INTRODUCTION — Allergic contact dermatitis (ACD) is a common inflammatory skin disease presenting with pruritic, eczematous lesions. ACD results from a T cell-mediated, delayed type hypersensitivity (DTH) reaction elicited by the contact of the skin with the offending chemical in individuals who have been previously sensitized to the same chemical. ACD is common in the general population and is the most frequent occupational skin disease. Its etiology may be suggested by the body sites of involvement, history of exposure, and morphology and distribution of the skin lesions.
This topic will discuss the immune mechanisms and pathophysiology of ACD. The clinical manifestations, diagnosis, and management of ACD are discussed separately. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Management of allergic contact dermatitis".)
OVERVIEW — The understanding of the cellular and molecular pathogenesis of allergic contact dermatitis (ACD) has expanded dramatically. In addition to CD4+ and CD8+ T cells, other cell types such as natural killer T (NKT) cells, natural killer cells, innate lymphoid cells, and T regulatory cells have emerged as critical participants (table 1). In the elicitation phase, Langerhans cells appear to play a role in the development of immune tolerance rather than hypersensitivity reaction (as was once thought). B cells also appear to be important during the initiation of ACD by secreting IgM antibody in response to NKT cell-derived interleukin (IL)-4, leading to complement activation and immune cell chemotaxis. As new mechanisms and molecules emerge as a result of advances in the understanding of ACD, new pharmacologic targets will become apparent.
HAPTEN-PROTEIN BINDING — Hapten binding is the initial step in the development of allergic contact dermatitis (ACD). Contact allergens are low molecular weight (<500 Daltons) chemicals called haptens, which are able to penetrate the stratum corneum barrier of the skin. Haptens are not immunogenic by themselves, but they can be efficiently recognized by the immune system after binding to a skin protein carrier. Haptens may be naturally occurring substances such as urushiol found in the resin of poison ivy, synthetic compounds, dyes, fragrances, drugs, or heavy metal salts.
The binding of haptens to skin proteins (protein haptenation) involves the formation of a covalent bond between the electrophilic components of the hapten and the amino acid nucleophilic side chains of the target proteins within the skin [1]. Examples of chemicals containing electrophilic components are aldehydes, ketones, amides, or halogenated compounds. Metal cations (eg, nickel [NIi]2+, one of the most common ACD-associated haptens; and chromium [Cr]3+) are also well-known electrophiles. Some haptens that are not normally electrophilic (prohaptens) can be converted to protein-reactive species via oxidation or metabolic transformation by epidermal keratinocytes and/or dendritic cells [1]. Additional factors influencing the sensitizing ability of haptens include lipophilicity, tridimensional chemical structure, and protein-binding affinity.
The most reactive nucleophilic side chains of proteins are found on lysine, cysteine, and histidine. The protein nucleophilicity is influenced by the microenvironment pH and protein location within the epithelium [1].
THE SENSITIZATION (AFFERENT) PHASE — The sensitization phase occurs after the first contact of the skin with a hapten and leads to the generation of hapten-specific T cells in the regional lymph nodes. Langerhans cells (LC) and dermal dendritic cells (DC) may be involved in the clinically inapparent sensitization phase. Both LCs and dermal DCs are professional antigen-presenting cells and express major histocompatibility complex (MHC) class I and II molecules, which are required for the activation of CD8+ and CD4+ T cells, respectively. (See "Antigen-presenting cells" and "The adaptive cellular immune response: T cells and cytokines".)
LCs are bone marrow-derived, immature epidermal DCs which express langerin (CD207), a C-type lectin associated with the Birbeck granules. Immature LCs form a dense network in the epidermis, where they scan the environment by extending and retracting their dendrites and take up antigens with high efficiency [2]. LCs are able to initiate an adaptive immune response by capturing, processing, and presenting antigens to naïve T cells in the paracortical areas of lymph nodes [3].
In the sensitization phase of allergic contact dermatitis (ACD), the hapten-protein complex is engulfed and processed by LCs, which subsequently migrate to the draining lymph nodes where they present the hapten–peptide–MHC complexes to naïve, allergen-specific T cells (priming). This process results in clonal expansion of hapten-specific memory/effector T cells, which circulate throughout the body and are subsequently recruited from the circulation into the skin during the elicitation phase [4]. (See 'The elicitation (efferent) phase' below.)
After cutaneous exposure to the sensitizing hapten, epidermal LC density decreases by approximately 50 percent in the following 24 hours as a result of migration to the regional lymph nodes [5-9]. During migration, LCs undergo a process of maturation and acquire the surface phenotype of a functionally mature dendritic cell. Cytokines released by keratinocytes, in particular interleukin (IL)-1, tumor necrosis factor (TNF)-alpha and IL-18, regulate the migration and functional maturation of dendritic cells. In addition to morphologic changes and decreased ability to capture additional antigen, mature LCs exhibit increased expression of CD83 (a marker for LC maturation), adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), and co-stimulatory molecules including CD40, CD80, and CD86 [10-15]. The expression of these markers is specific to hapten-exposed LCs, since dermal irritants, which also trigger LC migration, do not result in similar LC surface marker changes [14]. The increased expression of these signaling molecules on the cell surface of LCs is important for efficient activation/proliferation of T cells in the local lymph nodes.
Twenty-four hours after sensitization by cutaneous application of a strong hapten, lymph nodes of mice contain LCs and can transfer sensitization if implanted into allergen-naïve mice [10]. However, studies in LC-depleted mice indicate that contact sensitization is not abrogated in the absence of LCs [16]. A population of langerin+ dermal DCs is thought to induce contact sensitization in the absence of epidermal LCs, which supports the idea that LC may be dispensable in ACD, since there are other cutaneous antigen-presenting cells that can subserve this function [17,18].
At the end of the afferent phase, hapten-specific T cells that have been primed by hapten bearing DCs are found in the lymph nodes, in the blood, and in the skin. Upon re-exposure to the same hapten, T cells will be activated and massively recruited in the skin (the elicitation phase).
THE ELICITATION (EFFERENT) PHASE — The clinical manifestations of allergic contact dermatitis (ACD) are the result of a T cell-mediated inflammatory reaction occurring in the skin upon re-exposure to the offending hapten (elicitation phase) and mediated by the activation of hapten-specific T cells in the skin.
The inflammatory reaction occurs 48 to 72 hours after exposure. As in the sensitization phase, haptens enter the epidermis and react with endogenous proteins. The hapten-protein complexes are then taken up by the antigen-presenting cells (APCs) and presented to the antigen-primed T cells recruited in the epidermis and dermis.
Although LCs are capable of functioning as APCs, they are not required during the elicitation phase of ACD. Mice depleted in epidermal LCs by treatment with topical corticosteroids or exposure to UVB radiation show a paradoxically higher cutaneous hypersensitivity response compared with control animals, indicating that LCs are dispensable in the elicitation phase and may be involved in the regulation of ACD [19]. (See 'Regulatory mechanisms of allergic contact dermatitis' below.)
Other cell types that may function as APCs include mast cells, infiltrating macrophage, and keratinocytes [20]. Keratinocytes, which constitutively express major histocompatibility complex (MHC) class I, have been shown to also inducibly express MHC class II and exhibit APC-like properties in response to hapten exposure [21]. Instead of inducing T cell activation, class II MHC-bearing keratinocytes induce hapten-specific Th1-lymphocyte clonal anergy, a type of T cell tolerance, which may play a role in limiting the magnitude and duration of ACD [22,23].
The primary effector cells of ACD appear to be CD8+ Tc1 cells [24-28]. Experimental studies in mice indicated that MHC class I-restricted CD8+ T cells infiltrate the skin as early as six hours after the hapten challenge and induce keratinocyte apoptosis via the perforin/granzyme or the Fas/FasL pathway [29,30]. Activated T cells release type 1 cytokines, including IFN-gamma and TNF-alpha. Both cytokines are potent activators of keratinocytes and promote the up-regulation of intercellular adhesion molecules (ICAM-1) and MHC class II molecules and the release of chemokines, resulting in a massive recruitment of mononuclear and polymorphonuclear cells and amplification of the inflammatory response [4].
MHC class I knockout mice, which are deficient in CD8+ T cells, or mice acutely depleted in vivo of CD8+ T cells are unable to develop a hypersensitivity reaction to the cutaneous application of the strong hapten dinitrofluorobenzene (DNFB) [24]. Conversely, MHC class II-deficient mice, which are deficient in CD4+ T cells, develop a strong reaction to DNFB, supporting the hypothesis that CD8+ T cells are primed in the absence of CD4+ T cells and mediate the cutaneous hypersensitivity response.
The role of hapten-specific CD4+ T cells is not completely understood. CD4+ T cells appear in the site of challenge at a later time than CD8+ T cells and may have distinct roles in the inflammatory process [31]. CD4+ Th1 cells, producing high amounts of IFN-gamma and TNF-alpha, display cytotoxic activity against keratinocytes expressing MHC class II molecules and may cooperate with CD8+ T cells in amplifying the inflammatory response. By contrast, other subsets of CD4+ T cells may have a regulatory function (such as FoxP3+ and CD4+ T regulatory cells).
The afferent and efferent phases of ACD are illustrated in the figure (figure 1). The cell types involved in ACD and their functions are summarized in the table (table 1).
For many years, the convention has been that skin-associated lymphoid tissue involves transient populations of lymphocytes in the skin, circulating lymphocytes in the blood, and stable populations of lymphocytes in local lymph nodes. However, it is now recognized that there are also populations of skin resident T cells that persist long term in the skin (called effector memory T cells). This population of memory T cells provides local and rapid immune responses to pathogens and haptens, such as those that occur in ACD. In addition to ACD, these long-lived, resident T lymphocytes are relevant to other dermatologic diseases, such as psoriasis, cutaneous T cell lymphoma, and fixed drug eruption [32].
THE INNATE IMMUNITY IN ALLERGIC CONTACT DERMATITIS — Innate immune cells (dendritic cells [DC], mast cells, natural killer [NK], NKT-cells) play a critical role in allergic contact dermatitis (ACD) (table 1). Innate lymphoid cells are lymphoid cells that are distinct from conventional lymphocytes in that they lack antigen receptors, are distinct from other innate cell types, and can play a regulatory role in allergic diseases [33]. They reside in the skin and other tissues and are emerging as another cell type that may play an important role in the early events of ACD, as their numbers are increased in positive patch tests to nickel [34,35]. In addition, antigen-presenting cells (macrophages, DC, monocytes, and B lymphocytes) express membrane-bound innate immune receptors called pattern recognition receptors (PPR), which include the toll-like receptor (TLR) family. TLRs are transmembrane receptors that recognize pathogen-associated molecular patterns such as cell wall components (eg, bacterial endotoxin), proteins, and nucleic acids of bacteria, parasites, viruses, and fungi [36]. TLRs also recognize damage-associated molecular patterns, which are released during cell necrosis [37]. TLR signaling results in changes in the transcription factors that regulate a multitude of genes, including those encoding important proinflammatory cytokines. (See "Toll-like receptors: Roles in disease and therapy".)
In mouse models of contact hypersensitivity, TLR2 and TLR4 recognize low molecular weight breakdown products of hyaluronic acid that are produced by reactive oxygen species in response to exposure to haptens [38-42]. In humans, the TLR4 (hTLR4) has been identified as the receptor for nickel, which is the most common cause of ACD [43]. Binding of nickel to hTLR4 requires the presence of two nonconserved histidines (H) in H456 and H458 in the extracellular domain of hTLR4. The binding of nickel to hTLR4 triggers a signal transduction cascade via the nuclear factor for the kappa light chain enhancer in B cells, resulting in the production of proinflammatory cytokines and the activation of DC early in the afferent phase of ACD. Because mice lack H456 and H458, they do not develop contact hypersensitivity to nickel. Other metal salts, such as cobalt and palladium, that can induce ACD have also been demonstrated to trigger TLR4 activation similar to nickel [44]. These data suggest a novel mechanism for the "adjuvancy" (or immune-activating properties) of common allergens.
In 2006, it was discovered that mice devoid of conventional T cells and B cells demonstrated substantial contact hypersensitivity responses to 2,4-dinitrofluorobenzene and oxazolone (two strong, experimental contact allergens) [45]. The response was dependent on natural killer cells specific to these allergens and long lasting, demonstrating for the first time that innate immune cells could substitute for conventional T cells in mediating contact hypersensitivity. This was a surprising observation, considering that natural killer cells do not express an antigen receptor, as do T cells and B cells.
REGULATORY MECHANISMS OF ALLERGIC CONTACT DERMATITIS — Regulatory T cells (Treg) may have a role in the sensitization and elicitation phase of allergic contact dermatitis (ACD) and in the downregulation of the inflammatory response that was initially attributed to the clearance of the hapten from the skin [46,47]. Tregs are a heterogeneous cell population that includes natural Tregs (CD4+CD25+Foxp3+ cells) and inducible Tregs (Tr1- and Th3-cells) [4,48]. The skin contains predominantly inducible Tregs, which can be triggered by Langerhans cells or dermal dendritic cells [49,50]. Following exposure to a contact allergen, Tregs can lower or suppress the process of sensitization [50-53]. During the elicitation phase, they can suppress effector T cells in the lymph nodes and inhibit the influx of leukocytes through IL-10 or CD39 mechanisms [54,55]. Tregs may also be involved in the control and eventual termination of the inflammatory response in ACD [56].
MECHANISMS OF TISSUE DAMAGE IN ALLERGIC CONTACT DERMATITIS — In the early phase of allergic contact dermatitis (ACD), tissue damage is mostly due to CD8+ T cell-induced apoptosis of keratinocytes bearing the hapten-protein complex on MHC class I molecules, via the perforin/granzyme or the Fas/FasL pathway. The induction of keratinocyte apoptosis is accompanied by a rapid cleavage of CH1 intercellular adhesion molecules (E-cadherins). The loss of intercellular adhesion and the infiltration of lymphocytes in the epidermis are responsible for the intercellular edema and vesiculation as well as the typical spongiotic appearance of the epidermis in ACD [57].
Type 1 cytokines, released by infiltrating CD8+ and CD4+ T cells, in particular IFN-gamma, stimulate keratinocytes to release cytokines and chemokines, resulting in the massive recruitment of activated T cells, neutrophils, macrophages, and eosinophils that form the cellular inflammatory infiltrate in the dermis.
SUMMARY
●Allergic contact dermatitis (ACD) is a delayed type hypersensitivity reaction elicited by the contact of the skin with the offending chemical in individuals who have been previously sensitized to the same chemical. The understanding of the cellular and molecular pathogenesis of ACD has expanded dramatically. In addition to CD4+ and CD8+ T cells, other cell types, such as natural killer T (NKT) cells and T regulatory cells, have emerged as critical participants (table 1). (See 'Overview' above.)
●Hapten binding is the initial step in the development of ACD. Haptens are low molecular weight (<500 Daltons) chemicals that are able to penetrate the stratum corneum of the skin. Haptens are not immunogenic by themselves but can be efficiently recognized by the immune system after binding to a skin protein carrier. (See 'Hapten-protein binding' above.)
●In the clinically inapparent sensitization phase, Langerhans cells and dermal dendritic cells initiate an adaptive immune response by capturing, processing, and presenting antigens to naïve T cells in the paracortical areas of lymph nodes. In the elicitation phase, the clinical manifestations of ACD are the result of a T cell-mediated inflammatory reaction occurring in the skin upon re-exposure to the offending hapten and mediated by the activation of hapten-specific T cells in the skin. The primary effector cells of ACD appear to be CD8+ cells (figure 1). (See 'The sensitization (afferent) phase' above and 'The elicitation (efferent) phase' above.)
