T Cells and Dendritic Cells in Immuno Mediated Skin Pathology

Karin Loser, Jenny Apelt, Stefan Beissert*

Department of Dermatology, University of Münster, Münster, Germany

1. Introduction

Autoimmune diseases play an increasingly important role in public health systems of the First World since according to the American Autoimmune Related Diseases Association (AARDA) about 20% of the US population is affected by autoimmune symptoms (http://www.aarda.org/ qa_frames.html). Within the most prevalent autoimmune diseases in dermatology are cutaneous as well as systemic lupus erythematosus, bullous autoimmune disorders, dermatomyositis, scleroder-ma, psoriasis, vitiligo, lichen planus, and many more some of which are described throughout this book. Also, autoimmune disorders of the skin can be paralleled by autoimmune symptoms in other organs such as the thyroid gland or the insulin-producing Langerhans' islets of the pancreas indicating that cutaneous lesions can mirror internal autoimmune processes. Cutaneous autoimmune diseases are rarely lethal, however, significant morbidity and disabilities can result. The underlying pathomechanism of loss of immunotolerance against the skin is largely unknown. The current hypothesis is that genetic predisposition and environmental factors participate in the multifaceted aspects of disease development and contribution of susceptibility to autoimmune reactions. Until now most studies on the early events of autoimmune

*Corresponding author.

Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, D-48149 Münster, Germany. Tel.: +49-251-835-8599; Fax: +49-251-835-8579. E-mail address: [email protected] (S. Beissert).

development are restricted to processes after the outbreak of diseases. Of great help are several animal models, mostly of systemic lupus erythematosus, with spontaneous loss of immunotolerance and disease development (Theofilopoulos and Dixon, 1985; Stoll and Gavalchin, 2000). These models and the emerging new 'high thruput' technologies such as expression profiling of whole human and murine genomes will enable us in the future to study all stages of disease progression and to identify early genes or proteins that are already expressed without overt symptoms. In addition, these technologies will lead to the detection of new drug targets, which will hopefully result in the development of new treatment regimes that are specific, effective, and safe to use.

2. Self-reactive T cell subsets

Originally the immune system has evolved to combat infections. Accordingly, immunocompetent cells can be specifically activated by microbial antigens via Toll-like receptors (TLR). Furthermore, activation of immune responses needs to be controlled or 'switched off after accomplishment of its effector functions. Based on experimental data several models have been proposed on how the immune system works: The so-called self/non-self model predicts that the immune system is based on its ability to discern between self and foreign constituents thus, allowing the subsequent destruction of foreign pathogens. The infectious non-self model (danger model) adds the aspect that activation of antigen-presenting cells (APC), generally the first immunocytes to be involved in a primary immune response, via TLR's and costimulatory molecules is a necessary event in initiation of an immune response. APCs are not antigen-specific and present a variety of different antigens. The danger model proposes that these danger signals supplied by tissues or cells injured by trauma, pathogens, toxins, etc. activate the APCs possibly in a tissue-dependent manner (Matzinger, 1994). APCs activated in the vicinity of danger signals become mature, develop potent T cell stimulatory capacity such as the high expression of MHC as well as costimulatory molecules, and migrate from the site of danger to the draining lymph node. There they encounter naive T cells, which can be activated in a MHC class I- or MHC class II-re-stricted fashion. Upon stimulation, these effector cells must be able to recognize the antigenic constituents along with the danger signals that mark the presence of an invading pathogen. Complex interactions of a vast array of cell-types and cell-signaling processes along with the specific onto-logical development of two of the major cell-types involved in the immune process, the T- and B cells, are necessary to achieve this goal.

During intrathymic development, somatic selection processes allow a fraction of T cells to differentiate, mature, and to emigrate into the circulation. It is the current belief that auto-antigens play an essential role in establishing the repertoire of mature T cells. In the first phase of T cell selection within the thymus termed 'positive selection', T cells with a sufficient affinity to self-antigens bind to these antigens, which are expressed on thymic epithelial cells, and become selected for survival whereas the remaining T cells die by neglect via apoptosis. In the second phase termed 'negative selection', T cells with an excessive affinity to self-epitopes are once again deleted from the system via the apoptotic pathway. These developmental processes have been described in the cortex and the medulla of the thymus. However, recent experimental evidence questions such a strict compartimentali-zation in the thymus (Derbinski et al., 2005). A gene that appears to play an important role in regulating antigen expression on thymic epithelial cells is AIRE (autoimmune regulator) since AIRE

knockout mice suffer from a severe form of auto-immunity (Johnnidis et al., 2005; Kuroda et al., 2005; Villasenor et al., 2005). In certain forms of human autoimmune diseases mutations in the AIRE gene have been detected suggesting that, indeed, AIRE plays an important role in autoimmune development (Cavadini et al., 2005).

The remaining T cells then constitute the T cell population enabling the recognition and combat of foreign pathogens. Some are polyactive and can recognize self-antigens as well as foreign antigens (Joshi et al., 2001; Martin et al., 2001). A similar mechanism for the selection of self-reactive B cell precursors within the bone marrow has been postulated although this pathway has not been extensively investigated. Yet under the conditions prevailing in the thymus, not all auto-antigens are presented and T cells possessing high avidity to auto-antigens can 'slip' through the selection process. In contrast to the longstanding dogma that auto-reactive T cells are completely removed from the system via clonal deletion, new studies on T cell receptor rearrangements revealed that in fact auto-reactivity is perhaps necessary for immune functions as low grade exposure to auto-antigens within the periphery seem to be required for T cell maintanence (Anderton and Wraith, 2002). As these T cells are per definition auto-reactive it is essential to differentiate between autoimmunity and autoimmune disease in this context (Ermann and Fathman, 2001).

In dermatology, auto-reactive T cells have been also detected in the peripheral blood of patients suffering from pemphigus vulgaris or bullous pe-mphigoid, both disorders are acquired bullous autoimmune diseases (Budinger et al., 1998; Hertl and Veldman, 2003; Veldman et al., 2004b). In pemphigus vulgaris the auto-antigen is desmoglein 3 (Dsg 3) a hemidesmosomal protein, which is important for the firm adhesion of keratinocytes. Stimulation of PBMC with Dsg 3 revealed the presence of Dsg 3-reactive T cell clones. However, in pemphigus vulgaris auto-antibodies to Dsg 3 are crucial and pathogenic, because they induce loss of keratinocyte adherence as well as blister formation. How do, therefore, auto-reactive T cells participate in disease development? It might be possible that Dsg 3-reactive T cells could provide T cell help to B cells for the development of plasma cells and subsequently anti-Dsg 3 auto-antibody production. Similarly, in patients suffering from bullous pemphigoid BP180-reactive T cell clones were identified in the PBMC fraction of the patient's blood samples. Interestingly, BP180-reactive T cells were also detectable in HLA-matched individuals without disease (Budinger et al., 1998). These findings suggest that auto-reactive (effector) T cells are present in the periphery of patients suffering from autoimmune skin disorders and that these cells are present without onset of overt disease.

An important cellular mechanism for the inhibition of autoimmunity is the active suppression of auto-reactive effector T cells by regulatory ('suppressor') T cells (Sakaguchi et al., 2001; Sakaguchi, 2003; Shevach, 2002; Shevach et al., 2001). Suppressor T cells have been described already several decades ago, however, the lack of molecular markers to further characterize these cells has drawn their existence into question for a long time (Gershon et al., 1972, 1974; Gershon and Kondo, 1970; Janeway, 1988). While studying colitis development in adoptively transferred SCID mice Sakaguchi et al. (1995) have detected CD4 + CD25 + T cells with potent suppressor function (Sakaguchi et al., 1995). Since then the term regulatory T cells (Treg) has been coined although the main function of these cells is to suppress the activation and proliferation of auto-reactive effector T cells. CD4+CD25 + T cells represent one subset of regulatory T cells, which make up about 6-9% of the CD4+ T cell population. This subset has been detected in humans and rodents with similar suppressor function (Sakaguchi et al., 1995; Jonuleit et al., 2001; Dieckmann et al., 2001). Treg have to be activated via the T cell receptor to exert their inhibitory function. This activation can be achieved by exposure to specific antigens or mi-togenic antibodies. Once activated Treg suppress the activation of effector T cells in an antigen nonspecific fashion (bystander suppression) (Thornton and Shevach, 2000; Thornton et al., 2004). In contrast to effector T cells, Treg are anergic upon activation. The molecular mechanisms that mediate suppression are incompletely understood. In vitro investigations indicate a cell contact-dependent form of suppression, which is mediated in part by the expression of granzyme B, modulation of tryptophan metabolism and perhaps killer C-type lectins expressed on the surface of Treg (Fallarino et al., 2003; Gondek et al., 2005). Coincubation of Treg and effector T cells results in the downregu-lation of IL-2 expression in the latter. IL-2 appears to be an important growth factor for Treg and perhaps the high expression of CD25 reflects this need for IL-2 (Malek et al., 2002). Besides CD25 a number of surface molecules, which are associated with Treg have been identified such as intracellular cytotoxic T lymphocyte activation antigen 4 (CTLA-4; CD152), neuropilin-1 (Nrp-1), CD45RBlow, glucocorticoid-induced TNF family related receptor (GITR), the chemokine receptors CCR4 and CCR8, CD62L (L-selectin), LAG-3, and integrin aEJS7 (CD103) (Read et al., 1998, 2000; McHugh et al., 2002; Lehmann et al., 2002; Huang et al., 2004; Iellem et al., 2001; Salomon et al., 2000; Takahashi et al., 2000; Bruder et al., 2004). Some of these molecules have been shown to be important for the suppressor function of Treg.

Treg develop in the thymus and the transcription factor that controls lineage commitment is Foxp3 (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003). Foxp3 is highly expressed in CD4 + CD25 + T cells in humans and rodents. In mice, deletion of Foxp3 results in loss of Treg and development of severe lymphoproliferation. In humans, the IPEX syndrome has been associated with a mutation in the Foxp3 gene resulting in a multi-organ inflammatory disorder (Bennett et al., 2001; Wildin et al., 2001). Overexpression of Foxp3 conveys suppressor function to nai've T cells, which can be used for immunotherapy of ongoing systemic autoimmunity in mice (Loser et al., 2005). Using a Foxp3-specific antibody, Foxp3+ cells can be detected in situ in the T cell area of human lymph node tissue demonstrating their distribution pattern (Fig. 1).

Another subset of regulatory T cells is T regulatory type 1 cells (Tr1), which are characterized by the expression of high amounts of IL-10 (Foussat et al., 2003; Groux et al., 1997; Kemper et al., 2003). Tr1 cells appear to play a role in the inhibition of colitis in animal models. In humans, however, there is recent evidence that Tr1 cells play a role in controlling cutaneous autoimmune disorders. Dsg 3-specific Tr1 cells were identified in

humans, which may maintain and restore natural tolerance against Dsg 3 (Veldman et al., 2004a). Dsg 3-responsive IL-10-secreting Tr1 cells were isolated from healthy carriers of the pemphigus-associated HLA class II alleles, DRB1*0402 and DQB1*0503, but were only rarely detected in pemphigus patients. In addition, it was shown that growth of Dsg 3-responsive Tr1 cells requires the presence of IL-2, and that they exert their Dsg 3-dependent inhibitory function by the secretion of IL-10 and TGF-b. Thus, these Tr1 cells may be critically involved in the maintenance and restoration of tolerance against Dsg 3.

Besides CD4+ T cells, CD8 + T cells with suppressor activity have also been described, which were able to inhibit the development of experimental allergic encephalomyelitis (EAE) (Jiang et al., 1992). CD8 + suppressor T cells abrogated the activation of encephalitogenic CD4+ Th1 cells. However, CD8+ suppressor T cells required priming during the first episode of EAE to regulate CD4+ T cells triggered by secondary MBP stimulation in vivo. Since the suppressor function of CD8+T cells could be blocked by antibodies to the MHC class 1b

Qa-1 molecule it was proposed that perhaps the non-classical MHC class 1b pathway plays a role in restricting the suppression mediated by CD8 + T cells. Indeed, Qa-1_/_ mice display severe EAE, which is associated with the escape of Qa-1_/_ CD4+ T cells from CD8+T cell suppression (Hu et al., 2004). Qa-1 is of limited polymorphism and is expressed on activated but not resting T cells. Qa-1 has the potential to present foreign and auto-antigens to CD8+T cells, indicating that Qa-1 may serve as a target antigen for CD8+T cells. Because Qa-1 auto-antigen complexes can bind to CD94-NKG2 receptors on CD8+T cells, CD8+ suppressor T cells may regulate T cell responses via CD94-NKG2 receptors.

Since several subsets of Treg have been described their function was recently determined in inflammatory skin diseases. In psoriasis, it was found that a CD4+ T lymphocyte subpopulation in peripheral blood, phenotypically resembling Treg (CD25hlgh, CTLA-4+, Foxp3high) is deficient in its suppressor activity. This was associated with accelerated proliferation of CD4+ responder T cells in psoriasis (Sugiyama et al., 2005). In addition, CD4 + CD25 +

T cells were found significantly increased in patients with atopic dermatitis compared with asthmatic patients or nonatopic healthy control subjects. These cells effectively suppressed proliferative responses of CD4+CD25" cells after anti-CD3 stimulation. In contrast, after stimulation with staphylococcal enterotoxin B CD4 + CD25 + cells were no longer anergic and had lost their suppressive function (Ou et al., 2004). This indicates that patients with atopy have significantly increased numbers of peripheral blood Treg cells with normal immunosuppressive activity. However, activation of innate response pathways induced after stimulation with staphylococcal antigens, resulted in loss of suppressor activity in these Treg. These data suggest a novel mechanism by which staphylococci may augment T cell activation in atopic patients. Besides their role in inflammatory skin disorders Treg appear to play a role in cutaneous malignancies. It was recently shown that cutaneous T cell lymphoma (CTCL) cells adopt a Treg phenotype expressing CD25/CTLA-4 and Foxp3 and secreting IL-10 and TGF-b (Berger et al., 2005).

Taken together, effector as well as regulatory T cells can respond to self-antigens and are therefore per definition both auto-reactive. However, once activated these T cell populations exert completely different functions. Whereas effector T cells can induce pathology upon stimulation, activated Treg are able to suppress the proliferation of these effectors resulting in inhibition of autoimmunity. Thus, the presence and homeostasis of especially auto-reactive Treg is required for the maintenance of tolerance to self. In this context, a more semantic difficulty becomes apparent since actually both T cell subpopulations are per se effectors, which induce or suppress immune responses upon activation.

3. Dendritic cells—key regulators of immune responses

As described above auto-reactive effector T cells are present in both rodents and humans before the overt onset of disease (Anderson et al., 2001; Yan and Mamula, 2002). These auto-reactive effectors are normally not activated as effective checks and balances such as active suppression by Treg or antigen-presentation in the absence of costimula-tion prevent their stimulation and the subsequent induction of autoimmune responses. This raises the question by which mechanisms autoreactive effector T cells become activated resulting in the breakdown of immunological self-tolerance. Since APC are specialized in activating T cells, they can logically be implicated in the stimulation of auto-reactive effector T (and B) cells. Among the different APC subsets, dendritic cells (DC) are the most potent professional APC known today (Bancher-eau and Steinman, 1998). In the periphery, DC built a network of sentinel cells that untiringly sample antigens. They are extremely adept in antigen uptake as they are equipped with the means to ingest antigens by a manifold of different mechanisms, e.g. via pinocytosis, macropinocytosis, mannose receptor-mediated endocytosis, and phagocytosis. The antigenic material is internalized, processed, and loaded onto the MHC class I or MHC class II molecules. DC play a key role in antigen translocation as antigen transport from periphery to lymph nodes is primarily achieved by DC. Intrinsic and extrinsic signals, such as trauma or infection, induce the release of various cyto-kines, like tumor necrosis factor (TNF) alpha, which constitute a 'danger' signal for DC (Matzinger, 1994). These danger signals induce profound morphological and physiological changes in DC as they begin to migrate from the periphery to the regional lymph nodes. They simultaneously mature and switch from an antigen uptake mode to an antigen presentation mode. The antigen presentation mode is characterized by upregula-tion of the various costimulatory and adhesion molecules required for effective T cell stimulation along with an intracellular redistribution of MHC molecules, which results in an increase of antigen-laden MHC on the cell surface. Upon contact with T cells, the very high density of MHC molecules on the cell surface at this stage makes DC extremely well equipped to present antigens to T cells via antigen-specific TCR engagement.

However, not only the TCR/MHC engagement (signal 1) is required for effective antigen presentation, but also costimulatory molecules (signal 2) need to be present to elicit an immune response. Among these costimulatory molecules one receptor/ligand pair plays a prominent role in this context and that is the CD40 receptor on DC and its ligand CD154 (CD40L) on T cells. Ligation of this receptor pair leads to activation signals both in DC as well as in T cells (Brenner et al., 1997). Furthermore, ligation of CD40 provides one of the strongest activation signals for DC resulting in the production of IL-12 and tipping the T cell responses toward the Th1-type (Cella et al., 1996). As CD40/CD154 interaction is also crucial for B cell stimulation and immunoglobulin class switching, this suggests that CD40 engagement plays an essential role in the communication between DC, T and B cells. Therefore, it has been proposed that CD40/CD40L cross-linking contributes to the generation of autoimmune responses. DC can prime both CD4+ or CD8 + T cells and B cells independently of each other (Dubois et al., 1999; Ridge et al., 1998). They consequently not only play a role in initiating cytotoxic immune responses but also play a role in the regulation of humoral responses.

On the other hand, DC also play a contrasting and yet pivotal role in promoting tolerance. During T cell development, thymic DC are involved in processes for deleting autoreactive T cells (Anderson et al., 1996). In addition, it was shown that in particular DC of the immature phenotype are responsible for downregulating immune responses. Although mature DC do not seem to be affected by IL-10, the presence of IL-10, a Th2 promoting cytokine, during the initial stages of activation of DC causes a reduction in the maturation process of DC and can induce tolerance (Steinbrink et al., 1997, 2002; Enk et al., 1993). This includes the downregulation of inflammatory cytokines such as IL-6, IL-1b and TNFa along with a downregulation of MHC class II molecules and various costimulatory as well as adhesion factors. Jonuleit et al. (2000), reported that repeated stimulation of T cells with immature DC results in the generation of regulatory IL-10 producing CD4+ CD25 + T cells which in turn promote tolerogenicity. Interestingly, two reports in which hemaglutinin or ovalbumin function as model self-antigens of the periphery, revealed that presentation of auto-antigens via DC are a prerequisite for CD4 and CD8 mediated tolerance (Adler et al., 1998; Kurts et al., 1998). In mice, DC that were generated in the presence of TNF a and pulsed with auto-antigenic peptide ameliorated experimental autoimmune encephalo-myelitis already upon the first injection (Menges et al., 2002). TNF a-treated DC expressed MHC class II as well as costimulatory molecules, but produced significantly higher concentrations of IL-10 compared to CD40L-treated DC. In two volunteers, injection of immature DC pulsed with influenza matrix peptide (MP) led to a specific inhibition of MP-specific CD8 + T-cell effector function (Dhodapkar et al., 2001). Additionally, it was demonstrated by the same investigators that application of immature DC induced hapten-specific CD8+ regulatory T cells in vivo (Dhodapkar and Steinman, 2002). More recently DC have been shown to be able to directly expand CD4+CD25 + Treg (Yamazaki et al., 2003). These data suggest that DC might be a useful tool under certain conditions for the therapeutic downregulation of antigen-specific immunity.

In the case of autoimmunity, players in the immune system go astray, the most well known being dysregulated T- and B cells. Normally, these cells are held in abeyance by the simple lack of the costimulatory molecules in the microenvironment necessary to stimulate them (Steinman and Nussenzweig, 2002). T cells and in particular CD8+ but also CD4+ T cells are the effector cells that attack or activate target cells and elicit tissue destruction in this scenario. B cells produce large quantities of antibodies and various mechanisms can lead to tissue injury, e.g. the formation of large deposits of immune complexes in the kidney often leading to nephritis and tissue damage. Furthermore, auto-antibodies can initiate cytolysis of these cells or opsonize them for elimination via phagocytosis. Activated B cells also play another role in the elicitation of autoimmune responses, namely they themselves can function as antigen presenting cells that present auto-antigens to the relevant T cells and contribute to epitope spreading. In the past few years, evidence has accumulated, that DC play a much larger role in autoimmune responses than originally thought.

DC are accomplices in the elicitation of autoimmunity in that they play a pivotal role in the activation of both T- and B cells and by delivering the auto-antigens with the appropriate factors necessary to elicit an immune response. Because DC cannot discriminate between the antigens they capture at the site of inflammation and will thus inadvertently present auto-antigens along with pathogen-specific antigens, a complex interplay of factors has evolved as a necessity for the prerequisite maturation of DC needed for the activation of naive T cells. DC react differently to dying cells as necrotic cells elicit other responses than apoptotic cells (Sauter et al., 2000). DC promote stimulatory responses from CD4+ and CD8 + T cells following exposure to necrotic cells (cell death due to trauma or infection), whereas DC that have had contact to apoptotic cells (physiologic cell death) do not.

An emerging factor in the induction of autoimmune disease is the uptake and processing of autoantigens originating from apoptotic cells. This model has received increased attention as latest evidence seems to support the idea that the self-determinants involved in autoimmune responses are supplied by dying cells as the reservoir for auto-antigens. Physiologic apoptosis is generally considered to promote tolerogenicity and not au-toimmunity. Apoptosis usually occurs sporadically and asynchronously within tissues with no proin-flammatory cytokines present. Under steady state conditions, T cells presented with autoantigens by DC either become anergic or are deleted. Yet, during the apoptotic process, many proteins and other cell constituents are uniquely modified which can expose cryptic epitopes or even generate novel autoantigens (Rosen and Casciola-Rosen, 1999). Antiphospholipid antibodies are found in some patients afflicted with SLE. Phosphatidyl-serine is generally located on the inner surface of the plasma membrane yet it is exposed to the outside on the surface of apoptotic blebs thus making it accessible as an epitope (Casciola-Rosen et al., 1996). Other modifications are the apoptosis-specific proteolytic cleavage and/or phosphorylation of the substrate molecules. Defects in apopto-tic cell clearance also seem to play a central role. Macrophages and DC scavenge apoptotic cells, ingest these cell components and present them to

T cells via MHC complexes thus initiating the signaling cascade leading to autoimmune disease. Furthermore, increased or aberrant apoptotic rates have been reported in tissue-specific as well as systemic autoimmune disorders. At this point it is important to note that exposure to high numbers of apoptotic cells is able to mature DC even in the absence of further inflammatory signals and this may explain why the threshold for an autoimmune response is reached (Rovere et al., 1998a,b).

This is especially interesting when microbial insult leads to the generation of an immune response to such antigens. Emerging evidence also points to a role of pathogens in the modulation of DC function. The infectious agents associated with autoimmune disease are diverse and include the involvement of streptococci in rheumatic fever, Borrelia burgdorfii in Lyme arthritis, Coxsackie virus in myocarditis, Cytomegalie virus or rubella in type 1 diabetes, etc. (Benoist and Mathis, 2001). Although, only circumstantial evidence is yet available and the underlying mechanisms as to how they set off disease are unclear, it intriguingly incriminates APC in this context. One possibility is that APC present self-determinants, a simple bystander activation process takes place and non-specifically activates the cells of the immune system in the close vicinity or within the lymph node during the immune response to the microbes. The process of 'T cell epitope mimicry' has also been proposed to be a major factor in the proclivity of microbial infection to elicit processes leading to autoimmune diseases (Benoist and Mathis, 2001). In this case, as antigen recognition/specificity by T cells can be degenerated, T cells can recognize autoantigens that are similar to those of the pathogen. A report by Ludewig et al. (2001) revealed that stringent threshold levels not only of antigen load but also of the duration of (auto)an-tigen presentation determines whether stimulation of self-reactive CTLs with subsequent autoimmu-nity ensues or not in this context, the maturation status of the DC is of prime importance: immature DC have a high turnover rate of MHC/antigen complexes on their cell surface whereas mature DC downregulate turnover rates and stabilize the presence of the antigen/MHC complex on the surface of the DC (Cella et al., 1997).

3.1. Dendritic cells in mixed connective tissue disease

Mixed connective tissue disease (MCTD) is an autoimmune overlap syndrome that shows aspects of lupus erythematosus, scleroderma, and der-matomyositis. We were interested in investigating the role of epidermal APC, the Langerhans cells (LC), in regulating cutaneous immunity. In the skin LC express the CD40 receptor, the CD40L co-receptor can be detected on activated keratin-ocytes, to address the relevant role of CD40-CD40L(CD154)-signaling during the induction of immune responses, transgenic (tg) mice were generated that overexpress the CD40L on LC neighboring keratinocytes (Mehling et al., 2001). Interestingly, these CD40L tg mice show almost complete depletion of epidermal LC and increased numbers of activated DC in skin-draining lymph nodes. Additionally, CD40L tg mice spontaneously develop autoimmune dermatitis, lymphadenopa-thy, splenomegaly, lung fibrosis, and nephritis (Mehling et al., 2001). Anti-nuclear antibodies are detectable within the serum of these mice and indirect immunofluorescence studies show that these autoantibodies bind to the skin. CD40L tg mice lose weight as disease progresses and have a significantly reduced life expectancy. These results point to an inherent role of aberrantly activated LC in breaking self-tolerance resulting in the development not only of cutaneous but also of widespread systemic autoimmunity resembling MCTD.

correlating results in the human counterparts (van Blokland et al., 2000b). A differentiation was made between patients suffering from Sjogren's syndrome and those with focal sialoadenitis without the clinical criteria of Sjogren's syndrome.

3.3. Dendritic cells induce psoriasis

Psoriasis in one of the most common autoimmune diseases affecting the human skin (Lebwohl, 2003). Similar to other forms of autoimmunity psoriasis results from a self-perpetuation of auto-reactive T cells (Lew et al., 2004). Recently, it was demonstrated in a xenograft model of human psoriasis that plasmacytoid predendritic cells (PDC) are able to initiate lesion formation via secretion of interferon(IFN)-a (Nestle et al., 2005). PDC are a rare cell population in the peripheral blood and secondary lymphoid organs characterized by plasma cell-like morphology and a unique surface phenotype (Liu, 2005). Blocking IFN a or inhibition of PDC to produce IFN a abrogated psoriasis development. PDC were also found in human psoriatic skin lesions. Interestingly, IFN a reconstitution experiments suggested that PDC-derived IFN a is necessary to induce psoriasis development in vivo. These data suggest an innate immune pathway for the initiation of cutaneous inflammatory autoimmune disorder.

Acknowledgments

3.2. Dendritic cells in Sjogren's syndrome

Sjorgen's syndrome is another autoimmune disorder affecting the skin and mucous membranes in which DC play an essential role in course of the illness. This disease is characterized by lymphocytic infiltrates in the salivary and lacrimal glands resulting in the loss of function. To this end, van Blokland et al. (2000a) used the NOD and MRL/lpr mouse models to particularly focus on APC in the pathogenic process. Increased numbers of DC were detected in the submandibular glands of NOD/SCID mice prior to lymphocytic infiltration and the outbreak of sialoadenitis in these mice. The same group found

Due to space restrictions many publications could not be referenced, we apologize to their authors. This work was supported by the German Research Association (DFG) grants BE 1580/6-2, BE 1580/ 7-1, SFB 293 B8, and a grant from the Interdisciplinary Clinical Research Center (IZKF) Münster, Germany.

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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

CHAPTER 3

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