Cellular Factors

Introduction

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin disease characterized by impaired skin barrier function, marked inflammatory infiltration of activated leukocytes, intense itching, and eczematous lesions. AD is a heterogeneous disease with several subtypes, involving multiple CD4 ⁺ helper T-cell (Th) subsets and inflammatory cells. The pathologic mechanism of AD is divided into three phases: sensitization, acute inflammation, and chronic inflammation. During sensitization, specific T cells and immunoglobulin E (IgE) antibodies are produced in response to allergen(s). The first step of sensitization is allergen capture by antigen presenting cells (APCs), such as epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs), which are mainly located in epidermis and dermis, respectively. This induces the activation of Th2, Th22 cells, and follicular Th (Tfh) cells, which are subsets of CD4 ⁺ Th cells ( Fig. 14.1 ). The cytokines produced by Th2 and Tfh cells, as a result of T cell–B cell interaction, trigger IgE production in B cells and elicit acute inflammation in adult AD patients ( Fig. 14.2 ). Evidence has suggested that Th2 cells also play a role in itching sensation and scratching behavior. Th22 cells cause diffuse epidermal hyperplasia. In acute inflammation, a complex interplay among several inflammatory cells, such as mast cells, granulocytes (basophils and eosinophils), and group 2 innate lymphoid cells (ILC2), is induced by both IgE-associated and -nonassociated mechanisms (see Fig. 14.2 ). In chronic inflammation, multiple subsets of CD4 ⁺ Th cells, including Th1, Th2, Th17, and/or Th22 cells, together with inflammatory cells, are accumulated in the lesional tissues (see Fig. 14.2 ). Th1 and Th17 cells aggravate inflammation and tissue remodeling, whereas Th22 cells deteriorate diffuse epidermal hyperplasia. Notably, recent studies have suggested that Th17 cells are also involved in the onset of acute inflammation in pediatric patients, indicating that pathology of AD is complex ( ). In this chapter we will review how these T-cell subsets, APCs, and inflammatory cells contribute to the development of AD. Humoral factors are reviewed in Chapter 13 .

Antigen presenting cells

APCs are a group of immune cells that are capable of processing and presenting antigens for recognition by T cells to initiate the adaptive cellular immune responses. Professional APCs in human skin include DCs, LCs, and B cells. Dermal DCs and LCs are central to the skin APC networks by physically interacting with neighboring cells, including keratinocytes, mast cells, and sensory nerve fibers for antigen acquisition and transfer, as well as signal activation and delivery, which collectively translate into skin T-cell responses. In AD, those APCs play a key role in the induction of pathogenic inflammatory T cells.

Dendritic cells

DCs are derived from hematopoietic progenitor cells in the bone marrow. They express various types of receptors for pathogen-associated pattern recognition molecules (PAMPs) for dictating pathogenic insults. Once they are activated by PAMPs, DCs upregulate major histocompatibility complex (MHC) molecules and costimulatory receptors, and act as the major professional APCs in establishing immunity against pathogens. Alternatively, upon sensing certain ligands such as those binding to C-type lectins carrying an immunoreceptor tyrosine-based inhibitory motif (ITIM) (e.g., DC-SIGN), they mature into suppressive DCs actively inducing tolerance against self-components, commensal microbacteria, and environmental antigens ( ). Recent high-dimensional phenotypic mapping of human DCs revealed that human dermal DC subsets are distinct from blood and lymphoid tissues, exhibiting interindividual variation ( ). Dermal DCs are grouped into multiple phenotypic and distinct functions, which include conventional DC1s (cDC1s), cDC2s, and monocyte-derived DCs ( ). Based on the genetic ablation approach in mouse models, primary functions of DC subsets have been defined. cDC1s (CD141 ⁺ DCs) are essential for cross-priming and Th1 responses, whereas cDC2s (CD1c ⁺ DCs) promote Th2 immune responses ( ). Under inflammatory conditions, monocyte-derived DCs are differentiated in the epidermis and act as local APCs along with LCs (see next section) ( ). Dermal DCs not only locally can activate tissue resident T cells within the skin but also carry acquired antigens to skin-draining lymph nodes where they prime naïve and memory T cells.

In AD, DCs mature in the presence of a cytokine, thymic stromal lymphopoietin (TSLP), which plays a prominent role in the induction of inflammatory Th2 responses. TSLP is highly expressed by keratinocytes in AD lesions, which is also associated with LCs activation and migration ( ). In vitro, TSLP strongly up-regulates the expression of MHC class II and costimulatory molecules, including OX40L on DCs ( ). TSLP-matured DCs produce CC chemokine ligand 17 (CCL17; also known as thymus and activation-regulated chemokine [TARC]) and CCL22, which recruit pathogenic Th2 cells in AD but fail to produce Th1 polarizing cytokine interleukin-12 (IL12) or proinflammatory cytokines ( ). Furthermore, TSLP-matured DCs can induce robust proliferation of naïve CD4 ⁺ T cells, which subsequently differentiated into Th2 cells that produce allergy-associated cytokines IL4, IL5, IL13, and tumor necrosis factor (TNF), but not IL10 and interferon-gamma (IFN-γ) ( ).

Langerhans cells

LCs are highly unique professional APCs that reside in the epidermis under steady conditions, and make up 3% to 5% of all nucleated cells in the epidermis ( ). LCs originate from tissue-resident macrophage precursor cells that directly seeded to the epidermis during embryonic development ( ) and are maintained by self-renewal mechanism via autocrine transforming growth factor-β (TGF-β) production ( ). Despite their macrophage origin as defined by a lineage-specific transcription factor Mafb expression, LCs share many phenotypic features with cDCs. For example, they have migratory capacity to draining lymph nodes via CC chemokine receptor (CCR) 7–mediated signals and express MHC class II as well as CD1a and CD1c that are MHC class I–related molecules involved in lipid antigen presentation ( ). A recent lineage tracking study indeed shows that LCs express Zbtb46, the transcription factor enforcing cDC identity ( ).

Under homeostatic conditions, LCs are thought to constantly migrate to the lymph nodes and present self antigen to establish immune tolerance ( ). Also, as a part of the first line of defense to pathogens, they protrude their dendrites via tight junctions toward the stratum corneum and can acquire antigens across epidermis ( ). After barrier disruption, such as in the case of AD or in patients with filaggrin deficiency, LCs exhibit activated phenotype with increased proliferation and expression of costimulatory molecules: CD80, CD86 ( ), and FcεRI ( ), the high-affinity IgE receptor that binds allergen-specific IgE thereby promoting allergen deposition and uptake ( ). In subsequent bacterial infection in the AD lesions, LCs likely mediate Th17 responses to certain bacteria. For example, in a mouse model of AD, infiltrating γδT cells and Th17 cells in response to Staphylococcus aureus were abrogated when mice lacked LCs ( ). Human LCs have also been shown to induce IL22 production by γδT cells, clearing S. aureus infection ( ).

B cells

As discussed in Chapter 13 , B cells act as APCs to support differentiation of Tfh cells, leading to high-affinity allergen-specific IgE production. In addition, B cells can modulate immune response through cytokine productions. Evidence suggests the existence of skin-specific B-cell subsets with restricted usage of heavy chain V gene and lower representation of IgG1 compared to bloodborne counterparts. These B cells may play a role in skin homeostasis by regulating wound healing and cutaneous microbiome through production of various cytokines such as IL6, granulocyte macrophage colony-stimulating factor (GM-CSF), IFN-γ, IL4, and IL10 ( ). Evidence has suggested the existence of skin-specific B-cell subsets that may play a role in skin homeostasis by regulating wound healing and cutaneous microbiome through production of cytokines such as IL6, IL10, TGF-β, platelet-derived growth factor, and basic fibroblast growth factor ( ). In addition, skin-associated B1-like regulatory B cells have emerged as critical negative regulators of skin inflammation via IL10 production.