The Skin as an Immunologic Organ

Giampiero Girolomonia, Gianpaolo Tessaria, Jan D. Bosb aDepartment of Biomedical and Surgical Sciences, Section of Dermatology, University of Verona,

Verona, Italy bDepartment of Dermatology, Academic Medical Center University of Amsterdam, The Netherlands

1. Introduction: the skin as an organ of defence

Human skin is the largest organ of the body that provides a protective barrier to ensure that exogenous 'noxious' agents do not affect the homeostasis of the organism. Being situated at the interface between external and internal milieus, a number of remarkable structural and functional characteristics of skin have been delineated that contribute to its effectiveness at maintaining homeostasis. The skin has two main systems of defence. The first is related to its physical and chemical properties, the other is the 'immunolog-ical' defence. The major physical properties of the skin are impermeability for water and water-soluble compounds, and mechanical resistance to exogenous traumas and optic properties making it relatively insensitive to ultraviolet (UV) radiation. The barrier function of the skin is provided by the stratum corneum (Elias, 2004) that is an effective barrier to the loss of endogenous water and to the penetration of exogenous potentially dangerous substances. Key constituents of the stratum corn-eum include corneocytes packed by lipids, among which are prominent o-hydroxylated long-chain N-acyl fatty acids (ceramides) (Madison, 2003). During the normal process of keratinization, ker-atinocytes undergo a unique form of programmed cell death, which leads to their transformation into corneocytes. Corneocytes are anucleated cells where the plasma membrane is replaced by the cornified envelope, which consists of keratins that are enclosed within an insoluble amalgam of proteins, crosslinked by transglutaminases and surrounded by a lipid envelope (Candi et al., 2005). Multiple sheets of ceramides and sphingolipids are generated by keratinocytes and discharged into the extracellular space. For this reason, molecules larger than 500 Da cannot easily penetrate into the normal skin, penetration of larger molecules can occur if they are lipophylic or if the skin is damaged (e.g., chronic or acute eczema) (Bos and Meinardi, 2000). The stratum corneum acts also as a biosensor, and can transfer information to the underlying living epidermal cells.

The skin has many eccrine and sebaceous glands. While eccrine glands produce predominantly a watery type of sweat important for thermoregulation, sebaceous glands secrete a complex mixture of triglycerides, fatty acids, squalene and cholesterol, which forms a film on hair follicles and the epidermal surface. Sebum has several protective functions, including its ability to repel water and protect the surface of the skin from growth and invasion by bacteria and fungi (Nickoloff, 2001). In addition, after exposure to various microorganisms or inflammatory cytokines, keratinocytes secrete several antimicrobial peptides, including defensins and cathelecidins (Bardan et al., 2004). These antibiotics introduce pores in bacterial walls, which can directly kill the infectious microbe in the absence of a specific immune reaction. Moreover, they can attract and activate immature dendritic cells, thus providing an important link between innate and adaptive immunity.

UV radiation induces the formation of free radicals, but many defence mechanisms (free radical-trapping molecules, thiols, melanin and enzyme systems) can neutralize these DNA-damaging, potentially carcinogenous substances (Parrish, 1983; Agar and Young, 2005). Other relevant physiological functions of the skin are the maintenance of body temperature, production of hormones and bearing of peripheral nerve receptors and endings.

In addition, the skin has a complex and well organized immune system, with the normal resident skin cells displaying an impressive armamentarium of defence strategies and the ability of recruiting circulating cells that are present throughout the body to complement the initial tissue response (Bos, 2005).

2. Evolving concepts of the skin as an immunological organ

In the early 1970s, the skin was considered to be a first-level lymphoid organ, similar to the thymus (Fichtelius et al., 1970). The authors identified some lymphoepithelial micro-organs in the skin of new-borns and human foetuses, which can be detected at orifices of the body (preputial fornix, vagina, external ear canal) and in other skin sites (nail bed, pilosebaceous unit, scrotum, mammary gland). In these organs, lymphocytes are educated to discern self from non-self antigens. These lymphoid accumulations may recur in adult life and are then diagnosed as benign lymphoprolifer-ative diseases (lymphadenosis cutis benigna). Also, it has been suggested, but not definitively confirmed, that the secondary classic type IV hypersensitivity reaction can occur entirely in the skin, without the involvement of regional lymph nodes. At the present time, a primary lymphoid function of the skin during the embryonal or foetal life cannot be excluded. But further studies are needed to better elucidate these mechanisms. In the following years, other models of the skin as an immunologic organ have been proposed. In 1978, Streilen proposed the Skin Associated Lymphoid Tissue (SALT), which included the professional (e.g., Langerhans cells) and non-professional

(e.g., keratinocytes) antigen-presenting cells, epidermotropic T lymphocytes, endothelial cells and regional lymph nodes. Langerhans cells, process and carry antigens into the regional lymph nodes, where the immune response is induced (Streilein, 1978). In 1990, Streilen detected in the epidermis of mice a dendritic T cell expressing the T-cell receptor gd that is involved in the primary immune response (Streilein, 1990). Till now, a human equivalent of these cells has not been clearly identified. Seven years later, Bos introduced a new model denominated Skin Immune System (SIS) (Bos and Kapsenberg, 1986). A detailed description of this system is reported in Tables 1 and 2. In 1989, Sontheimer considered the dermis as the very center of immune reactivity in many immunemediated dermatoses (Sontheimer, 1989). He observed that most of the T cells, monocytes and other cells involved in the immune reactions can be found in the papillary dermis. Accumulations of T cells, monocytes and macrophages, mast cells and dendritic cells are often detected around the post-capillary venules in the dermis. He proposed that the Dermal Microvascular Unit (DMU) should be a sub-unit of the SIS (Sontheimer and Tharp, 1991).

In 1993, Nicoloff introduced the definition of Dermal Immune System (DIS), as a humoral and cellular counterpart of SALT, including dermal fib-roblasts in the immune skin system, because of their

Table 1

Normal human skin: overview of cell types present and differentiation between immune-response associated and non-immune response-associated cells

Table 1

Normal human skin: overview of cell types present and differentiation between immune-response associated and non-immune response-associated cells

Immune response-associated

Non-immune response-associated

Keratinocytes

Merkel cells

Epidermal Langerhans cells

Melanocytes

Dermal dendritic cells

Fibroblasts/fibrocytes/

myofibroblasts

Monocytes

Pericytes

T lymphocytes

Eccrine glandular cells

Vascular/lymphatic

Apocrine glandular cells

endothelial cells

Granulocytes

Sebocytes

Tissue macrophages

Schwann cells

Mast cells

Smooth muscle cells

Table 2

Cellular and humoral constituents of the skin immune system

Table 2

Cellular and humoral constituents of the skin immune system

Cellular constituents

Humoral constituents

Keratinocytes

Defensins, cathelicidins

Epidermal Langerhans cells

Complement and complement

regulatory proteins

Dermal dendritic cells

Mannose binding lectins

Plasmocytoid dendritic cells

Immunoglobulins

T lymphocytes

Cytokines

Monocytes/macrophages

Chemokines

Granulocytes

Growth factors

Mast cells

Neuropeptides

Vascular endothelial cells

Eicosanoids and

prostaglandins

Lymphatic endothelial cells

A comparison of the proposed constituents of the skin associated lymphoid tissues (SALT), the dermal microvascular unit (DMU), the dermal immune system (DIS), and skin immune system (SIS)

Table 3

A comparison of the proposed constituents of the skin associated lymphoid tissues (SALT), the dermal microvascular unit (DMU), the dermal immune system (DIS), and skin immune system (SIS)

SALT

DMU

DIS

SIS

Keratinocytes

+

-

-

+

Langerhans cells

+

-

-

+

Epidermal T lymphocytes

+

-

-

+

Dermal T lymphocytes

-

+

+

+

Mast cells

-

+

+

+

Vascular endothelial cells

+

+

+

+

Lymphatic endothelial cells

+

-

-

+

Dermal dendritic cells

-

+

+

+

Monocytes/macrophages

-

+

+

+

Fibroblasts

-

-

+

-

Granulocytes

-

-

-

+

Free radicals

-

-

-

+

Secretory immunoglobulins

-

-

-

+

Complement factors

-

-

-

+

Eicosanoids

-

-

-

+

Cytokine/chemokine network

-

-

+

+

Coagulation/fibrinolysis system

-

-

-

+

Neuropeptides

-

-

+

+

Skin draining lymph nodes

+

-

-

-

strict relationships with the other skin components of the epidermis (Nickoloff, 1993). More details are reported in Table 3. Recently, Paus et al. (1998) proposed a hair follicle immune system scheme based largely on murine models of hair cycling and immune privilege (Paus et al., 2005).

Table 4

Innate and adaptive cells of the SIS, divided over resident, recruited and recirculating populations

Table 4

Innate and adaptive cells of the SIS, divided over resident, recruited and recirculating populations

Resident

Recruited

Recirculating

Innate

Keratinocytes

Monocytes

Natural killer

cells

Endothelial

Granulocytes

cells

- Vascular

- Eosinophilic

- Lymphatic

- Neutrophilic

Mast cells

Monocytes

Tissue

Epithelioid

macrophages

cells

Adaptive

T lymphocytes

T lymphocytes

T lymphocytes

Dendritic cells

Dendritic cells

B lymphocytes

3. The skin immune system

Various cellular constituents of the skin contribute to innate immunity as well as adaptive immune responses of the skin (Bos, 2005). Immunocompe-tent cells of the skin may also be divided in cells of the innate SIS as well as cells of the adaptive SIS, each having recirculating, recruitable and resident subpopulations. In addition to the cellular constituents of the SIS, a wide variety of inflammatory and immune mediators are present within the normal integument (Bos and Kapsenberg, 1993). A part of them reach the skin by the circulatory route, whereas many are constitutively produced within the organ itself. A summary of all these constituents is reported in Table 4.

Keratinocytes can be directly activated by a high number of exogenous stimuli (UV rays, infectious agents, exogenous chemicals), then they take place in the generation, perpetuation and termination of the subsequent immune reactions (Barker et al., 1991). Also they may act as antigen-presenting cells. Activated keratinocytes express interleukins (IL-1a, IL-1b, IL-6, IL-15), tumour necrosis factor-a (TNFa), granulocyte-macrophage colony-stimulating factor (GM-CSF) and adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) (Albanesi et al., 2005). Moreover, keratinocytes can produce and secrete an array of chemokines that can recruit blood immunocompetent cells into the epidermis (Pastore et al., 2004). Also, all these mediators activate the underlying dermal microvascular endothelial cells (Nickoloff and Naidu, 1994) that express adhesion molecules to facilitate recruitment of circulating cells into the local tissue (i.e. dermis). The most potent stimuli for activation of keratinocytes are cytokines produced by T cells, particularly interferon (IFN)-g, TNF-a and IL-17. Therefore, keratinocytes appear very relevant in the amplification of immune responses. Keratin-ocytes can act as antigen-presenting cells for experienced T lymphocytes and become target of cytotoxic T cells, such as in allergic contact dermatitis and drug eruptions. Indeed, IFN-g derived from activated T cells and natural killer (NK) cells induces the expression of both class I and class II major histocompatibility complex (MHC) molecules and the adhesion molecule ICAM-1 on the surface of keratinocytes, which facilitates their subsequent stimulation of recruited memory T cells bearing appropriate T-cell receptors. In addition to initiating and perpetuating T-cell-mediated immune responses, keratinocytes can also potentially terminate such reactions by expressing Fas ligand (CD95L) which can induce apoptosis in T cells bearing Fas (CD95) as well as other immuno-regulatory surface receptors such as programmed cell death ligand-1 and RANK-L.

The major antigen-presenting cells that are critical to the skin immune system are the dendritic cells (Langerhans cells, dermal dendritic cells), which are the only ones capable of activating naive T lymphocytes (Girolomoni and la Sala, 2005). The epidermal Langerhans cell is a bone marrow-derived cell that is normally present in the suprabasal layer of the epidermis, where it extends its dendritic processes to the surface of the skin as well as interacting not only with adjacent keratinocytes, but also with nerve fibres emanating from and interconnecting with dermal mast cells. This anatomical configuration appears to provide a hard-wiring type of arrangement in which surface stimuli can be rapidly transmitted horizontally among the epidermal cells as well as vertically into the dermis (Rowden, 1981; Schuler, 1991). Plasmocytoid dendritic cells (the major source of IFN-a) occur rarely in normal, unperturbed skin, but accumalate during disease states (e.g., allergic contact dermatitis, lupus erythematosus) thanks to the expression of specific chemokines on the surface of dermal endothelial cells. Dendritic cells are not only involved in the initiation of protective or immunopathologic immune responses, but also in the induction of immune tolerance. A low-grade migration of immature dendritic cells from the skin to the regional lymph nodes may indeed favour the activation of these T regulatory cells (Cavani et al., 2005).

An integral cellular component for all of these models is the T lymphocyte (Cavani et al., 2005). A high number of T cells are normally present in healthy epidermis and dermis. The existence of skin-selective and skin-seeking T-cell subsets has been recently demonstrated. These T cells express a specific homing receptor, named the cutaneous lymphocyte-associated antigen (CLA). This surface molecule contains an oligosaccharide determinant that has an affinity for E-selectin (and also P-selectin) expressed by cutaneous postcapillary venules endothelial cells. Other receptors involved in the selective accumulation of T cells in the skin include the chemokine receptors CCR4 and CCR10 (Boehncke et al., 2005). In adult human skin, almost all T cells possess the CD3-associated T-cell receptor containing a and b chains rather than the gd heterodimers present on early foetal thymocytes. In general CD8+ T cells tend to predominate in the epidermis, whereas CD4+ T cells are more commonly seen in the dermis. There is a non-random distribution of certain T-cell subsets bearing specific Vb T-cell receptors in normal human skin. While the majority of T cells in the skin belong to memory rather than naive populations, only a fraction of cutaneous T cells express activation markers such as the high-affinity IL-2 receptor (CD25) or CD69, or display evidence of cell cycle progression beyond G0/G1. Thus, it appears that the majority of skin-homing T cells are actively stimulated to proliferate and become activated extracutaneously (i.e. in peripheral lymph nodes), and they tend to accumulate not so much by local proliferation as by selective recruitment and retention (Cavani et al., 2005). Some specialized subsets of T lymphocytes exert suppres-sive functions on immune responses. In particular, T regulatory cells 1 producing high level of IL-10

suppress immune responses by blocking the functions of dendritic cells, whereas CD4+CD25 + regulatory T cells prevent immunopathological reactions and maintain peripheral tolerance by acting via a cell-to-cell contact mechanism (Cavani et al., 2003). These cells represent important targets for new therapies aimed at reinforcing naturally occurring immunoregulatory mechanisms.

Another important cell type in the skin capable of contributing to the skin immune system, besides the keratinocyte, dendritic cell and T cell, is the mast cell (Galli et al., 2005). Mast cells, like neutrophils and eosinophils, are haematopoietic cells that are confined primarily to the dermis near nerve axons where they participate in both inflammation and immune-based reactions. Dermal mast cells contain high-affinity receptors for IgE, and also produce and secrete vasoactive substances such as histamine, as well as primary cytokines such as TNF-a. Thus, mast cells can function in both innate and acquired-type immune responses in the skin. Mast cells are activated by many stimuli such as neuropeptides, complement components, physical stimuli (cold or hot temperatures, sunlight). The ability of mast cells to produce TNF-a can facilitate recruitment of circulating cells since the mast cells are adjacent to endothelial cells which respond to TNF-a by up regulating various adhesion molecules such as ELAM-1, VCAM-1 and ICAM-1. Given the diverse repertoire of mast cells, it should not be surprising that they are involved in both immediate type I 7hypersensitivity responses as well as in contact hypersensitivity and de-layed-type hypersensitivity reactions. When specific IgE antibodies bound by Fc receptors on the surface of mast cells recognize their respective antigen, the mast cell is triggered to release potent pre-formed substances such as histamine. Besides participating in humoral reactions involving circulating IgE, mast cells also influence T cells as exemplified in T-cell-mediated skin reactions (e.g. allergic contact dermatitis). In these skin reactions, mast cells influence the local im-munological microenvironment by producing immunomodulatory cytokines such as TNF-a, IL-1, as well as chemokines, histamine and eicosanoids.

4. Immune responses in skin

Since the skin is the largest organ of the body and thus is continuously exposed to a tremendous diversity of antigenic stimuli, there is a bewildering array of immune responses that occur in the dermal and/or the epidermal compartments. In general, the adaptive immune responses that occur in skin are beneficial to the host, but if they occur in response to an inappropriate and innocuous stimulus, or proceed in an exaggerated fashion, they produce various pathological conditions. These reactions are classically named hypersensitivity-type responses and have been classified by Coombs and Gell into four different types (Gell et al., 1974). It should be noted that the skin may not only be the site at which a hypersensitivity reaction begins, but it may also be the site where an immunological reaction that began elsewhere (i.e. extracutaneous-ly) becomes clinically manifest.Type I hypersensi-tivity reactions (immediate hypersensitivity) are rapid (from minutes to hours) responses featuring the role of IgE which is initially produced upon first exposure to the allergen. Mast cell degranulation occurs when the allergen is reintroduced into the patient's environment and binds to surface IgE on the mast cell. On mast cell activation, many potent mediators of inflammation are released (histamine, proteolytic enzymes, chemotactic poly-peptides, prostaglandins, leucotrienes and throm-boxanes), all of which contribute to the clinical manifestations in the skin and the participation of other inflammatory cells (neutrophils, macrophages, eosinophils and lymphocytes).In this group are included the anaphylactic skin response to a bee or wasp sting, which manifest as an urticarial reaction. Type II hypersensitivity reactions are rare in the skin and are referred to in the context of antibody-dependent cytotoxicity. These reactions feature IgG and IgM antibodies which interact with the complement system. Once the complement system is activated, inflammation ensues producing membrane damage and keratinocyte cyto-pathic changes. In patients with pemphigoid, IgG and various complement components (including C3) are deposited at the dermoepidermal junction, and initiate inflammatory reactions with the accumulation of neutrophils, mast cells, lymphocytes and eosinophils. This reaction is implicated in the disruption of the attachment mechanism resulting in blister formation (Schmidt and Zillikens, 2000). Type III hypersensitivity reactions involve immune complex deposits; a frequent site includes the postcapillary venules of the superficial vascular plexus in the skin. Patients who develop allergic or hypersensitivity reactions to various medications may present with palpable purpuric skin lesions or vasculitis caused by deposits of immunoglobulins and complement in the vessel walls. Such deposits provoke neutrophil- or lymphocyte-mediated inflammatory reactions; how these immune complexes form and why they become deposited in the skin, or persist in the circulation, remain unanswered questions. Type IV hypersensitivity reactions are also referred to as delayed-type reactions since they generally require several days to become clinically manifest. This immune response requires T lymphocytes. Two of the most common type IV immune hypersensitiv-ity responses in the skin include allergic contact dermatitis from epicutaneous exposure to antigens, and tuberculin-type reactions in which intradermal antigens are deposited. In both types of reactions, Langerhans cells and dermal dendritic cells initiate a complex series of steps leading to T-cell activation. In eczematous skin reactions, T cells in turn induce tissue damage by exerting direct cytotoxicity (mostly CD8+ T cells) against keratinocytes or other resident cell types, and by releasing cytokines, which amplify the inflammatory response by targeting resident skin cells.

In light of recent advances, it appears however, that the Gell and Coombs classification may represent an oversimplification, and other classifications that have been proposed to better describe the complexity of events occurring during immunopathological reactions, as proposed for drug-induced exanthems (Lerch and Pichler, 2004). The characteristics involvement of certain cell types (e.g., eosinophils or neutrophils) in some cell-mediated skin reactions underlies the expression of mediators specifically targeting these cells. Moreover, the diversity of the T-cell response with the prevalent recruitment and activation of different T-cell subsets (e.g., type 1 vs. type 2T cells), and the involvement of distinct T regulatory cells in different skin diseases await a more complex classification of immunopathological reactions.

5. Conclusions

Knowledge of skin immunological defence mechanisms is advancing rapidly and provides new insights into the normal homeostasis of this vital organ, as well as improving our understanding of various disease processes. Structure-function correlations are being expanded to include detailed molecular dissection of the events that are principally responsible for the SIS, and which guide the coordinated intercellular interplay crucial for immune surveillance involving the skin. We believe that it is essential for our understanding of cutaneous immunology, to keep in mind what distinguishes the skin from other organs. From such a platform of specific immunophysiology of the skin, one might try to understand its dysregulations as we know them in the form of a surprisingly large number of inflammatory and immunodermatological diseases.

Key points

• The skin provides a complex microenvironment where several cell types actively participate in the initiation and regulation of inflammatory and immune responses.

• Cutaneous dendritic cells serve as dominant antigen-presenting cells in the induction of T-cell-mediated immune responses and subsequent reactivation of T cells. Under homeostatic conditions, however, dendritic cells are primarily involved in the maintenance of immune tolerance to self and innocuous non-self antigens.

• T lymphocytes with specificity for antigens entered through the skin acquire a propensity, based on the expression of specific homing receptors, to recirculate in the skin.

• Keratinocytes have the capacity to secrete an array of cytokines and chemokines very important for the regulation of T-cell and dendritic cell functions, and the recruitment and activation of inflammatory cells.

• Mast cells and peptidergic nerve endings form an integrated unit, which can readily release factors involved in the initiation of the vascular phase of acute inflammation, but, together with endothelial cells, they also regulate cell-mediated immune responses._

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Handbook of Systemic Autoimmune Diseases, Volume 5 The Skin in Systemic Autoimmune Diseases

Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn, editors

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