Immune response to skin antigens modified by ultraviolet (UV) radiation is currently proposed as the pathomechanism for skin lesions in lupus erythematosus (LE) (Cas- ciola-Rosen and Rosen 1997, Norris 1993, 1995, Norris et al. 1997). Cellular apoptosis brought about by UV radiation is believed to have an important role in inducing and perpetuating the disease, but the in vivo role for apoptosis in cutaneous LE (CLE) remains unclear (Orteu et al. 2001). A multistep model has been proposed in which the first step is the release of soluble proinflammatory epidermal and dermal media- tors, which may be genetically regulated. A particular allele of interleukin (IL) 1 has been associated with systemic LE (SLE) severity and photosensitivity (Blakemore et al. 1994), and a high tumor necrosis factor (TNF)-α response is linked to the HLA- DR3 gene (Wilson and Duff 1995, Wilson et al. 1993). The HLA-DR3 gene is reported to associate with the most photosensitive variant of CLE, subacute CLE (SCLE) (Callen and Klein 1988, Sontheimer et al. 1982), also in Scandinavia (Johansson- Stephansson et al. 1989). The second step is increased expression of cellular adhesion molecules (CAMs) on keratinocytes and on subepidermal endothelial cells. The increases in cytokine and CAM expression direct cytotoxic T cells to the skin. Nuclear antigens such as Ro/SSA, translocated to the keratinocyte surfaces, possibly involving the heat-shock proteins, are then targeted by circulating anti-Ro/SSA antibodies and cytotoxic T cells (Bennion and Norris 1997, Norris 1993, 1995, Norris et al. 1997).
T Lymphocytes
Antigen-stimulated, so-called armed T cells are generally of CD8 (mainly “killer” T cells) or CD4 (T helper [Th]) type. CD8 cells recognize peptides bound to major his- tocompatibility complex (MHC) class I molecules. The membrane-bound receptor on these cells is a ligand for Fas and is involved in apoptosis. CD4 cells recognize the antigen-MHC class II complex. They are further subdivided into two groups by the cytokine profile they produce. Type 1 T-helper (Th1) cells secrete IL-2, IL-12, and interferon (IFN)-γ. They are involved in cell-mediated immune reactions and stimu- late B cells to produce complement-fixing antibodies. Type 2 T-helper (Th2) cells secrete IL-4, IL-5, IL-6, and IL-10 and are involved in IgE-mediated allergic reactions and the production of non-complement-fixing antibodies (Janeway and Travers 1994). In addition, there are also so-called Th0 cells producing IL-4 and IFN-γ. Also, IL-10, a cytokine that has down-regulating properties, is produced by both Th1 and Th2 cells (Stevens and Bergstresser 1998). In normal human skin, some T cells are
The Role of T Cells and Adhesion Molecules in Cutaneous Lupus Erythematosus
Filippa Nyberg, Eija Stephansson
E. Stephansson has also published articles under the author name E.A. Johansson
19
found, mostly around dermal postcapillary venules and appendages. Most of them express theαβ T-cell antigen receptor, and vβs 1, 7, 14, and 16 are enriched compared with circulating T cells (Sugerman and Bigby 2000).γδ T cells have cytotoxic poten- tial and are present in murine epithelia with a possible role in immunosurveillance of epithelia but are not found in normal human skin (Alaibac et al. 1992, Bos et al. 1990).
Based on CD45 isoforms, T cells can be divided into CD45RA+ (suppressor inducer) cells, with functional characteristics of naive T lymphocytes, and CD45RO+ (helper inducer) cells, with functional characteristics of memory T cells, responding to recall antigens (Kristensson et al. 1992, Morimoto et al. 1985a, b). Also, CD31 cell surface antigen (platelet endothelial adhesion molecule-1) has been shown to define naive T cells (Morimoto and Schlossman 1993, Torimoto et al. 1992). UVB irradiation has been shown to recruit nonactivated CD4+CD45RO+T cells into both the epider- mis and the dermis. Antigen presentation to these cells is thought to result in activa- tion of the suppressor pathway (Di Nuzzo et al. 1998). Contrary to this, UVA irradia- tion has been shown to deplete skin-infiltrating T cells via apoptosis (Morita et al.
1997).
T Lymphocytes in Cutaneous Lupus Erythematosus
The model of antibody-dependent cellular cytotoxicity fits well with Ro/SSA anti- body-associated forms of LE, such as SCLE, neonatal LE, and possibly SLE. However, non-antibody-associated forms of CLE, such as chronic CLE (CCLE), fit less well, although low levels of anti-Ro/SSA antibody production have been noted in patients with CCLE (Lee et al. 1993). Furthermore, polyclonal B-cell activation was detected in serum from patients with discoid LE (DLE) compared with healthy controls (Wangel et al. 1984). Instead, it has been suggested that autoantigen-specific lymphocytes are involved in the pathogenesis of skin lesions of CCLE with a delayed-type hypersensi- tivity reaction (Sontheimer 1996, Volc-Platzer et al. 1993). Several authors have found higher numbers of CD4 than CD8 cells in the dermal inflammatory infiltrate in CLE (Hasan et al. 1999, Jerdan et al. 1990, Tebbe et al. 1994, Velthuis et al. 1990, Viljaranta et al. 1987). Monoclonal CD4 antibodies have been successfully used to treat severe CLE (Prinz et al. 1996).
A mixed cytokine pattern with IFN-γ-induced intercellular adhesion molecule-1 (ICAM-1) expression, as in Th1-type response, and a Th2-type response with signif- icant IL-5 production and detectable IL-10 production was found in LE lesions (Stein et al. 1997). The authors found no differences in cytokine profiles between LE sub- groups.
Recent reports indicate a central role for the T-cell receptor on autoreactive T cells in SLE, and a genetic background was proposed (Tsokos and Liossis 1998). The sig- nificance of these findings to CLE is not known at present. Vβ8.1 CD3+cells were ele- vated in skin lesions from CCLE and acute CLE (ACLE) compared with psoriasis and atopic dermatitis, with a higher percentage of vβ8.1 and vβ13.3 in skin lesions from CCLE than from ACLE. There was also a skew toward these vβ types in the peripheral blood (Furukawa et al. 1996, Werth et al. 1997). This is consistent with an antigen- driven response. Sequencing of T-cell receptor clones from infiltrates in skin of patients with SLE further supports antigen-induced clonal accumulation (Kita et al.
1998). The chemokine receptor CXCR3 is expressed by CD45RO+(helper inducer) cells, preferentially by the Th1 subset and by natural killer cells. In a recent study, CXCR3 was expressed by both CD4+and CD8+dermal T cells in various inflamma- tory skin conditions, including CLE. CXCR3-activating chemokines CXL9, CXL10, and CXL11 were expressed at the dermoepidermal junction at sites where macrophages and lymphocytes were in close contact with the epidermis. The distri- bution patterns were different, with a patchy pattern and distribution around hair fol- licles in CLE. A strong correlation with ICAM-1 and HLA-DR expression was seen.
IFN-γ induces CXR3-activating chemokines, ICAM-1, and HLA-DR (Flier et al. 2001).
A specific subset ofγδ T cells has been observed in the epidermis of CCLE lesions but not in the blood, and the authors proposed that these cells were preferentially expanded within the epidermis (Volc-Platzer et al. 1993).γδ T cells recognize heat- shock proteins, and response by these cells to heat-shock proteins released from UV- injured keratinocytes has been suggested as a mechanism in UV-induced LE (Sont- heimer 1996). In SLE, numbers ofγδ T cells were lower in peripheral blood than in healthy controls, but the percentage ofγδ T cells in clinically healthy skin of patients with SLE was twice as high as in healthy persons. A correlation with SLE activity was found (Robak et al. 2001). However, other authors did not findγδ T cells in the epi- dermis of patients with CLE (Fivensson et al. 1991), and all our biopsies from lesional skin were negative (F. Nyberg, E. Stephansson, unpublished observation).
A decreased number of epidermal Langerhans’ cells is found in human CLE lesions (Andrews et al. 1986, Sontheimer and Bergstresser 1982) and during the induction of cell-mediated hypersensitivity reaction (Mommaas et al. 1993). Dermal dendritic macrophages (CD36+), which infiltrate the human dermis after UVB irradi- ation (Meunier et al. 1995), associate with CD4+cells and are suggested to be patho- genically important in CLE lesions (Mori et al. 1994). They also activate human CD45RA+(suppressor inducer) cells (Baadsgard et al. 1988). A major proportion of inflammatory cells were CD45RA+cells in photo-provoked and spontaneous CLE lesions, but not in polymorphous light eruption (PLE); in serial biopsies, CD45RO+ (helper inducer) cells tended to infiltrate the epidermis and subepidermal area ear- lier than CD45RA+and CD31+cells (Hasan et al. 1999). The authors concluded that CD45RA+cells may have a role in maintaining the CLE skin lesions by their ability to induce CD8+cells. CD8+cells have been found to mediate delayed-type hypersensi- tivity reactions (Kalish and Askenase 1999).
The binding of co-stimulatory molecules (B7 family) on antigen-presenting cells to their counterreceptors CD28 and CTLA-4 on T cells results in activated Th or cyto- toxic T cells, which is required to optimally activate T cells and prevent antigen-spe- cific tolerance (June et al. 1994, Werth et al. 1997). In situ expression of B7 and CD28 was examined in active skin lesions of patients with SLE, SCLE, and CCLE by immunohistochemical analysis and reverse transcription polymerase chain reaction.
B7–1(CD80) and B7–2(CD86) were expressed on dermal and minimally on epidermal antigen-presenting cells and T cells but not on keratinocytes. These cells were able to bind CTLA-4 immunoglobulin in situ. CD28 was expressed by most T cells infil- trating the dermis and epidermis and was reduced during treatment (Denfeld et al.
1997). Plasmacytoid dendritic cell (PDC) precursors in peripheral blood produce large amounts of IFN-α/β when triggered by viruses. On stimulation with IL-3 and CD40 ligand, the same precursors differentiate into mature DCs that stimulate naive
CD4+ T cells to produce Th2 cytokines. In a recent study, PDCs were present in human CLE lesions but not in normal skin, and the density of PDCs in affected skin correlated with the number of cells expressing the IFN-α/β-inducible protein MxA.
This could suggest that PDCs produce IFN-α/β locally. Accumulation of PDCs coin- cided also with the expression of L-selectin on dermal vascular endothelium (Farkas et al. 2001).
A recent study showed dissociation of target organ disease in beta(2)-microglo- bulin–deficient MRL-Fas(lpr) mice: lupus skin lesions were accelerated, whereas nephritis was ameliorated. Beta(2)-microglobulin affects the expression of classic and nonclassic MHC molecules and thus prevents the normal development of CD8– as well as CD1-dependent NK1+T cells. The finding was not reproduced in CD1-defi- cient mice, excluding CD1–or NK1+T-cell-dependent mechanism. The authors con- clude that regulation of autoimmunity can also occur at the target organ level (Chan et al. 2001).
Adhesion Molecules
A necessary step for lymphocytes to leave the blood vessel and migrate to the target organ, in this case the skin, is the expression of CAMs. CAMs are necessary for cell- cell and cell-matrix contact in inflammatory reactions (Chapman and Haskard 1995, McMurray 1996, Shiohara et al. 1992, Springer 1990).
ICAM-1 and vascular adhesion molecule-1 (VCAM-1) are members of the immunoglobulin gene superfamily and are induced or up-regulated on several cell types in the skin during inflammation. E-selectin is exclusively expressed by activated endothelial cells (Frenette and Wagner 1996). Soluble forms of these CAMs have been reported and are possibly related to disease activity in LE as well as many other neo- plastic and inflammatory conditions (Gearing and Newman 1993).
CAMs in the Skin
ICAM-1 is an 85- to 110-kDa transmembrane glycoprotein mapped to human chro- mosome 19 and constitutively expressed by a variety of cells. Binding of ICAM-1 to its ligand, lymphocyte function-associated antigen 1, is the major pathway for kera- tinocytes and Langerhans’ cells to interact with leukocytes and mediates both anti- gen-independent and antigen-dependent adhesion (Trefzer and Krutmann 1995). In addition, ICAM-1 has been shown to function as a receptor for human rhinoviruses (“common cold”) (Greve et al. 1989, Staunton et al. 1989) and as an endothelial cell receptor for Plasmodium falciparum in malaria (Behrendt et al. 1989).
Keratinocytes normally express no or minimal ICAM-1, and this is regulated at the transcriptional level (Norris 1995). ICAM-1 can be induced or up-regulated by cytokines such as TNF-α, IL-1, and IFN-γ (Dustin et al., 1986) and by TNF-β (Krut- mann et al. 1990, 1991). The responsiveness to cytokines that induce ICAM-1 tran- scription differs between tissues (Cornelius et al. 1993, 1994). An example of this dif- ferent responsiveness is that IL-1 induces ICAM-1 on endothelial cells but, although debated, probably not on keratinocytes (Norris 1995, Trefzer and Krutmann 1995).
ICAM-1 expression induced by TNF-α and IFN-γ is maximal in basal, undifferenti-
ated keratinocytes. IFN-γ from dermal inflammatory cells and histamine from der- mal mast cells are thought to influence basal ICAM-1 expression (Norris 1995).
Expression of CAMs on endothelial cells is essential for leukocyte margination, rolling, adhesion, and emigration from the bloodstream into tissue (Butcher 1991, Butcher et al. 1986, Shimizu et al. 1992).
VCAM-1 is minimally expressed on resting endothelial cells, but it is expressed by various cell types on activation. IL-1 and TNF-α but not UV light induces VCAM-1 on endothelial cells. The receptor for VCAM-1 is VLA-4 on monocytes and lymphocytes (Norris 1993).
E-selectin (115 kDa) is one of three proteins in the selectin family encoded on the long arm of human chromosome 1. E-selectin is only expressed by activated postcap- illary venules (Rodhe et al. 1992) and shows specificity for skin homing T cells (Picker et al. 1991, Zimmerman et al. 1992).
Effects of UV Irradiation on CAMs
In the past decade, many researchers have studied the effect of UV irradiation on adhesion molecule expression, with possible clinical implications for photosensitive disorders such as CLE. A nuclear factor (NFκB) has been implicated by DNA sequenc- ing as potential transcriptional activator for ICAM-1 (Muller et al. 1995), and it has been shown in vitro that UVB activates the NFκB in the cytosol of epidermal cells (Simon et al. 1994). A direct effect of UVA on transcription of the ICAM-1 gene has been shown via a singlet-oxygen-dependent mechanism (Grether-Beck et al. 1996).
After UVB irradiation of cultured keratinocytes, a biphasic effect is seen on ICAM-1 expression, with suppression in the first 24 h and then up-regulation (Norris 1995).
DNA photoproducts such as pyrimidine-dimers are directly involved in the UV- induced suppression of IFN-γ-induced ICAM-1 expression on keratinocytes (Krut- mann et al. 1994).
In vitro studies have shown direct induction of ICAM-1 but not of VCAM-1 or E- selectin by UVB irradiation of cultured human dermal endothelial cells (Cornelius et al. 1994, Rhodes et al. 1996). Anti-double-stranded DNA has been shown to induce ICAM-1 and VCAM-1 but not E-selectin on cultured human umbilical vein endothe- lial cells, and increased levels of soluble ICAM-1 and VCAM-1 were also found in supernatants from the cell cultures (Lai et al. 1996).
PA Norris and coworkers reported in vivo sequential expression of CAMs in UVB- induced erythema compared with intracutaneous injection of purified protein deri- vative (PPD). E-selectin expression on endothelial cells was seen after 6 h in both reactions, with a prolonged expression (1 week) in the PPD reaction. PPD but not UVB induced basal keratinocyte ICAM-1 expression and VCAM-1 expression on stel- late-shaped cells in the upper dermis, first seen at 24 h (Norris et al. 1991). In PLE, similar findings regarding CAM expression were found as after PPD injection, but keratinocyte ICAM-1 expression was strong already after 5 h, and VCAM-1 was expressed on perivascular cells (Norris et al. 1992). UVA irradiation in vivo on healthy skin increased endothelial ICAM-1 after 24 h, whereas ICAM-1 expression on cul- tured keratinocytes decreased after UVA but increased on cultured fibroblasts 6–48 h after irradiation. These authors also reported constitutive keratinocyte ICAM-1 expression (Treina et al. 1996), whereas most authors claim that keratinocytes nor-
mally do not express ICAM-1 in vivo (Trefzer and Krutmann 1995). In another study, both UVA and UVB induced endothelial ICAM-1 and E-selectin expression in vivo, but only UVA induced these molecules on cultured human dermal endothelial cells.
The induction was dose dependent, peaking at 20 J/cm2for both molecules, and time dependent, peaking at 6 h for E-selectin and 24 h for ICAM-1 (Heckmann et al. 1994).
CAMs in Cutaneous Lupus Erythematosus
Different patterns of ICAM-1 expression in the epidermis have been documented in LE vs other cutaneous inflammation and also between subsets of LE. In experimen- tally UVA- and UVB-induced lesions in patients with LE and PLE, those with SCLE showed ICAM-1 expression throughout the epidermis, those with DLE showed basal ICAM-1 staining, and those with PLE showed focal basal ICAM-1 staining associated with lymphocyte infiltrates (Stephansson and Ros 1993). SCLE, erythema multi- forme, and lichen planus showed diffuse ICAM-1 expression throughout the epider- mis in SCLE, basal and focal suprabasal ICAM-1 expression in erythema multiforme, and ICAM-1 expression on basal keratinocytes in lichen planus. Virus, UVB, and per- haps other triggers of cytokine release or possibly of ICAM-1 directly were suggested to explain these different ICAM-1 expression patterns (Bennion et al. 1995). Another group found no significant differences in CAM expression patterns in biopsy samples from spontaneous CCLE and SCLE lesions; they found ICAM-1 expression on kera- tinocytes, dermal inflammatory cells, and endothelial cells in the LE lesions (Tebbe et al. 1994).
Endothelial VCAM-1 staining was increased in biopsy samples from LE lesions compared with scleroderma and morphea (Jones et al. 1996), and increased expres- sion of VCAM-1 has been found in nonlesional skin in patients with SLE and corre- lated to disease activity (Belmont et al. 1994). Activated endothelium, perhaps associ- ated with increased endothelial expression of nitric oxide synthase, has been proposed as a unifying hypothesis for the diverse nature of SLE vascular lesions (Bel- mont and Abramson 1997). Patients with LE display aberrant kinetics and a pro- longed time course of the epidermal expression of inducible nitric oxide synthase after UV provocation (Kuhn et al. 1998).
To study possible differences in CAM expression in PLE vs different subsets of CLE, photoprovocation and serial biopsy samples were studied (Hasan et al. 1997, Nyberg et al.1997,Nyberg et al.1999).We found different expression patterns of ICAM- 1,VCAM-1, and E-selectin in patients with SLE and SCLE compared with patients with DLE and patients with PLE in our serial biopsy samples from evolving UV-induced reactions (Figs. 19.1–19.5). Transient vs persistent skin reactions revealed differences especially regarding ICAM-1 expression by day 7. It is possible that these early differ- ences indicate different control mechanisms in different UV radiation-induced skin lesions. Negative control of ICAM-1 is associated with the f-actin cytoskeleton net- work, and disruption of f-actin enhances cytokine-induced ICAM-1 transcription (Trefzer and Krutmann 1995). A possible interpretation of the findings that patients with SLE and SCLE show linear expression of ICAM-1 in the whole epidermis whereas patients with DLE show mostly focal, basal staining is that UV irradiation plays a more direct role in the induction of ICAM-1 in SLE and SCLE.In DLE,cytokines such as IFN- γ and TNF-α released from the dermal infiltrate on UV irradiation are more likely to
Fig. 19.2. Intense, bandlike ICAM-1 expression in the whole epidermis. UV-induced lesion in subacute CLE (×250)
Figs. 19.1–19.5. Examples of expression patterns of cellular adhesion molecules (CAMs) in UV- induced skin lesions in patients with cutaneous lupus erythematosus (CLE). Cryostat sections, mouse monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular adhesion molecule-1 (VCAM-1) (Vectastain Elite ABC)
Fig. 19.1. Basal expression of ICAM-1 on kera- tinocytes and increased expression in the folli- cular epithelium. Endothelial cells and scattered inflammatory cells in the upper dermis express ICAM-1. UV-induced CLE lesion in a patient with chronic CLE (×250)
Fig. 19.3. Lymphocyte function-associated antigen 1-positive lymphocytes accumulating around hair follicle. UV-induced lesion in a patient with chronic CLE (×250)
Fig. 19.4. E-selectin expression on upper dermal vessels. Staining is seen also without sur- rounding infiltrate. UV-induced lesion in a patient with chronic CLE (×250)
induce the up-regulation of ICAM-1. Most UVB wavelengths do not penetrate the epi- dermis,and yet UVB induces reactions in the skin of patients with CCLE,perhaps indi- cating a role for the isomerization of trans- to cis urocanic acid, and the concomitant release of TNF-α.However,the cis-form of urocanic acid was found to be lower in light- protected skin of patients with DLE compared with patients with PLE and controls (Hasan et al. 1999). Our impression of biopsy samples from induced lesions in patients with LE is that the E-selectin-positive vessels are mostly found in upper and mid-der- mis (data not shown). Endothelial CAMs were up-regulated also in nonlesional skin of our patients with LE in accordance with earlier studies in which it was suggested t hat activated endothelial cells are a common denominator for the diverse symptoms in LE (Belmont et al. 1994). VLA-4 (the counterreceptor for VCAM-1) and lymphocyte function–associated antigen 1 (the counterreceptor for ICAM-1) have been reported to be overexpressed on lymphocytes from patients with SLE, VLA-4 only in patients with vasculitis (Tsokos 1996).
Soluble CAMs
Circulating, soluble isoforms of CAMs are biologically active in that they retain their binding function (Seth et al. 1991). It is regarded as most likely that the circulating forms of ICAM-1 and E-selectin are proteolytically cleaved at the cell membrane (Leeuwenberg et al. 1992). Possible physiologic roles for soluble CAMs are inhibition of binding by competition, or that the shedding of surface molecules is a process that serves to down-regulate the adhesion of the relevant ligand (Gearing and Newman 1993, Trefzer and Krutmann 1995).
Fig. 19.5. VCAM-1 positive endothelial cells and some infiltrating cells in a patient with chronic CLE 14 days after UVB photoprovocation (×250)
Elevated levels of soluble (s)E-selectin were found in serum samples from 25 patients with active, widespread CLE lesions and without systemic symptoms. Most patients had a history of PLE (Nyberg 1997, Nyberg and Stephansson 1999, Nyberg et al. 1997). E-selectin is a specific marker for activated endothelial cells, which indicates that endothelial cells play a more central role in CLE than previously assumed. E- selectin is mainly expressed on the luminar surface of cytokine-activated endothe- lium, only in postcapillary venules but not by arterioles (Walsh et al. 1990). Hence, the conflicting results reported on (s)E-selectin in patients with vasculitis (Mrowka and Sieberth 1994, Spronk et al. 1994) can be due to involvement of vessels with different calibers.
Increased levels of sICAM-1 and sVCAM-1 were found in patients with SLE and SCLE (Nyberg 1997, Nyberg and Stephansson 1999). Increased levels of VCAM-1 in SLE serum have been reported by several authors and have been correlated to disease activity (Mrowka and Sieberth 1994, 1995). In one study,VCAM-1 levels were elevated in patients with SLE and also in patients with DLE, although to a lesser extent than in those with SLE (Koide et al. 1996).
Soluble E-selectin might be useful clinically as an activity marker in CLE. Block- ing of (s)E-selectin might be considered as possible therapy. An analogy is treatment with anti-ICAM-1 antibody that has decreased the rejection of skin grafts in experi- mental animal models (Trefzer and Krutmann 1995) and prevented neurologic symp- toms and vasculitic skin lesions in SLE-prone mice (Brey et al. 1997).
Hypothetically, an altered CAM expression, induced by an unbalanced cytokine network brought about by an altered T-cell/B-cell repertoire in genetically suscepti- ble individuals, could be a unifying concept for the related studies. It is possible, that studies of CAMs or certain subsets of T cells are useful in the evaluation of clinically doubtful, sunlight-induced cutaneous reactions.
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