Early immune events in the induction of allergic contact dermatitis

Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity

The development of contact hypersensitivity after epicutaneous application of dinitrochlorobenzene in guinea pigs was suppressed by antidinitrophenyl γ1 and γ2 antibody which was injected locally at the sensitization sites. Some results suggested that small amounts of antibody may enhance rather than suppress the induction of allergic contact dermatitis. The elicitation of the delayed epidermal reactions was suppressed by antibody. These results indicate that the final outcome of sensitization to a simple chemical is dependent on several possible effects of preexistent or newly formed antibodies. They suggest that a lowered skin reactivity to an allergen in allergic contact dermatitis may be due to antibody-mediated depression of delayed hypersensitivity.

Contact hypersensitivity (CHS) has long been used to treat alopecia areata, an autoimmune disease caused by autoreactive T cells ( Kaplan et al., 2012 Kaplan D.H. Igyártó B.Z. Gaspari A.A. Early immune events in the induction of allergic contact dermatitis. Nature Reviews Immunology. 2012; 12: 114-124 Crossref PubMed Scopus (423) Google Scholar , Vocanson et al., 2009 Vocanson M. Hennino A. Rozieres A. Poyet G. Nicolas J.F. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy. 2009; 64: 1699-1714 Crossref PubMed Scopus (281) Google Scholar ). In alopecia areata, anagen hair follicles (HFs) enter telogen prematurely, followed by the prolonged arrest of HF stem cells (HFSCs) quiescence ( Pratt et al., 2017 Pratt C.H. King L.E. Messenger A.G. Christiano A.M. Sundberg J.P. Alopecia areata. Nature reviews Disease primers. 2017; 3: 1-17 Crossref Scopus (421) Google Scholar ). CHS can induce hair growth in patients with and mouse models of alopecia areata ( Pratt et al., 2017 Pratt C.H. King L.E. Messenger A.G. Christiano A.M. Sundberg J.P. Alopecia areata. Nature reviews Disease primers. 2017; 3: 1-17 Crossref Scopus (421) Google Scholar , Tang et al., 2003 Tang L. Lui H. Sundberg J.P. Bissonnette R. McLean D.I. Shapiro J. Restoration of hair growth with topical diphencyprone in mouse and rat models of alopecia areata. Journal of the American Academy of Dermatology. 2003; 49: 1013-1019 Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar ). How CHS activates HFSCs remains unclear. The beneficial effect has been attributed to its immunomodulation, which alleviates local autoimmunity ( Pratt et al., 2017 Pratt C.H. King L.E. Messenger A.G. Christiano A.M. Sundberg J.P. Alopecia areata. Nature reviews Disease primers. 2017; 3: 1-17 Crossref Scopus (421) Google Scholar ). In addition to immunomodulation, whether CHS also directly stimulate HFSCs to accelerate anagen entry is unknown.

Allergic contact dermatitis is a common occupational disease that manifests as a cell-mediated hypersensitivity reaction following skin exposure to small reactive chemicals termed haptens. Haptens penetrate the stratum corneum and covalently modify proteins in the epidermis, inducing intracellular stress, which further leads to the release of damage-associated molecular patterns (DAMPs), such as uric acid, reactive oxygen species, hyaluronic acid fragments and extracellular adenosine triphosphate (ATP). These DAMPs are recognized by pattern recognition receptors (PRRs) in innate immune cells, namely dendritic cells (DCs), leading to their maturation and migration to the draining lymph nodes where they activate naïve T lymphocytes. Among all PRRs, several studies emphasize the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome on the allergic contact dermatitis (ACD) sensitization phase. However, skin allergens—danger signals—NLRP3 inflammasome axis is yet to be completely elucidated. Therefore, in this review, we sought to discuss the molecular mechanisms underlying DAMPs release and NLRP3 inflammasome activation triggered by skin allergens. The elucidation of these key events might help to identify novel therapeutic strategies for ACD, as well as the development of nonanimal alternative methods for the identification and potency categorization of skin sensitizers.

As sensors of invading microorganisms, Toll-like receptors (TLRs) are expressed not only on macrophages and dendritic cells (DCs) but also on epithelial cells. In the TLR family, Tlr11 appears to have the unique feature in that it is expressed primarily on epithelial cells, although it is also expressed on DCs and macrophages. Here, we demonstrate that transcription of the Tlr11 gene is regulated through two cis-acting elements, one Ets-binding site and one interferon regulatory factor (IRF)-binding site. The Ets element interacts with the epithelium-specific transcription factors, ESE-1 and ESE-3, and the IRF motif interacts with IRF-8. Thus, Tlr11 expression on epithelial cells is regulated by the transcription factors that are presumably distinct from transcription factors that regulate the expression of TLRs in innate immune cells such as macrophages and DCs. Our results imply that the distinctive transcription regulatory machinery for TLRs on epithelium may represent a promising new avenue for the development of epithelia-specific therapeutic interventions.

Thymic stromal lymphopoietin and allergic disease

A variety of chemicals are able to cause allergic disease in susceptible individuals. Chemical-induced allergy may take several forms, chief among them being skin sensitization or allergic contact dermatitis and respiratory hypersensitivity. It has been found that contact and respiratory chemical allergens induce in mice qualitatively divergent immune responses consistent with the preferential activation of discrete T-helper (Th) cell subpopulations, Th1 and Th2 cells, respectively. Despite the selective stimulation of Th2-type responses by chemical respiratory allergens, such materials are nevertheless able to induce contact sensitization in mice, which is a form of delayed-type hypersensitivity usually considered to be effected by Th1 cells. Indeed, the available evidence indicates that chemicals known to cause respiratory allergy in humans test positive in both mouse and guinea pig assays used for the prospective identification of skinsensitizing chemicals. The activity of chemical respiratory sensitizers in such tests has important implications for the toxicological evaluation and classification of potential chemical allergens. Paradoxically, however, although chemical respiratory allergens show a potential for contact sensitization in predictive tests, this hazard rarely translates into an important risk of allergic contact dermatitis in humans.

Contact and respiratory sensitization by chemical allergens: Uneasy relationships

Evolution has provided two distinct and highly sophisticated defense mechanisms to human beings for survival in a hostile environment. The innate immune system is aimed to react rapidly (from within minutes to a few hours) and in a rather simple way with little variation to attacks of pathogens. In contrast, the acquired immune system provides a more adaptive and highly specific defense response to foreign structures. In addition, it has the unique ability to induce tolerance of self-structures. The mechanisms of acquired immunity involve several steps of recognition and reactions in which various different cell types are engaged. Among antigen-presenting cells (APC), dendritic cells (DC) fulfill a pivotal function by providing information about invading pathogens under optimal conditions to other partners (e.g., effector cells) of the immune system. Thus, after having been neglected for years, DC research is experiencing a revival due to the central role of these cells in the complex machinery of the adaptive immune response. Moreover, understanding the role DC play in pathophysiologic conditions may be a key step in developing treatment strategies for several disease entities. Since many different DC types have been identified during the last years, including follicular DC and thymic DC, the present review will focus on the "classical" DC as they have been described initially by Steinman and Cohn. The first member of the DC system was described more than 100 years ago by Paul Langerhans (1868) and was originally thought to be a type of cutaneous nerve cell. After it had then been considered for a time to be an immature melanocyte, Birbeck (1) described the unique ultrastructural feature of the Langerhans cell (LC), which was named after him. Birbeck granules (BG) are rod-shaped structures with a central, periodically striated lamella and, depending on the section viewed, are tennis-racket shaped. BG are found exclusively in LC from man and other mammals, but not in other DC. They are considered the primary marker of epidermal LC. Nowadays, LC are best recognized in the skin by their CD1a expression. In the 1970s, Steinman & Cohn first described the structure and function of DC from mouse spleen suspensions (2). Morphologically, DC are characterized by their numerous thin, elongate cytoplasmic processes, which give them a veil-like appearance. They exhibit features of metabolically active cells with scattered mitochondria; a recognizable Golgi apparatus; some lysosomes, phagolysosomes, and lipid droplets; and a well-developed endoplasmic reticulum. They have large and often indented nuclei with heterochromatin preferentially deposited at the nuclear membrane (3). DC have been found in virtually all types of epithelia (skin, mucous membranes, lung) and as interstitial DC in the heart and kidney as well as in other organs. In addition, various subtypes of DC were also discovered in blood and in the lymphatic system (4). These represent different stages of maturation and are connected by circulatory pathways. Beside their typical dendritic structure in tissue and in suspension, DC were initially characterized mainly by their high expression of major histocompatibility complex (MHC) class II HLA-DR and their high stimulatory activity toward allogeneic T cells. Although they ultimately act as highly specialized APC, DC have to undergo four main stages of differentiation and maturation before they fulfill their main function in the lymphoid organs. Since the first demonstration that epidermal LC are derived from bone-marrow cells by Katz et al. (5), many efforts have been made to characterize the precursor cells of DC and LC in bone marrow and blood (Fig. 1). Thus, the ontogenesis and the development of techniques for in vitro generation of DC have been the focus in this field of research, especially considering possible therapeutic implications (see below). Ontogenesis of dendritic cells (DC). Before being able to activate naive T cells (Tn) (primary immune response), DC must undergo profound maturation step which occurs during their migration to regional lymph nodes. In peripheral tissue, DC may also trigger secondary immune response when encountering memory T cells (Tm) in transit through tissue. Although it is well established that DC derive from bone-marrow CD34+ stem cells, two main strategies have been followed over the past years. First, in 1992, Caux et al. described a system that generates CD1a+ LC-like DC from CD34+ stem cells by supplementing granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor-necrosis factor alpha (TNF-α) (6). The generation of LC/DC was optimized later by adding stem cell factor (SCF) and/or FLT-3 ligand, resulting in a higher yield of CD1a+ cells, with a typical dendritic structure, strong expression of MHC class II antigens, CD4, CD40, CD54, CD58, CD80, CD83, and CD86, and the presence of BG in 10–20% of the cells. Most importantly, these cells exhibit a potent capacity to stimulate the proliferation of naive T cells and to present soluble antigens to clones of CD4+ T cells. On the other hand, in 1994, Sallusto & Lanzavecchia (7) were able to generate CD1a+ DC corresponding to interstitial DC in their phenotype by culturing monocytes with GM-CSF and interleukin (IL)-4. CD14+ monocytes undergo maturation into CD1a+ DC, which, however, lack BG and are therefore not considered LC but are more similar to dermal DC since they express CD11b, CD68, and the coagulation factor XIIIa. Typically, after 7 days of culture with GM-CSF and IL-4, monocytes give rise to immature DC which need further stimulation with CD40 ligand, endotoxin, or TNF-α to reach the full maturation stage of highly stimulatory DC. However, if monocytes are cultured with macrophage colony stimulating factor (M-CSF) alone, they differentiate into macrophage-like cells (CD14+, CD1a−, CD83−) and synthesize IL-10 (8). While these DC are now classified as myeloid DC because they are known to derive from myeloid precursors (see below), more recently, a novel type of so-called lymphoid DC has been described. These lymphoid DC derive from CD4+/CD3−/CD11c− plasmocytoid cells from the blood and the tonsils (9, 10). These precursors do not differentiate into macrophages with GM-CSF or M-CSF. Lymphoid DC are dependent on IL-3, but not on GM-CSF, and are less active in phagocytosis. When localized in peripheral blood or in nonlymphoid tissue, DC are considered to be functionally immature. This refers to the fact that DC in tissues are highly specialized for capturing and processing foreign or autologous protein antigens or haptens. Uptake of high-molecular-weight antigens by DC may occur through macropinocytosis or more specifically through a number of membrane receptors such as FcγRII and FcεRI loaded with the adequate antibodies. DC also express membrane receptors bearing multiple lectin domains such as the mannose receptor and the DEC-205 molecule(11). These structures enable DC to internalize antigens by receptor-mediated endocytosis, a pathway which leads to antigen uptake into specialized compartments inside DC and allows efficient processing and subsequent loading of these antigens on MHC class II molecules. In contrast, uptake of low-molecular-weight haptens, e.g., DNCB or oxazolone (12, 13), mostly occurs via binding to surface glycoproteins and subsequent internalization. Experiments with MHC knockout mice suggest that presentation of such haptens is achieved through MHC class I molecules to CD8+ T cells rather than via MHC class II. A further characteristic of DC is the high stability of MHC class I or class II molecules on their cell surface, allowing them to be loaded for a long time with defined antigens. At this stage of maturation, DC are able to stimulate memory T cells trafficking through the tissue, initiating a secondary immune response at the site of contact with the captured antigen. However, since macrophages and other cells are as efficient as DC in this type of stimulatory activity, it is assumed that triggering a secondary immune response is not the primary task of DC under normal conditions. In recent years, it has become clear that the migration of many cell types including DC is tightly regulated by chemokines. The expression of chemokines at different anatomic sites and in different pathologic states in combination with the differential expression of chemokine receptors on cells during different maturation stages is the basis of a complex signaling network that orchestrates cell migration and cell interaction in the immune response (14). Specifically for DC, it has been shown that the chemokine receptor profile expressed on immature DC (CCR1, CCR2, CCR5, and CCR6) mainly recognizes chemokines that are released during inflammatory processes. This allows the accumulation of DC that are geared toward antigen uptake at sites of inflammation. Release of cytokines such as IL-1 and TNF-α further perpetuates this process by inducing immature DC to release even more inflammatory chemokines. Conversely, mature DC downregulate their receptors for inflammatory chemokines and express different chemokine receptors (CCR4, CCR7, CXCR4, SLC, and ELC). These allow them to receive signals which will attract them to the regional lymphatics and eventually to the T-cell-rich areas of the lymph node. Thus, after antigen uptake, tissue DC migrate to the regional lymph nodes. For example, LC seem to be able to migrate quite fast; i.e., several millimeters within 30 min (15). On their way to the lymph node, DC begin a profound metamorphosis, leading to significant changes in their structure and phenotype. In the afferent lymphatic vessels, DC have been described as so-called veiled cells and as interdigitating cells in the T-cell-rich paracortical zones of secondary lymphoid tissues. As DC mature, they lose their antigen uptake capacity and their function shifts toward antigen presentation. One of the hallmarks of this development is the upregulation of peptide-loaded MHC class II and costimulatory molecules (CD80, CD86) on the surface of these cells. In the meantime, DC rapidly downregulate and sometimes completely abolish the expression of Fc receptors. Migration and maturation of DC seem to be linked processes in vivo since factors such as lipopolysaccharides (LPS), TNF-α, and IL-1 induce both processes (16). In vitro, TNF-α has been shown to induce maturation of monocyte-derived DC, also leading to upregulation of CD80, CD86, CD83, and MHC class II. All these molecules are crucial for efficient antigen presentation to resting naive T cells. Priming of naive T cells is one of the crucial tasks that DC have to fulfill. To do so, DC and naive T cells have to colocalize in the paracortical zone of the lymph nodes. An interesting finding was the fact that naive T cells express chemokine receptors (e.g., CCR7) that allow them to receive the signals sent by mature DC which release ELC and DC-specific chemokines (DC-CK1). After having reached the T-cell area, a single DC can prime hundreds of naive T cells. In this process, peptides bound to MHC class II or MHC class I on DC are presented to T cells via the T-cell receptor complex (TCR). Recently, it became clear that, in addition to the signals received via the TCR, costimulatory signals are of key importance in initiating and directing a T-cell response. Interaction of the costimulatory molecules CD80 and CD86 with their counterparts on T cells, i.e., CD28 or CTLA-4, determines whether this stimulation will result in an antigen-specific proliferation of T cells or tolerance. Indeed, additional factors present at the site of DC–T-cell interaction such as IL-10 may modify CD80/CD28 signaling by blocking downstream events in signal transduction, thereby leading to antigen-specific tolerance (17). An important observation was that DC can release IL-12. This cytokine is involved in the induction of a Th1 T-cell response. Likewise, other cytokines such as IFN-γ may induce a Th1 response, whereas IL-4 has been shown to direct the T-cell response toward Th2. This capacity to influence the type of T-cell response may explain why some antigens induce an allergic reaction and others do not. It is interesting that the cytokines and factors released during T-cell priming also induce a different chemokine receptor repertoire on stimulated T cells. Whereas Th1 cells express CCR1, CCR2, CCR5, CXCR3, and CXCR5, Th2 cells are characterized by the expression of CCR2, CCR3, CCR4, and CXCR5 (14). The differential expression pattern may recruit these cells to specific types of inflammation (allergic vs nonallergic) and determine which other cell types may be involved in a particular inflammatory response. As far as allergic reactions are concerned, it is noteworthy that Th2 cells, eosinophils, and basophils share the expression of the chemokine receptor CCR3, whereas Th1 cells and monocytes, which can differentiate into DC, share CCR1 and CCR5. Once antigen presentation has been achieved, DC are not supposed to recirculate in peripheral blood or lymphatic vessels. Indeed, it is assumed that DC will be killed by T cells or will die by apoptosis on site (18, 19). As mentioned above, the primary task of DC is to inform the immune system about the invasion of foreign and potentially harmful proteins. Much interest has been focused over the last 25 years on the possible pathophysiologic role of DC in a variety of conditions, especially in allergic inflammatory diseases. Allergic contact dermatitis (ACD) is the archetype of cell-mediated hypersensitivity reactions in which DC play a pivotal role in the sensitization process. While the contact of irritant compounds on the skin leads to the secretion of TNF-α and GM-CSF by keratinocytes, low-molecular-weight haptens (e.g., nickel, DNCB, or oxazolone) stimulate the additional release of IL-1α, IP-10, and MIP-2. These chemokines activate DC and endothelial cells, leading to an accumulation of even more DC at the site of antigen contact. Moreover, application of hapten induces the release of IL-1β by epidermal LC and thereby promotes their egress from the epithelium. After the uptake of the antigen, DC process it while migrating to the regional lymph nodes where it will be presented to antigen-specific naive T cells. Little is known about the mechanisms which enable DC to be highly efficient in priming naive T cells. Another remarkable property of DC is their ability to present exogenous antigens on MHC class I and II molecules. This leads to the activation of both CD4+ and CD8+ hapten-specific T cells (20, 21). Whereas classical delayed-type hypersensitivity reactions are mediated by CD4+ effector cells, contact dermatitis is mediated by CD8+ effector cells (22-24). Other cytokines released during the sensitization process have been implicated in directing the type of immune response mounted by T cells. It has been shown that IL-10 converts LC/DC from potent inducers of a primary immune response to hapten-specific tolerizing cells. A significant decrease in mRNA signals for IL-1α, IL-1β, and TNF-α confirms the immunomodulatory role of this cytokine in contact hypersensitivity reactions (25, 26). On the other hand, IL-12 which is released by keratinocytes and by DC themselves (25, 27), is known as a strong inducer of the Th1 response. After a second contact with a contact allergen, antigen-specific memory T cells can be stimulated either by DC or by APC less potent than DC (e.g., macrophages or monocytes) and, due to their specific homing molecules, elicit an immune response at the appropriate anatomic site. Atopic diathesis is characterized by three major diseases, i.e., allergic rhinoconjunctivitis, allergic asthma, and and is with Thus, it is assumed that mechanisms e.g., secretion of IL-4 and are of crucial importance in diseases. specific may play a role in the of these conditions. Since of the react do not have direct to cells in the blood or in lymphoid tissue, and presentation to T cells must be by APC localized in tissues at the with the i.e., in the the and other Thus, as they the first of defense in these peripheral DC are considered the best for priming naive T cells toward In the of the which has research during the last it was resting T cells are into Th1 or Th2 cells during antigen presentation. While it became clear that IL-12 by DC is mainly for the to Th1 it was a of which cells may be the of IL-4, which shifts T-cell response to the Th2 et al. some that may be the signal which cells to the Th2 type recently, et al. have shown that myeloid DC are for T cells into Th1 to as while lymphoid DC direct T cells into Th2 in an way to as (Fig. Moreover, mechanisms are these DC and T cells. of the mechanisms of Th2 stimulation by lymphoid or other and/or costimulatory will modify understanding of has the immune system to an appropriate of immune types of dendritic cells and DC types seem to derive from different and are to Th1 and Th2 It has been that monocytes, and myeloid express the receptor for lymphoid this structure has not been The FcεRI on LC and several important from this receptor on effector cells of i.e., cells and Indeed, it is not expressed on these cells but to be regulated by signals of the inflammatory the cells. Thus, the FcεRI expression is on LC and a described inflammatory dendritic epidermal cell from skin of dermatitis However, the lack or the surface expression of the receptor complex is due to the expression of the which is for the surface expression of the structure, while the is present in a inside the cells the FcεRI on LC and as well as on monocytes, the This has in to LC and from normal LC receptor are not receptor is of a role of FcεRI in antigen by monocytes, and blood DC that have been by FcεRI receptor-mediated are into MHC class II compartments such as in which processing and loading of MHC class II molecules occur This in leads to an optimal antigen presentation to CD4+ T cells, as a for antigen In this one may about the role of DC in the of It is well that molecules and effector cells such as cells, or are the result of an efficient defense system. It has been that this system has been toward because of the lack of have been to the role of DC in the network of immunity and allergic As mentioned above, antigen uptake, and presentation are the main of DC. Among the of antigen which and receptor endocytosis, the last provides the efficient and specific This to be the for Indeed, the expression of high FcεRI on DC of several important First, DC their ability to react to by binding large of molecules with various This the of FcεRI by a defined at the cell the allow the of rather large which, under normal are not via the i.e., by of FcεRI on DC is followed by via receptor-mediated via and However, in to the receptor where and different compartments this for antigen uptake by DC, i.e., specifically via and may whether the foreign structure will be and to MHC class ultimately leading to a higher of specific peptides in the of surface MHC class II molecules. DC high receptor will full cell activation FcεRI inducing the and release of defined may to the subsequent antigen presentation. One may that DC with specific can the secondary immune response and further trigger the by and more antigen-specific Th2 cells. DC are the potent of naive T i.e., they are to a primary immune response. At first antigen uptake and subsequent presentation seem rather in the primary reaction since specific be present at the However, it be that complex structures captured via FcεRI on DC are by these cells in a way leading the and presentation of the T cell This then a primary reaction these antigens, thereby to the variety of the It is a that, as above, antigen uptake and FcεRI on DC to the and release of of directing T cells toward a defined phenotype and/or i.e., Th1 or Th2 cells. This in the of DC to be especially considering recent an important role of IL-12 and in T cells toward either Th2 or The role and function of APC in allergic disease high of both and DC were found in the and the of the of from DC of the BG a feature which them as LC. the represent LC at a different maturation stage or DC of a different to be The number of DC is in the and rapidly further the that higher are in the to with the antigen Indeed, it has been in after that the number of DC after antigen At the of the CD1a+ DC were in the and vessels, to the epithelium. In the second of these cells were found the of the As is little that DC are able to within the these changes are to in their and/or The pivotal role of DC for antigen processing is further by their with a of This with the in epithelia such as the normal human where the corresponding DC e.g., are with a of days or The interaction of DC with other cell types such as cells that can be identified in the to be The of is Although are this is a complex that is characterized by and Whereas the is characterized by release from cells, the is by an inflammatory in the the inflammation leads to to the is a allergic disease with a response and it has been that the of and other be due to a higher of Thus, pathogens that prime for a Th1 immune response. In addition, stimulation of the immune system with to for Th2 memory and thereby the type of immune response with The maturation of DC function in the is an important factor in the of the memory cell in the of this maturation process may be a key of the of Recently, it has been by et al. that different of DC may a direct over Th1 vs Th2 differentiation of naive T cells The first for the induction of an immune response to is that these molecules to cells. Although the a highly regulated and is in the to after In addition, induces cells to express GM-CSF, which DC to the site of antigen contact As far as antigen uptake by DC is concerned, the response within the tissue is the of MHC class II DC The class cells within the a within after antigen the DC their and to a more of veiled cells. DC within the is and in an in the of these cells from the to the lymph nodes. Another that may to an response of to may be that in the inflammatory process DC are from It is known that monocyte-derived DC from allergic in the expression of and the receptor for and even an upregulation of and into more potent cells than from normal Whereas DC are in priming the immune system to other APC may play a crucial role in the secondary immune response to In this they may to the of The major APC in the of the macrophages the and DC, the specific cells, type II cells, and, to a cells. The interaction of DC with other APC as well as with other effector cells of the immune system an active field of on DC in the skin the and release of which may a inflammatory as has been for cells. Thus, from a pathophysiologic of DC, and LC and DC in the have been to play a crucial role in dermatitis since they may represent the the and antigen-specific cells the skin This is by the observation that the presence of LC bearing molecules is a to by application of on the skin of may represent the of an delayed-type hypersensitivity reaction in and The of may be by cytokines derived from cells. The expression of and on endothelial cells is leading to the and invasion of other cells, such as macrophages or and by cytokines as well as have been shown to leading to an activation of and Th1 and cells. Thus, IL-12 may for the of the cytokine pattern and the from a Th2 to a Th1 response with the subsequent release of This cytokine is for the and of and determines the of the disease Indeed, the observation that IFN-γ mRNA in such was by a of IL-12 expression the of the Th2 to Th1 in the of As a DC have a crucial role in the of various especially in direct contact with the environment. pathophysiologic role in allergic contact as well as in other allergic diseases, is now well Moreover, they seem to have a central role in the and presentation of antigens. strategies have now been to DC in the of hypersensitivity reactions and, on the other hand, to these cells as a to Recently, have that the unique function of DC to In of their at tissues such as the skin and or DC be for therapeutic In the is known to the of LC/DC well as that of cells) and is in the treatment of inflammatory skin diseases. the capacity of DC to induce an immune response, the mechanisms are far from Indeed, DC seem to their expression of several functionally molecules such as HLA-DR or CD86, but they their stimulatory activity recently, it has been shown that a generation of i.e., and which, in to can be interesting with to DC They the expression of costimulatory molecules, the of distinct DC in inflammatory tissue and decrease the stimulatory activity of DC in vitro, as well as in after application of molecules with the binding of to receptor or compounds defined activation mechanisms by DC in represent in the of conditions. made in understanding the ontogenesis of DC and the techniques for their generation in vitro have to an and therapeutic in vitro DC may be either to hypersensitivity reactions in contrast, to the immune response in a as for A number of pathologic conditions are known to be by distinct of hypersensitivity Among diseases, and allergic are the DC with appropriate and by cytokines such as IL-10 or may be to and as well as T cells. have been because with LC in a of hapten-specific tolerance Another interesting is the of the immunomodulatory of such as This to the phenotype and the function of DC. It the expression of the costimulatory molecules CD86 and CD40, and the and release of IL-1 and but the of IL-10 Thus, may represent a and able to DC and to them from potent to The first therapeutic for the treatment of by with DC have been established Thus, DC may as for as the and of an immune response is regulated at the of DC. are to antigens or peptides to particular presentation class II vs class within DC. are and DC can induce primary and secondary immune of all years after the of the DC in the skin by Paul of the of these cells and especially the made in the last may be considered in the understanding of crucial pathophysiologic in diseases. Most importantly, this is about to of therapeutic and the of in vitro DC in has a in This was by the of the and by the

Introduction Inflammation is triggered when innate immune cells detect microbial infection or tissue damage. Surveillance mecha­ nisms involve pattern recognition receptors on the cell surface and in the cytoplasm. Most pattern recognition receptors respond to pathogen­ associated molecular patterns or host­derived damage­associated mole­ cular patterns by triggering activation of various transcription factors. Induction of cytokines promotes the activation and recruitment of leukocytes, which are critical for elim­ inating pathogens and host debris. In order to avoid immunopathology, the system is very tightly regulated by numerous molecules that limit the magnitude and duration of the inflammatory response. In this review we present current knowledge on pathogen recognition through diff­ erent pattern recognition receptors and the complex signalling pathways responsible for activation of inflam­ matory and antimicrobial responses. Conclusion There are still many unresolved questions, such as the exact nature of the molecular events leading to diff­ erent immune receptor activation and also identity of some unknown ligands for the receptors. Unravelling of these will offer insight into what critical components might be target­ ed for better therapeutic benefits in inflammatory disorders. Introduction The role of inflammatory response is to combat infection and tissue injury. The innate immune system constitutes the first line of host defence during infection and therefore plays a very crucial role in the early recognition and subsequent trigger­ ing of a pro-inflammatory response to invading pathogens1. The adaptive immune system, on the other hand, is responsible for elimination of pathogens during the late phase of infection and in the generation of immunological memory. The innate immune response is mediated pri­ marily by phagocytic cells and antigen­presenting cells (APCs), such as macrophages, and dendritic cells (DCs), and has been regarded as relatively non-specific2, whereas the adaptive immune response is charac­ terized by antigen-specific receptors on lymphocytes generated by clonal gene rearrangements. Innate immune cells of tissues such as macrophages, fibroblasts and dendritic cells, as well as circulating leukocytes, recognize pathogen inva­ sion or cellular damage with pattern recognition receptors (PRRs). These receptors detect pathogen­associated molecular patterns (PAMPs), such as pathogen­derived nucleic acids and cell wall components, fungal β-glucan, bacterial flagellin, and lipopolysaccharide (LPS) from Gram­ negative bacteria. PRRs also recog­ nize damage­associated molecular patterns (DAMPs), released from injured cells during apoptosis or necrosis. DAMPs include uric acid, ATP, and the DNA­binding nuclear protein HMGB1 and amyloid β fibrils. Activated PRRs then initiate signal­ ling cascades to trigger the release of factors that promote recruitment of leukocytes to the infected region. In this review, we look into the inflammatory signalling response emanating from the recognition of microbial infection and cellular injury by PRRs. Among PRRs, membrane­bound toll­like receptors (TLRs) play a cen­ tral role in the initiation of immune response against pathogen invasion. However, other PRRs are also involved—including membrane­bound C­type lectin receptors (CLRs), cyto­ solic proteins such as NOD­like recep­ tors (NLRs) and RIG­I­like receptors (RLRs). Among these receptor types, TLRs and RLRs are primarily important for the production of type I interfer­ ons (IFNs), whereas NLRs are known to regulate interleukin-1β (IL-1β) production through activation of caspase­1. Discussion Toll-like receptors TLRs were the first PRRs to be iden­ tified. They are also the most well characterized and recognize a wide range of PAMPs3–5. TLRs are trans­ membrane proteins which comprise an ectodomain, which contains leucine­rich repeats that mediate the recognition of PAMPs, a transmem­ brane region, and cytosolic Toll­IL­1 receptor (TIR) domains that activate downstream signalling pathways. TLRs are expressed either on the cell surface or on intracellular vesicles. To date, 10 and 12 functional TLRs have been identified in human and mice, respectively. Each TLR detects distinct PAMPs from bacteria, viruses, fungi and parasites. Upon recognition of respective PAMPs, TLRs recruit a specific set of adaptor molecules that have TIR doma ins, such as MyD88 and TRIF, and initiate downstream signalling

The process of sensitisation by specific contact allergens is indispensable for the induction of allergic contact dermatitis. Oxazolone is a well-characterised contact allergen. Previous studies suggested that immune cells bearing the FcRγ subunit are essential for oxazolone-induced contact hypersensitivity, but the biological functions of the FcRγ subunit in the process of sensitisation to oxazolone remain unknown. In this study, we show that FcRγ deficiency decreases ear-swelling responses to oxazolone in mice. However, we found that oxazolone-sensitised FcRγ(-/-) mice and oxazolone-sensitised wild-type (WT) mice have comparable numbers of CD11c(+) MHCII(hi) dendritic cells (DCs) in their draining lymph nodes (LNs). In addition, oxazolone-sensitised LN cells from both FcRγ(-/-) and WT mice showed considerable production of interferon-gamma (IFNγ), interleukin-4 (IL-4) and IL-17A upon oxazolone-keyhole limpet haemocyanin loading. Consistent with these data, oxazolone-sensitised FcRγ(-/-) and FcRγ(+/+) LN cells conferred contact hypersensitivity to WT naïve mice challenged with the hapten. Our findings clearly indicate that, in an experimental mouse model, the FcRγ subunit positively regulates contact hypersensitivity to oxazolone without affecting the contact sensitisation process.

Histone deacetylases inhibitor Trichostatin A ameliorates DNFB-induced allergic contact dermatitis and reduces epidermal Langerhans cells in mice

Chemical allergens of different types, those that cause in humans allergic contact dermatitis or occupational asthma induce in mice divergent immune responses characteristic, respectively, of T-helper 1 (Th1)- and Th2-type cell activation. Such responses are associated with the development of different cytokine secretion patterns by draining lymph node cells (LNC), such that contact allergens stimulate vigorous interferon-gamma (IFN-gamma) production, but little secretion of the Th2 cytokines interleukin-4 and interleukin-10 (IL-4 and IL-10), whereas the converse pattern is provoked by respiratory allergens. Using selective depletion with antibody and complement we have here examined the relative contribution of CD4+ and CD8+ T lymphocytes to the cytokine secretion patterns of draining LNC isolated from mice sensitized to chemical allergens. Mice received repeated topical applications of respiratory allergens, trimellitic anhydride (TMA) or diphenylmethane diisocyanate (MDI), or of contact allergens 2,4-dinitrochlorobenzene (DNCB) or formaldehyde. Thirteen days following the initiation of exposure the production by draining LNC of IL-10, IFN-gamma and mitogen (concanavalin A)-inducible IL-4 was measured by enzyme-linked immunosorbent assay (ELISA) after various periods of culture. It was found that the high levels of IL-4 and IL-10 secretion stimulated by TMA or MDI, and the lower levels of these cytokines induced by DNCB or formaldehyde, were in all cases dependent upon the presence of CD4- cells. In contrast, the comparatively high concentrations of IFN-gamma observed following exposure to contact allergens were found to be derived from CD4+ cells, and in the case of DNCB from CD8+ cells also. The low levels of IFN-gamma induced by treatment with TMA or MDI were associated largely or wholly with CD8+ cells. These data indicate that the type 2 cytokine responses induced to different extents by both contact and respiratory chemical allergens are almost exclusively a function of CD4+ cells, but that IFN-gamma is produced by either CD4+ cells in the case of contact allergens or largely by CD8+ cells in the case of chemical respiratory allergens.

Dendritic cells (DC) are highly specialized antigen-presenting cells located in many nonlymphoid tissues, and Langerhans cells (LC), a specialized form of DC, are found in the skin. LC as antigen-presenting cells play a critical role in the induction of allergic contact dermatitis. LC research is difficult because few LCs can be isolated from human skin, so efforts have focused on obtaining DCs from alternative sources. Mononuclear cells from peripheral blood and CD34+ stem cells from human cord blood and marrow can be induced to form phenotypic and functional DCs, but experiments of this type are expensive and the DC yield is low. We report here the induction of the myeloid leukemia cell line (KG-1) to a DC morphology and phenotype by culturing the cells in a defined cytokine cocktail. Morphologically, the KG-1-derived DCs are large irregularly shaped cells with prominent dendritic processes and hair-like cytoplasmic projections. Phenotypically, the KG-1-derived DCs lack lineage-specific markers, and express MHC class II, costimulatory molecules CD80 and CD86, and CD83. Functionally, KG-1-derived DCs are capable of phagocytosing latex microspheres and are able to induce a potent allogeneic T-cell response. Within the KG-1-derived DCs, a subpopulation maintains the DC phenotype and morphology described above but further develops CD1a+ marker expression similar to that of resident skin-derived LCs. These findings illustrate that phenotypic, morphologic and functional DCs can be derived from the KG-1 cell line.

Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease?