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 The skin is an extremely active immunologic organ.

 The skin has many resident immunologically active cells.

 The skin defense system includes a physical barrier (stratum corneum and hair), a chemical barrier (fatty acids and antimicrobial peptides), an immunologic barrier (innate and adaptive immune system), and a microbiological barrier (beneficial microorganisms).

 Keratinocytes are the most immunologically active cells in the epidermis.

 The skin is commonly affected by immune system disorders.

The skin is the largest organ in the body. It has long been known as the primary physical barrier between an organism and its environment, but since the early 1980s the skin has been recognized as an active immune organ with its own skin‐associated immune system. The skin’s defense system consists of physical, chemical, immunologic, and microbiologic components that protect the body against trauma, chemicals, toxins, and microorganisms.

The physical barrier represents the first line of defense against invaders. It is composed of keratinocytes tightly bonded together by a lipid‐rich mortar in the stratum corneum (top layers) and keratinocytes joined together by tight cell‐to‐cell junctions in the lower layers. The chemical barrier consists of compounds with active antimicrobial activity, including fatty acids and antimicrobial or host defense peptides secreted by sebaceous glands and keratinocytes. If the physical and chemical defenses of the skin are overcome by invaders, components of the innate and active immune system along with beneficial microorganisms in the skin microbiome become important. Beneficial microorganisms compete for the same niche as pathogens and actively secrete antimicrobial peptides (AMPs) that inhibit the proliferation of pathogenic competitors.

When pathogenic microorganisms breach the physical and chemical defenses of the skin, they activate the skin‐associated lymphoid tissue (SALT) (Table 1.1). SALT includes dendritic cells, mast cells, lymphocytes, and keratinocytes, and forms part of the innate immune system (Figure 1.1). Innate immunity, which is considered the most ancient branch of the body’s immune defenses, is characterized by a rapid onset of action (minutes to hours), a lack of specificity (it recognizes common microbial structures as opposed to specific organisms), and a lack of memory, which means the response does not improve with each exposure. Cells of the innate immune system include macrophages, dendritic cells, neutrophils, natural killer (NK) cells, mast cells, and keratinocytes. When innate immunity is overwhelmed, the adaptive branch of the immune system (Figure 1.2), primarily made of T and B lymphocytes, is activated. The adaptive immune response is characterized by a slow onset of action (days to weeks), high specificity (recognizes unique antigens), and memory, which means the speed and magnitude of the response improve with each exposure. The innate and adaptive branches of the immune system are highly interconnected. When cells of the innate immune system are activated, they secrete numerous inflammatory cytokines and chemokines that prime and direct the adaptive immune system’s response.

Table 1.1 Cells of the innate and adaptive immune system discussed in this chapter.

	Cell type	Functions	Location	Cytokines produced	Expressed molecules
Innate	Keratinocyte	Mechanical barrier, epidermal production Immune function	Epidermis	IL‐1, IL‐6, TNF, IL‐8, IL‐10, IL‐12, IL‐15, IL‐18, IL‐19, IL‐20, TGF, IL‐20, IL‐23, GM‐CSF, G‐CSF	TLR, MHC‐I, MHC‐II, AMP
Langerhans cell	Antigen‐presenting cell	Epidermis	IL‐12, IL‐23, IL‐6, TNF	Fc and mannose receptors, ICAM‐1, IL‐12, MHC‐II
Dermal dendritic cell	Antigen‐presenting cell	Dermis	IL‐12, IL‐23, IL‐6, TNF	Fc and mannose receptors, ICAM‐1, IL‐12, MHC‐II
Mast cell	Hypersensitivity reactions, vasodilation, chemotaxis, inflammation	Dermis	TNF, IL‐1, IL‐4, IL‐5, IL‐6, IL‐13, CCL3, CCL4, IL‐3, GM‐CSF	TLRs, NF‐kB, NFAT, AP‐1
Eosinophil	Hypersensitivity reactions, vasodilation, chemotaxis, inflammation	Dermis	IL‐3, IL‐5, IL‐8, IL‐10, leukotrienes, GM‐CSF, hydrolases	Fc receptor
Neutrophil	Innate immunity, phagocytosis	Dermis	ROS, proteolytic enzymes	TLRs, lectin receptor, mannose receptor
M1 macrophage	Phagocytosis, antigen presentation, bactericidal activity	Dermis	IL‐6, IL‐12, TNF, iNOS	JAK1, JAK2, STAT1, STAT2
M2 macrophage	Phagocytosis, antigen presentation, regenerative effects	Dermis	IL‐10, TGF, arginase‐1	JAK1, JAK2, JAK3, STAT6
ILC (Innate lymphoid cell)	Innate immunity	Dermis	IL‐1, IL‐23, IL‐25, IL‐33, TSLP	Id2, T‐bet, GATA 3, ROR
Both innate and adaptive	γ/δ T cell	Elimination of intracellular microorganisms and infected cells; cell death	Dermis	IL‐17, IFN	MHC‐ I
Natural killer cell	Innate immunity against viruses and intracellular bacteria	Dermis	IFN, GM‐CSF, IL‐3	MHC‐I
Natural killer T cell	Elimination of lipid antigens	Dermis	IL‐4, IL‐17, IL‐22, IFN	MHC‐1
Adaptive	B lymphocyte	Humoral response	Dermis	IL‐2, IL‐4, IL‐6, IL‐11, IL‐13, TNF, BAFF	Antibodies
T‐helper lymphocyte	Coordinates immune function	Dermis	Various depending on the type of T‐helper cell	Various depending on the type of T‐helper cell
T‐cytotoxic lymphocyte	Elimination of intracellular microorganisms and infected cells	Dermis	IFN	Perforin, granzyme, granulysin
T‐regulatory lymphocytes	Control of immune response	Dermis	IL‐10, TGF	FoxP3, STAT5

Key: AMP, antimicrobial peptides; AP, activator protein; BAFF, B‐cell activating factor; CCL, chemokine ligand; FoxP3, forkhead box P3 protein; GATA, transcription factor; G‐CSF, granulocyte colony‐stimulating factor; GM‐CSF, granulocyte macrophage colony‐stimulating factor; ICAM, intercellular adhesion molecule; Id2, DNA binding protein inhibitor 2; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T cell; NF‐kB, nuclear factor kappa B; ROR, retinoic acid‐related orphan receptors; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; T‐bet, T box transcription factor; TGF, transforming growth factor; TLR, Toll‐like receptor; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.

Figure 1.1 Innate skin immune system. 1. The innate immune system is activated when damage‐associated molecular pattern (DAMP) molecules released by damaged cells or pathogen‐associated molecular pattern (PAMP) molecules on pathogens are recognized by pattern‐recognition receptors such as Toll‐like receptors on both dendritic cells (Langerhans cells) and keratinocytes. 2. This leads to the activation of keratinocytes directly and the release of cytokines by the Langerhans cells that also activate the keratinocytes. 3. The activated keratinocyte releases various cytokines and AMPs to directly destroy the invading pathogen. 4. Neutrophils and macrophages are recruited to directly destroy the invaders. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.