Lupus erythematosus (LE) is an autoimmune disorder associated with specific and nonspecific skin lesions,UV sensitivity,anti-DNA antibodies,and increased interferon (IFN)-α/β production.Although the histopathology of LE is well defined,the pathoge- nesis of skin lesions in LE is still insufficiently understood and does not explain all the clinical aspects of LE. Approximately 55% of patients with systemic LE (SLE) develop clinically distinctive skin lesions, whereas patients with specific LE skin disease, such as subacute cutaneous LE (SCLE) or chronic discoid LE, may never develop systemic manifestations (Dubois and Tuffanelli 1964). LE is considered an autoimmune disease.
Because several autoimmune processes have been described in LE, it also has been assumed that the cutaneous lesions are based on an autoimmune etiology.
Dendritic cells (DCs) of the skin are believed to present relevant autoantigens to T cells, thus starting the unwanted immune responses of CLE. Several studies have investigated and found alterations in DCs in the skin lesions of LE. This chapter covers our current knowledge of the different types of DCs in the pathogenesis of CLE.
An Introduction to Cutaneous DCs
DCs, a growing family of morphologically and functionally defined cells, can be found in small percentages in most organs of the human body and may be further divided into a myeloid and a lymphoid type (Banchereau et al. 1998, Steinman 1991).
DCs are considered to be the most potent antigen-presenting cells (APCs) of the human body and are capable of initiating both primary and secondary immune responses. The term “dendritic cells” was coined in 1973, when Steinmann et al.
(Steinman et al. 1973) described a novel cell population in murine spleen cell suspen- sions. As a rule, T cells require efficient stimulation by APCs to become effector cells and to become involved in pathophysiologic processes. DCs originate from bone marrow precursors and are found in small amounts in most organs of the human body. Studies have shown that DCs can differentiate in vitro from human blood monocytes (Sallusto and Lanzavecchia 1994).
Two major DC types are found in normal human skin: epidermal Langerhans’ cells (LCs) and dermal DCs (DDCs). In contrast, inflammatory skin may harbor consider- able numbers of two additional major types of DCs: inflammatory dendritic epider- mal cells (IDECs) and plasmocytoid DCs (PDCs) (Wollenberg et al. 1996, 2002) (Fig.
20.1). Although LCs, IDECs, and PDCs are well-defined entities, the pool of DDCs probably comprises a heterogenous mixture of different cell types. In addition, any
The Role of Dendritic Cells
in Cutaneous Lupus Erythematosus
Andreas Wollenberg, Stefanie Wetzel
20
Fig.20.1a,b.PDCs,LCs,andIDECs innormal skinandinlesional skinfrompatients withatopicdermatitis,psoriasis vulgaris,contact dermatitis,and lupus erythematosus.Epidermal singlecell suspensions werepreparedfrombiopsies ofnormal skinandoflesional skinfrompatients withatopicder- matitis,psoriasis vulgaris,contact dermatitis,andlupus erythematosus.aSubsets ofDCs (PDCs,IDECs,andLCs) were quantifiedby four-color-staining withHLA-DR(PerCP),lineagemarkers (FITC),CD11c(APC),andCD123 (PE).bTheidentityofPDCs is confirmedby theFSCandSSCcharacteristics knownfromperipheralbloodderivedPDCs (modifiedfromWollenberget al.2002). APCs,antigenpresentingcells;DCs,dendriticcells;FITC,fluoresceinisothiocyanate;FSC,forwardlight scatter;IDECs,inflammatorydendriticepider- malcells;LCs,Langerhans’cells;PDCs,plasmocytoiddendriticcells;PE,phycoerythrine;SSC,sidelightscatter
epidermal nonkeratinocyte without cytoplasmic features such as melanosomes, Bir- beck granules, or Merkel cell granules may be labeled as “indeterminate cells”
(Breathnach 1975). In normal skin, indeterminate cells are rare.
Langerhans’ Cells
LCs were discovered by Paul Langerhans in 1868 when he applied a gold chloride stain to cutaneous tissue. Based on the available knowledge, he considered them to be of neural origin because of their dendritic shape (Langerhans 1868). Later, LCs were recognized as professional APCs capable of initiating primary and secondary responses in the skin immune system (Silberberg-Sinakin et al. 1976). Today, LCs are considered the prototype of immature DCs and represent the only major DC type in the normal human epidermis (Wollenberg and Bieber 2002).
Definition
LCs are defined as bone marrow-derived, epidermally located, dendritically shaped, Birbeck granule-containing APCs that express CD1a and major histocompatibility complex (MHC) class II molecules (Wollenberg and Bieber 2002). They are regarded as the prototype of immature skin DCs and are subclassified as myeloid DCs. LCs are located in the basal and suprabasal layers of the normal, uninflamed epidermis and are regarded as the first barrier of the skin toward the environment. All antigens penetrating the human body as well as locally produced self-antigens have to pass this first immunologic wall of defense. A small percentage of Birbeck granule-posi- tive CD1a-expressing DCs can also be found in the dermis and are considered to be migrating LCs (Meunier et al. 1993).
Distribution
The distribution of LCs in normal human skin is homogenous at a density of approx- imately 450/mm2along the entire body; only the palms and soles show lower cell den- sities of approximately 60/mm2(Berman et al. 1983). In normal human skin, LC fre- quency varies between 0.5% and 2.0% of all epidermal cells (Wollenberg and Bieber 2002).
The number of LCs is decreased in lesional skin of patients with LE compared with their nonlesional or perilesional skin, other inflammatory skin diseases, or normal skin (Bos et al. 1986, Shiohara et al. 1988, Sontheimer and Bergstresser 1982, Wollen- berg et al. 2002). In another study, LCs were found to be reduced only in atrophic areas of the lesions (Mori et al. 1994). In perilesional epidermis, the numbers of CD1a+and HLA-DR+DCs are similar or identical to those in normal skin of healthy individuals (Mori et al. 1994).
Light sensitivity is an important clinical characteristic of LE, which is mirrored by immunohistochemical abnormalities after light irradiation. In the lesional epidermis of patients with light-induced LE and patients with polymorphous light eruption, the number of CD1a+ cells is diminished compared with that in nonirradiated skin (Velthuis et al. 1990). Although a relatively high number of DCs is found in the der-
mis of patients with polymorphous light eruption, only a small number of LCs is seen in light-induced LE lesions (Velthuis et al. 1990).
Other skin diseases with reduced LC numbers include chronic graft-vs-host dis- ease, sarcoidosis, and acquired immunodeficiency syndrome (Aractingi et al. 1997, Belsito et al. 1984, Fox et al. 1983). In graft-vs-host disease, the reduced number of LCs may imply an attack by donor T cells (Suitters and Lampert 1983). The increase in CD1a-expressing epidermal DCs in inflammatory skin diseases such as atopic der- matitis and psoriasis, which has frequently been attributed to LC, is due to IDECs, a non-LC DC population (Wollenberg et al. 1999). Immunosuppressive treatment such as glucocorticosteroids or psoralen-UVA therapy may reduce LC numbers in the epi- dermis (Ashworth et al. 1989, Berman et al. 1983).
Ultrastructure
On electron microscopic analysis, LCs appear as dendritically shaped cells with a clear cytoplasm and a lobulated nucleus. The cytoplasm of LCs contains the specific tennis racket-shaped organelles with the characteristic trilamellar handle known as LC granules or Birbeck granules (Birbeck et al. 1961). Desmosomes and other identi- fying cytoplasmic features such as melanosomes or Merkel cell granules are absent.
Birbeck granules contain the LAG antigen CD207, which is a 40-kDa glycoprotein that can be stained with the monoclonal LAG antibody (Kashihara et al. 1986). The func- tion of the Birbeck granules is still unknown, but they may play a role in the antigen- presenting function of LCs.
Immunophenotype
The immunophenotype of LCs has been studied extensively in normal and inflamed skin by us and others using immunohistochemistry and flow cytometry. It is impor- tant to distinguish between normal and inflamed human skin because the immunophenotype of LC is subject to highly complex regulatory mechanisms: (a) freshly isolated LC change their phenotype (and function) during short-term culture toward highly stimulatory mature DCs, (b) the inflammatory microenvironment as such alters the immunophenotype of the LC in situ, and (c) in some skin diseases, for example, atopic dermatitis, a subset of membrane receptors shows evidence for dis- ease-specific regulation (Wollenberg et al. 1999).
A variety of immunoglobulin receptors, MHC class I and class II molecules, and multiple adhesion molecules are the immunophenotypic hallmark of normal LCs. The nonclassic MHC class Ib molecule CD1a is regarded as the most specific LC marker for normal human skin currently available (Fithian et al. 1981). This does not apply to inflammatory skin conditions because another CD1a-expressing population cell (IDEC) is present in the epidermis and may be mistaken for LCs (Wollenberg et al.
1996).
In the lesional epidermis of LE, a reduction in HLA-DR+DCs compared with CD1a+cells suggests reduced expression of HLA-DR antigen by CD1a+DCs (Mori et al. 1994, Sontheimer and Bergstresser 1982). In vivo studies of LCs in LE show altered morphologic characteristics when examined by cell surface ATPase activity, HLA-DR antigens, and OKT-6 antigens (Sontheimer and Bergstresser 1982). The most impor-
tant of these changes were reduced surface density, loss of dendritic processes, and bizarre shapes (Sontheimer and Bergstresser 1982). The morphologic and density alterations are said not to be associated with a decreased alloantigen-presenting capacity of LCs. Yet, a newer study revealed a diminished T-cell stimulatory capacity in the allogeneic mixed lymphocyte reaction in DC-enriched APCs from patients with SLE compared with healthy individuals (Scheinecker et al. 2001).
Function
After antigen uptake in the epidermis, LCs migrate into the T-cell areas of the lymph nodes, where they present their antigens to the T cells. The considerable changes in the immunophenotype, which occur during this migration in vivo, may be studied in vitro by investigating freshly isolated cells during short-term culture (Romani et al.
1989). Although LCs lose their characteristic BG and CD1a expression, several other surface molecules required for the initiation of immune responses are expressed de novo. This involves the up-regulation of MHC class I and II molecules, of adhesion molecules (e. g., intercellular adhesion molecule-1), and of co-stimulatory molecules such as CD80 and CD86 (Romani et al. 1989, Schuller et al. 2001, Teunissen et al. 1990).
LCs may play a role in the pathogenesis of LE (Bos et al. 1986, Mori et al. 1994, Sont- heimer and Bergstresser 1982), atopic dermatitis (Bruynzeel-Koomen et al. 1986), allergic contact eczema (Silberberg et al. 1973), psoriasis vulgaris (Bos et al. 1983), and mycosis fungoides (Pimpinelli et al. 1994) by presentation of (auto)antigens to T cells.
Outlook
At present, it is not clear which factors reduce the number of LCs in the skin lesions of LE and whether this decrease causes any of the clinical and histologic features of CLE. The possible significance of other DC types remains to be demonstrated.
Dermal DCs
Definition
In 1986, Headington (Headington 1986) described the dermal dendrocyte as DCs of the human dermis. These DDCs appear nowadays as an ill-defined, probably hetero- genous, dendritically shaped cell type within the dermal compartment exhibiting a considerable degree of immunophenotypic and functional heterogeneity. Some aspects of DDCs have been studied, for example, in psoriasis (Nestle et al. 1994), but no general or unifying concept of DDC biology has been established. The role of DDCs in the pathogenesis of inflammatory skin diseases is currently unclear.
Distribution
DDCs are located in the papillary dermis predominantly around the capillary vessels (Teunissen et al. 1997). In lesional dermis of LE, DDCs can be present in higher num- bers than in perilesional dermis or normal skin (Mori et al. 1994).
Ultrastructure
The ultrastructure of DDCs shows a dendritic shape but no Birbeck granules. In other aspects, they mostly resemble IDECs. Whereas DDCs exhibit a dendritic profile in two-dimensional sections, three-dimensional sections reveal the protrusion of thin membrane flaps.
Immunophenotype
Characteristically, DDCs express the blood clotting enzyme factor XIII (Cerio et al.
1990) and several surface markers, such as HLA-DR, but lack the typical LC markers CD1a, Birbeck granules, and ATPase, suggesting a closer relation of DDCs to macrophages than to other DCs (Headington 1986, Teunissen et al. 1997).
Another more detailed study showed that normal skin contains at least three sep- arate populations of DDCs by immunophenotypic analysis using a broad panel of 45 different antibodies based on the expression of blood clotting enzyme factor XIIIa that have distinctive phenotypic markers and immunologic capabilities (Nestle et al.
1993). By triple color staining, the relative distribution of factor XIIIa+DDCs is as fol- lows: subset 1 (65%–70% of total DDCs) expresses neither CD1a nor CD14; subset 2 (15%–20% of total DDCs) expresses CD1a but not CD14, and subset 3 (10%–15% of total DDCs) expresses CD14 but not CD1a.
Function
A major function of DDCs is their capacity to phagocytose large antigen-antibody complexes. This extensive phagocytic function is also demonstrated by their capacity to take up carbon particles, hemosiderin, or melanin and distinguishes them from LCs (Headington 1986).
The function of DDCs in the pathogenesis of LE is unclear. In psoriasis plaques, many DDCs have been identified that were able to induce T helper (Th) 1–type cyto- kines on phytohemagglutinin (PHA) addition, suggesting an important autostimula- tory capacity (Nestle et al. 1994).
Inflammatory Dendritic Epidermal Cells
IDECs are a non-LC DC population that accumulates in the inflamed epidermis and is best characterized in atopic dermatitis skin. These cells have been observed for many years by different research groups (Baadsgaard et al. 1987, Bani et al. 1988, Tay- lor et al. 1991), but ultrastructural and immunophenotypic delineation of LCs and IDECs as two different cell types has been achieved only recently in atopic dermati- tis (Wollenberg et al. 1996).
Definition
IDECs are defined as epidermally located, dendritically shaped cells with moderate CD1a but high CD11b expression that lack the LC-specific Birbeck granules (Wollen-
berg et al. 1996). IDECs may be regarded as a well-characterized subset of indetermi- nate cells. IDECs have been described in many inflammatory skin diseases but do not reach significant numbers in normal human epidermis. The ontogenesis of IDECs is unclear, but there is indirect evidence for a monocyte-derived origin of these cells.
Distribution
Whereas LCs are resident DCs of the epidermis, IDECs are assumed to migrate de novo in the epidermis after chemotactic stimuli (Wollenberg and Bieber 2002). IDECs typically represent 30%–80% of the total epidermal DCs in inflammatory skin dis- eases such as atopic dermatitis, psoriasis, and contact dermatitis but are almost absent in lesional skin of patients with LE (Wollenberg et al. 1996, 2002). The reduced number of LCs and IDECs in LE may result from an attack of cytotoxic T cells, but the exact cause is unknown.
Ultrastructure
The ultrastructure of IDECs shows a clear cytoplasm and a lobulated nucleus but no Birbeck granules, melanosomes, Merkel cell granules, or desmosomes (Wollenberg et al. 1996). Consequently, the immunohistochemical or flow cytometric analysis of epi- dermal DCs for the Birbeck granule–specific Langerin (LAG antigen, CD207) repre- sents an alternative technique to the ultrastructural analysis for delineation of IDECs and LCs (Wollenberg et al. 1996). Close to the cell membrane, IDECs show areas with numerous coated pits and coated and uncoated vesicles. These seem to be fusing with endosomes, thus confirming the endocytotic activity (Wollenberg et al. 2002).
Immunophenotype
The immunophenotype of IDEC has been thoroughly investigated and includes Fc receptors, MHC molecules, adhesion molecules, chemokine receptors, co-stimulatory molecules, the thrombospondin receptor CD36, and the mannose receptor CD206. All IDECs express moderate CD1a but high CD11b and CD11 c levels (Bieber et al. 2000, Wollenberg et al. 1996). Based on the results of these experiments, IDECs resemble the immunophenotype of immature myeloid DCs of the interstitial type (Banchereau et al. 1998). Thus, all essential structures for DC function have been identified on IDECs.
Some key features of epidermal DCs in atopic dermatitis lesions, such as in situ IgE binding and expression of the high-affinity IgE receptor FcεRI, are shared by IDECs and LCs (Wollenberg et al. 1999). The demonstration of IgE molecules on the surface of epidermal DCs, which has initially been attributed to the LC population, is in fact mostly due to the IDECs and the fact that IDECs and not LCs are the relevant FcεRI- expressing epidermal DC population in the epidermis (Wollenberg and Bieber 2002).
The same holds true for the expression of the co-stimulatory molecules CD80 and CD86 (Schuller et al. 2001).
Phenotypic analysis of IDECs in LE is hampered by the striking scarcity of IDECs in LE, which may be due to either lack of selective chemotactic recruitment or IDEC- specific apoptosis in LE lesions (Wollenberg et al. 1996, 2002).
Function
Functional aspects of IDECs have been investigated in atopic dermatitis by different research groups, but there are no data or evidence for a direct functional role of IDECs in LE at this time.
Plasmacytoid Dendritic Cells
Definition
PDCs are a distinct DC subset best characterized in human peripheral blood. These cells produce large amounts of type 1 IFN (IFN-α and IFN-β) on recognition of viral infection and thus are important players in the antiviral defense strategy of the immune system (Cella et al. 1999, Siegal et al. 1999).
PDCs were originally described as plasmacytoid T cells or plasmacytoid mono- cytes (Facchetti et al. 1988) and are identical to the “natural type 1 IFN-producing cell” (Cella et al. 1999, Siegal et al. 1999) described many years ago as a rare CD4+/MHC II+population (Abb et al. 1983, Chehimi et al. 1989, Fitzgerald-Bocarsly et al. 1993). On maturation, this cell type develops characteristic features of DCs (Cella et al. 1999, Siegal et al. 1999).
There are hints that PDCs may be involved in the pathogenesis of LE (Ronnblom et al. 2001), allergy (Jahnsen et al. 2000), viral infections (Feldman et al. 2001), and cancer (Zou et al. 2001).
Distribution
Low percentages of PDCs circulate in the human peripheral blood (<0.3%) and also constitute a cell subset in organized lymphoid tissue. Under special conditions they may accumulate in the skin: PDCs apparently have the capacity to migrate into the inflammatory skin lesions of patients with LE, where they produce and secrete high amounts of type 1 IFN. PDCs are also present in skin lesions of patients with pso- riasis and contact dermatitis, where they were demonstrated as frequently as in peripheral blood (Wollenberg et al. 2002). PDCs were reduced or absent in lesional skin of patients with atopic dermatitis and in normal skin (Wollenberg et al. 2002), whereas the PDC frequency is increased in peripheral blood of patients with atopic dermatitis.
In skin sections of LE, PDCs predominantly accumulate along the dermoepider- mal junction, around hair follicles, and perivascularly (Farkas et al. 2001). Whereas the number of PDCs is decreased in peripheral blood of patients with LE, their num- bers were increased in lesional skin of patients with LE, indicating their capacity to migrate into LE lesions, where they produce and secrete IFN-α (Farkas et al. 2001, Wollenberg et al. 2002).
There is an apparent dichotomy of PDC and IDEC accumulation in skin, which depends on the diagnosis. The extremes are, on the one hand, atopic dermatitis, with many IDECs and few if any PDCs, and, on the other hand, LE lesions, with a pro- nounced infiltrate of PDCs but very few IDECs (Wollenberg et al. 2002).
Immunophenotype
The simultaneous expression of cell surface antigens and intracellular IFN-α in her- pes simples virus-stimulated PDCs was examined by flow cytometry. PDCs were con- firmed to lack leukocyte lineage-specific markers and to express CD4, CD36, and HLA-DR (Svensson et al. 1996). Furthermore, high levels of CD44, CD45RA, and CD45RB and moderate levels of CD40, CD45R0, CD72, and CD83 were detected.
Expression of CD13, CD33, and FcεRI was weak, whereas no CD5, CD11b, CD16, CD64, CD80, or CD86 was detected at all (Svensson et al. 1996). Today it is clear that the immunophenotype of PDCs somewhat resembles that of immunoglobulin- secreting plasma cells. Common gating strategies for PDCs from peripheral blood are based on a class II-positive (HLA-DR+), lineage-negative (CD3–, CD14–, CD16–, CD19–, CD20–, CD56–), interleukin (IL)-3 receptor α-chain-positive (CD123+), CD11 c–cell population (Wollenberg et al. 2002).
In skin sections of patients with discoid LE and SLE, PDCs are easily identified by their high expression of CD123 and HLA-DR and co-expression of CD45RA and CD68 (Farkas et al. 2001). The density of PDCs correlates with the presence of a high number of cells expressing the IFN-α- and IFN-β-inducible protein MxA (Farkas et al. 2001).
Flow cytometric detection of PDCs from different inflammatory skin lesions has recently been described and may be performed by gating strategies for either HLA- DR+, lineage-negative, CD123+, CD11 c-negative cells or for HLA-DR+, lineage- nega- tive, BDCA-2-positive cells (Wollenberg et al. 2002). The BDCA-2 antibody is directed against a recently identified C-type lectin, which is expressed weakly but very specifi- cally on PDCs in peripheral blood and inflamed skin (Dzionek et al. 2001).
Function
PDCs may induce Th1- or Th2-predominated immune responses. In the presence of IL-3 and CD40 ligand, PDCs develop into mature DCs and induce naive T cells to pro- duce Th2 cytokines (Rissoan et al. 1999). On the other hand, virus-triggered PDCs can induce a Th1 response by activating naive CD4+T cells to produce IFN-γ and IL- 10 (Cella et al. 2000, Kadowaki et al. 2000). Thus, PDCs may play an important role in several inflammatory skin diseases.
Patients with LE have high systemic IFN-α levels that are associated with disease activity. PDCs have been proposed to be the main source of IFN-α in LE (Kim et al.
1987). Anti-double-stranded DNA antibodies in combination with immunostimula- tory plasmid DNA mimic an endogenous IFN-α inducer in SLE (Vallin et al. 1999).
PDCs have been found to produce IFN-α in response to plasmid DNA/anti-DNA- antibody complexes (Dzionek et al. 2001).
Considering the many immunoregulatory actions of IFN-α, prolonged endoge- nous production of this cytokine may be an important pathogenic factor in LE.
Although IFN-γ modulates several immunologic processes, including inhibiting the granulocyte macrophage-colony-stimulating factor-induced expression of CD80 on LCs (Ozawa et al. 1996), it is not yet clear whether high levels of IFN-α may also have a direct effect on LCs. Although IFN-α-induced LE has not yet been described, SLE- like syndrome has been reported in a patient with malignant carcinoid tumor under- going IFN-α therapy (Ronnblom et al. 1990).
High IL-10 levels, which may be secreted by PDC-stimulated CD4+T cells, may also prevent the maturation of monocytes into DCs (Allavena et al. 1998).
Outlook on Lupus Erythematosus and DCs
Studies have confirmed the presence of large numbers of T lymphocytes in the der- mis of LE (Synkowski et al. 1983). LCs are diminished and IDECs are almost absent in the epidermis of LE lesions. Instead, PDCs seem to accumulate in lesional epidermis and dermis (Farkas et al. 2001, Wollenberg et al. 2002). In the dermal compartment, DDC numbers are increased (Mori et al. 1994).
In terms of LE pathophysiology, PDCs may be regarded as the most interest- ing DC type because of their accumulation in the skin lesions of LE as well as their capability to produce type 1 IFN. It is unclear whether the decreased num- ber of LCs and IDECs in the inflamed epidermis is causally linked with the epi- dermal accumulation of PDCs. Further investigations are warranted to clarify the complex and difficult interplay of several immunologic factors and cells in the pathogenesis of LE.
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