T Lymphocytes in Cutaneous Lupus Erythematosus

The model of antibody-dependent cellular cytotoxicity fits well with Ro/SSA antibody-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-y-induced intercellular adhesion molecule-1 (ICAM-1) expression, as in Th1-type response, and a Th2-type response with significant 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 subgroups.

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 significance of these findings to CLE is not known at present. Vß8.1 CD3+ cells were elevated in skin lesions from CCLE and acute CLE (ACLE) compared with psoriasis and atopic dermatitis, with a higher percentage of vß8.1 and vß13.3 in skin lesions from CCLE than from ACLE. There was also a skew toward these vß 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 inflammatory 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 distribution patterns were different, with a patchy pattern and distribution around hair follicles in CLE. A strong correlation with ICAM-1 and HLA-DR expression was seen. IFN-y induces CXR3-activating chemokines, ICAM-1, and HLA-DR (Flier et al. 2001).

A specific subset of y6 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). y6 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 (Sontheimer 1996). In SLE, numbers of y6 T cells were lower in peripheral blood than in healthy controls, but the percentage of y6 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 find y6 T cells in the epidermis 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 irradiation (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 earlier 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 hypersensitivity 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 cytotoxic T cells, which is required to optimally activate T cells and prevent antigen-specific 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 infiltrating 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-a/p 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-a/p-inducible protein MxA. This could suggest that PDCs produce IFN-a/p locally. Accumulation of PDCs coincided 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 CDl-dependent NK1+ T cells. The finding was not reproduced in CDl-defi-cient mice, excluding CD1- or NK1+ T-cell-dependent mechanism. The authors conclude that regulation of autoimmunity can also occur at the target organ level (Chan et al. 2001).

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