopic diseases, namely allergic rhinoconjunctivitis, allergic bronchial asthma, and food allergy. Here, sequential disease development is called the atopic march.2, 3, 4, 5 Recently, other comorbidities of AD have been the focus of epidemiologic studies.⁶ These studies report that AD

Comparative findings in patients with AD and psoriasis

Similar to psoriasis, AD skin lesions show epidermal hyperplasia, T-cell and dendritic cell (DC) infiltrates, and increased production of inflammatory mediators.20, 21, 22 However, a strong negative correlation and antagonistic clinical course were observed with the T_H17-driven disease psoriasis, and the latter can even be treated with the IL-4–targeting T_H17-driving cytokine IL-23.23, 24, 25, 26 In patients with psoriasis, increasing knowledge of inflammatory pathways led to bedside-to-bench

Immunology of endotypes in patients with AD

Although AD is primarily defined by clinical criteria,³¹ it is recognized as a complex disease with several distinct variants distinguished based on age of onset, race, acute versus chronic course, therapeutic response, and infectious or allergic/irritant triggers.21, 32, 33, 34, 35, 36 In addition to some differences in clinical characteristics (eg, pediatric vs adult AD), it is now established that various AD subtypes can also be distinguished based on their molecular and cellular

Comparative findings on immune parameters in childhood versus adult AD

Although there is increasing prevalence of AD in adults,43, 48 the pediatric population has the highest prevalence (15% to 25%) worldwide. Most children with early AD presentation in infancy will outgrow their disease before adolescence,³³ but 25% or more (often those with more severe AD) will persist into adulthood.33, 48 Thus it is important to define differences and similarities between early pediatric AD and chronic disease in adults, as well as factors that determine disease persistence.

The microbiome in patients with AD

The skin is colonized by myriads of microorganisms shortly after birth, which total approximately 10¹⁰ bacteria covering the whole skin.51, 52 These skin-associated microbial populations have become a major research interest because the microbiome closely interacts with the local immune system in health and disease. The majority of bacterial species on the skin are classified into 4 phyla (ie, Actinobacteria, Firmicutes, Bacteroides, and Proteobacteria).⁵³ Interestingly, the skin microbiota

Deviation of the innate immune system in patients with AD

Both the diversity of the microbiota on the skin and S aureus overgrowth are sensed and regulated by the innate immune system. One important group of regulators are antimicrobial peptides (AMPs) produced by the skin and bacteria to stabilize bacterial communities and prevent and fight infections.⁶¹ Compared with T_H1- and T_H17-associated inflammation, T_H2-associated inflammation in patients with AD does not upregulate some (but not all) AMPs based on T_H2 cytokine–mediated suppression.62, 63 AD

T lymphocytes and DCs as major cellular players in patients with AD

One of the most striking features of AD is the presence of T cells in the affected skin (Fig 1). Although their numbers are already moderately increased in the dermis in nonlesional sites, in lesional AD skin a marked influx of T cells is found in both the dermis and epidermis, leading to keratinocyte apoptosis and spongiosis in the epidermis between the stratum corneum and stratum basale (Fig 1).73, 74 In the atopy patch test model T cells in the skin display an initial T_H2 polarization, with

Eosinophils, mast cells, basophils, innate lymphoid cells, B lymphocytes, and their role in AD

The skin lacks eosinophils under physiologic conditions but is infiltrated by eosinophils in patients with a broad spectrum of cutaneous disorders, including AD.⁹⁹ Tissue eosinophilia is often associated with increased blood eosinophil levels and correlates with disease severity.¹⁰⁰ Eosinophils are often activated, leading to extracellular granule protein deposition in the skin.101, 102 Thus far, the role of eosinophils in the pathogenesis of AD remains uncertain. It seems possible that

Role of specific IgE in patients with AD

The course of AD is characterized by exacerbations and remissions. It is influenced by individual exogenous trigger factors, such as inhalant allergens, food allergens, or autoallergens; microbial factors; or climatic conditions.89, 113, 114, 115, 116 Because the vast majority are sensitized through specific IgE antibodies to inhalant or food allergens, the determination of IgE antibodies to inhalant allergens is common in clinical practice. However, their effect on the clinical course of AD is

Immune mechanisms and their interaction with FLG and other skin barrier proteins

FLG is a molecule that might in part explain the disease in a subgroup of patients with AD.¹²⁵ It has been shown that up to 50% of patients with AD carry FLG loss-of-function mutations. FLG is a structural protein that builds up the outer epidermal barrier through aggregation of intermediate filaments. This is considered a key step in establishing the structure and function of the stratum corneum. Moreover, FLG influences cell differentiation, and processed FLG contributes to natural

Pruritus in patients with AD and the immunology behind it

Chronic pruritus defined by persisting itch lasting longer than 6 weeks is considered the dominant clinical feature of AD, representing a major burden for affected patients.¹³⁴ Thus the understanding of the underlying mechanisms of chronic pruritus in patients with AD is of great importance not only to understand the disease course but also to develop new therapeutic strategies to provide relief for this dominant clinical symptom. Pruritus is a sensory phenomenon mediated by both

Effect of allergens and environmental factors on patients with AD

Environmental factors can influence the cause of AD. Climatic¹⁴⁴ and anthropogenic factors, such as indoor145, 146, 147 and outdoor148, 149 air pollutants and psychosocial stress,150, 151, 152 exert their greatest influence during prenatal and early postnatal life, causing enhanced predisposition for AD development (for an overview, see Table I).144, 145, 146, 147, 148, 150, 151, 152, 153, 154 In addition, other factors, such as reduced environmental UV exposure¹⁵⁵ or high water hardness,156,

Effect of immune deviation on diagnosis and therapy in patients with AD

Increasing knowledge on the pathogenesis of AD results in novel diagnostic and therapeutic strategies. Current diagnostic gold standards are clinical phenotype and histology, but they neither are valid for all phenotypes of AD nor do they predict therapeutic benefit at the individual patient level. Thus new molecular classifiers are needed. Several attempts to define classifiers of varying size and predictive value were made.169, 170 Recently, an accurate classifier to distinguish AD from

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Atopic Dermatitis Itch: Scratching for an Explanation
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Chronic pruritus is a cardinal symptom of atopic dermatitis (AD). The mechanisms underlying atopic itch involve intricate crosstalk among skin, immune components, and neural components. In this review, we explore these mechanisms, focusing on key players and interactions that induce and exacerbate itch. We discuss the similarities and differences between pruritus and pain in patients with AD as well as the relationship between pruritus and factors such as sweat and the skin microbiome. Furthermore, we explore novel targets that could provide significant itch relief in these patients as well as exciting future research directions to better understand atopic pruritus in darker skin types.
Lagerstroemia macrocarpa extract inhibits Th2-mediated STAT6 signaling pathway in human keratinocytes
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In this study, we examined physiological functions as a key material to develop cosmeceuticals using extracts of Lagerstroemia macrocarpa Wall. Ex Kurz (L. macrocarpa). Initially, the L. macrocarpa extract was treated by different concentration and antioxidant assay (DPPH and ABTS) were performed to measure free radical scavenging ability. In the cytotoxicity experiment, the extract was treated into human epidermal keratinocytes with different concentrations to measure cytotoxicity. We found that the extract induces differentiation markers such as keratin (KRT)1, KRT2, KRT9, KRT10 in keratinocytes. Furthermore, the extract significantly induces involucrin (IVL), loricrin (LOR), claudin1 (CLDN1), and filaggrin (FLG) expression, suggesting that it may enhance skin barrier functions. Especially, the extract restored FLG expression inhibited by interleukin (IL)-4/IL-13 in in vitro atopic dermatitis-like model. Therefore, we expect L. macrocarpa extract will be an effective material to develop the therapeutic and cosmeceutical of atopic dermatitis.
A Bispecific, Tetravalent Antibody Targeting Inflammatory and Pruritogenic Pathways in Atopic Dermatitis
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Inhibition of IL-4/IL-13 signaling has dramatically improved the treatment of atopic dermatitis (AD). However, in many patients, clinical responses are slow to develop and remain modest. Indeed, some symptoms of AD are dependent on IL-31, which is only partially reduced by IL-4/IL-13 inhibition. Thus, there is an unmet need for AD treatments that concomitantly block IL-4/IL-13 and IL-31 pathways. We engineered NM26-2198, a bispecific tetravalent antibody designed to accomplish this task. In reporter cell lines, NM26-2198 concomitantly inhibited IL-4/IL-13 and IL-31 signaling with a potency comparable with that of the combination of an anti–IL-4Rα antibody (dupilumab) and an anti–IL-31 antibody (BMS-981164). In human PBMCs, NM26-2198 inhibited IL-4–induced upregulation of CD23, demonstrating functional binding to FcγRII (CD32). NM26-2198 also inhibited the secretion of the AD biomarker thymus and activation-regulated chemokine (TARC) in blood samples from healthy human donors. In male cynomolgus monkeys, NM26-2198 exhibited favorable pharmacokinetics and significantly inhibited IL-31–induced scratching at a dose of 30 mg/kg. In a repeat-dose, good laboratory practice toxicology study in cynomolgus monkeys, no adverse effects of NM26-2198 were observed at a weekly dose of 125 mg/kg. Together, these results justify the clinical investigation of NM26-2198 as a treatment for moderate-to-severe AD.
Infections in the era of immunobiologicals
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Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.
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Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis.
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: Disclosure of potential conflict of interest: T. Biedermann has consultant arrangements with and has received payment for lectures from Phadia. K. Eyerich has consultant arrangements with AbbVie, Almirall, Berlin Chemie, Celgene, Janssen, and Novartis; has received grants from AbbVie; and has received payment for lectures from AbbVie, Almirall, Berlin Chemie, Celgene, Janssen, Hexal, Novartis, and MSD. E. Guttman-Yassky has received grants from Celgene, Dermira, Janssen Biotech, LEO Pharmaceuticals, Merck Pharmaceuticals, Novartis, Regeneron, and BMS; and has consultant arrangements with AbbVie, Amgen, Inc, Anacor, Celgene, Celsus Therapeutics, Dermira, Drais, Galderma, Genentech, Glenmark, LEO Pharmaceuticals, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, Mitsubishi, Eli Lilly, and BMS. W. Hoetzenecker has consultant arrangements with and has received payment for lectures from Novartis. E. Knol has received a grant from and has consultant arrangements with Merck and has received payment for lectures from Thermo Fisher. P. Schmid-Grendelmeier has consultant arrangements with and has received payment from lectures from Novartis Pharma and Thermo Fisher Diagnostics. C. A. Akdis has consultant arrangements with Actellion, Aventis, Stallergenes, Allergopharma, and Circacia; is employed by the Swiss Institute of Allergy and Asthma Research, University of Zurich; has received grants from Novartis, PREDICTA: European Commission's Seventh Framework programme No. 260895, the Swiss National Science Foundation, MeDALL: European Commission's Seventh Framework Programme No. 261357, and the Christine Kühne-Center for Allergy Research and Education. The rest of the authors declare that they have no relevant conflicts of interest.

: Terms in boldface and italics are defined in the glossary on page 337.

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Reviews and feature articleCellular and molecular immunologic mechanisms in patients with atopic dermatitis

Section snippets

Is AD limited to the skin or is it a systemic disease?

Comparative findings in patients with AD and psoriasis

Immunology of endotypes in patients with AD

Comparative findings on immune parameters in childhood versus adult AD

The microbiome in patients with AD

Deviation of the innate immune system in patients with AD

T lymphocytes and DCs as major cellular players in patients with AD

Eosinophils, mast cells, basophils, innate lymphoid cells, B lymphocytes, and their role in AD

Role of specific IgE in patients with AD

Immune mechanisms and their interaction with FLG and other skin barrier proteins

Pruritus in patients with AD and the immunology behind it

Effect of allergens and environmental factors on patients with AD

Effect of immune deviation on diagnosis and therapy in patients with AD

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Immunol Allergy Clin North Am

Reviews and feature article
Cellular and molecular immunologic mechanisms in patients with atopic dermatitis