Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

BACKGROUND: Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes. OBJECTIVES: To analyse skin biopsies of 15 patients with CLE [10 female, five male; localized CDLE (lCDLE), n = 5; disseminated CDLE (dCDLE), n = 5, subacute CLE (SCLE), n = 5] and five control biopsies taken from healthy controls and to characterize the inflammatory infiltrate. Methods We used immunohistochemistry, including staining for the cytotoxic molecule granzyme B, the skin-homing molecule cutaneous lymphocyte antigen (CLA) and the protein MxA, which is specifically induced by type I interferons (IFNs). RESULTS: We found a strong coexpression of granzyme B and CLA on lesional lymphocytes of patients with scarring lCDLE and dCDLE, which was significantly enhanced when compared with nonscarring SCLE and healthy controls. The increased expression of granzyme B was closely associated with the lesional expression of the type I IFN-induced protein MxA. CONCLUSIONS: Our results provide evidence that type I IFNs and potentially autoreactive cytotoxic lymphocytes targeting adnexal structures are highly associated with scarring lupus erythematosus lesions and might be responsible for their scarring character.     

The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score

Background There is increased expression of type I interferon (IFN)‐regulated proteins in the blood and target tissues of patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). Patients with SLE have increased IFN‐regulated gene expression pointing towards a possible underlying genetic defect. Objectives To determine expression levels of five type I IFN‐regulated genes that are highly expressed in SLE in the peripheral blood of patients with CLE and to correlate the expression levels with cutaneous disease activity. Methods Peripheral blood was obtained from 10 healthy controls and 30 patients with CLE, including eight with concomitant SLE. Total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real‐time polymerase chain reaction. Gene expression was normalized to GAPDH, standardized to healthy controls and then summed to calculate an IFN score for each patient. Disease activity was assessed with the Cutaneous Lupus Area and Severity Index (CLASI). Results Patients with subacute CLE (SCLE) and discoid lupus erythematosus (DLE) had elevated IFN scores compared with healthy controls regardless of concomitant SLE (P < 0·01 with SLE and P < 0·05 without SLE). There was no difference between patients with tumid lupus erythematosus (TLE) and healthy controls. The IFN score correlated with CLASI scores (Spearman’s rho = 0·55, P = 0·0017). Conclusions Patients with SCLE and DLE have an IFN signature, as seen in SLE. The level of gene expression correlates with cutaneous disease activity. These findings support a shared pathogenesis between SLE and some subtypes of CLE.     

Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus

Background  Lupus erythematosus tumidus (LET) is a rare disease which was first described in 1909 but has not always been considered as a separate entity of cutaneous lupus erythematosus (CLE) in the international literature.
Objectives  To compare characteristic features of different subtypes of CLE and to analyse whether LET can be distinguished as a separate entity in the classification system of the disease.
Methods  The study involved 44 patients with CLE, including 24 patients with LET, 12 with discoid lupus erythematosus (DLE) and eight with subacute CLE (SCLE), from two centres in Germany. A core set questionnaire and an SPSS database were designed to enable a consistent statistical analysis.
Results  Location of skin lesions did not differ significantly between the CLE subtypes; however, the activity score was significantly lower in LET than in DLE ( P  <   0·01), and the damage score was significantly lower in LET than in SCLE ( P  <   0·01) and DLE ( P  <   0·01). Photosensitivity and antinuclear antibodies were confirmed to be different in LET compared with SCLE and DLE but without statistical significance. Moreover, histological analysis of skin biopsy specimens showed that abundant mucin deposition is significantly more present in LET compared with SCLE ( P  <   0·01) and DLE ( P  <   0·01) while prominent interface dermatitis and alteration of hair follicles were absent in LET.
Conclusions  Several significant differences were found between LET and other subtypes of CLE with regard to clinical, histological and laboratory parameters. These data strongly indicate that LET should be defined as a separate entity in the classification of CLE.     

Identification of granzyme B‐expressing CD‐8‐positive T cells in lymphocytic inflammatory infiltrate in cutaneous lupus erythematosus and in dermatomyositis

Background. Lupus erythematosus (LE) and dermatomyositis (DM) are interface dermatitis, histologically characterized by formation of colloid bodies and a CD4+ CD8+ lymphocyte infiltrate. Colloid bodies are examples of intraepidermal apoptosis. Granzyme (Gr)B, synthesized by activated cytotoxic lymphocytes, is a serine protease able to prime apoptosis. GrB+ lymphocytes have been previously found in infiltrates in skin lesions from other types of interface dermatitis. Aim. To evaluate, on histological skin specimens from patients with LE and DM, GrB expression as a mediator of keratinocyte apoptosis in lymphocyte infiltrate. Methods. In total, 22 patients with cutaneous LE [9 with discoid lupus erythematosus (DLE), 9 with subacute lupus erythematosus (SCLE) and 4 with systemic lupus erythematosus (SLE)] and 20 patients with DM were studied. Skin specimens underwent immunohistochemical staining with antibodies to CD3, CD4, CD8 and GrB. Results. Immunohistochemical study with GrB was positive in 17 of the 22 patients with LE but only 2 of the 20 patients with DM. In LE, in systemic and subacute forms of LE, the median obtained was < 10 (+) whereas in the chronic forms, the median was 10–50% (++). Patients with DM were negative for GrB. Conclusions. In LE, a correlation between GrB+ lymphocyte and the presence of DLE form was found, but in DM, GrB is poorly expressed. GrB labels a subpopulation of effector cells involved in ongoing cytotoxic action and should be considered as a specific marker showing the extent of the direct local cytotoxic damage. GrB could play a role in the induction of skin apoptosis mechanisms in LE.     

Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus

Please cite this paper as: Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Experimental Dermatology 2010; 19: 123–131. Abstract: Lupus erythematosus (LE) is a heterogeneous disease ranging from skin‐restricted manifestations to a progressive multisystem disease. The specific skin lesions include chronic cutaneous, subacute cutaneous and acute cutaneous LE. Both genetic and environmental factors are involved in the development of LE. However, reports on the genetic background of cutaneous lupus erythematosus (CLE) forms, namely discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE), are sparse. We investigated whether the known systemic LE (SLE) susceptibility genes also predispose to CLE. Altogether, 219 Finnish patients with DLE or SCLE and 356 healthy controls were recruited. Single nucleotide polymorphisms tagging reported risk genes were genotyped. Tyrosine kinase 2 (TYK2) rs2304256 was associated with increased risk of DLE (P = 0.012, OR = 1.47, 95% CI = 1.01–1.98). Expression of TYK2 was demonstrated by immunohistochemistry in macrophage‐like cells and neutrophils and interferon regulatory factor 5 (IRF5) in macrophage‐ and fibroblast‐like cells of DLE, SCLE and SLE skin. IRF5 rs10954213 showed association with DLE (P = 0.017, OR = 1.40, 95% CI = 1.06–1.86) and SCLE (P = 0.022, OR = 1.87, 95% CI = 1.09–3.21). A haplotype of cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) showed association with DLE (P = 0.0065, OR = 2.51, 95% CI = 1.25–5.04). Our results show that the TYK2, IRF5 and CTLA4 genes previously associated with SLE also confer risk for DLE and SCLE, suggesting that different LE subphenotypes may share pathogenetic pathways.     

Expression of interleukin-17 is correlated with interferon-α expression in cutaneous lesions of lupus erythematosus

Background. Type I interferon (IFN) has been reported to have an important role in the development of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). A new subset of CD4+ T cells, T helper (Th)17 cells, also plays a role in the development of autoimmunity. Aim. To investigate expression of interleukin (IL)‐17 and IFN‐α in different CLE subsets, and their associations with the pathogenesis of LE. Methods. Skin tissue samples from 33 cases, including chronic discoid LE (n = 24), acute (A)CLE (n = 4), subacute CLE (n = 1) and lupus panniculitis (n = 4) were collected for immunohistochemistry. Expression of IL‐6, IL‐17A, IFN‐α, IFN‐γ, myxovirus protein (Mx)A and transforming growth factor (TGF)‐β was assessed in these samples. Results. All LE specimens had staining for IL‐6 and TGF‐β in the infiltrated inflammatory cells. IL‐17A staining was seen in 84.8% of specimens, and IFN‐α or MxA was seen in 93.9%. TGF‐β expression in ACLE was significantly greater than that in both chronic cutaneous (CC)LE and in lupus panniculitis (P = 0.02 for both). Expression of IL‐17A was positively associated with expression of IFN‐α and MxA (Spearman’s ρ = 0.56 and 0.39, respectively). In addition, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) correlated positively with expression of IFN‐α and MxA (ρ = 0.40 for both), whereas there was no correlation with IL‐17A expression. Conclusions. Two major cytokines, IL‐17A and IFN‐α, may play roles in the pathogenesis of CLE. Their patterns of expression positively correlated with each other.     

Characterization of the inflammatory infiltrate and expression of endothelial cell adhesion molecules in lupus erythematosus tumidus

Lupus erythematosus tumidus (LET) is a disease with characteristic clinical and histopathologic features that has not always been considered a subset of cutaneous lupus erythematosus (CLE). Although LET was first mentioned in the literature in 1930, it has rarely been documented, and immunohistochemical studies have never been performed. The aim of the present study was to characterize the inflammatory infiltrate and to analyze the expression of endothelial cell adhesion molecules in skin specimens from patients with LET and to compare the results with those from patients with other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Cryostat sections of lesional skin specimens from ten patients with LET demonstrated an infiltrate composed of more than 75% CD4+, CD8+, and HLA-DR+ cells. Interestingly, CD45RO+ cells, in contrast to CD45RA+ cells, were the prevailing inflammatory cell population. Compared with skin specimens from patients with DLE and SCLE, the mean expression of CD4+ and CD8+ cells was higher (but not significantly so) in LET, and no differences were observed with the other three antibodies. Furthermore, in contrast to controls, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, and P-selectin showed the same expression pattern in skin specimens from patients with DLE, SCLE, and LET. In conclusion, the inflammatory infiltrate of LET primarily consists of CD4+/CD8+ lymphocytes. Furthermore, expression of endothelial cell adhesion molecules was equally upregulated in LET compared with the expression in DLE and SCLE, suggesting a similar immunopathomechanism of these subtypes of CLE.     

Expression of CD30 on T helper cells in the inflammatory infiltrate of acute atopic dermatitis but not of allergic contact dermatitis

Abstract  The CD30 molecule has been proposed as a marker for a subset of CD4⁺CD45RO⁺ (memory) T cells with potent B cell helper activity producing IL-5 and IFN-γ and as a specific marker for Th2 cells. Recently, an association has been demonstrated between elevated serum levels of soluble CD30, which is shed by CD30⁺ cells in vitro and in vivo, and atopic dermatitis but not respiratory atopic disorders or allergic contact dermatitis. We studied the expression of CD30 in the inflammatory infiltrate of atopic dermatitis compared with that of allergic contact dermatitis, with special regard to skin disease activity (acute vs subacute/ chronic). Biopsies were obtained from 16 patients suffering from atopic dermatitis (acute n = 6, subacute/ chronic n = 10), from 7 patients with acute allergic contact dermatitis and from 5 positive patch-test reactions. Paraffin-embedded as well as snap-frozen material was stained with anti-CD30 and anti-CD45RO mAbs according to standard procedures. Double-staining procedures for CD30CD3, CD30CD4, CD30CD45RO and CD30CD68 were also performed. Abundant CD45RO⁺ cells were detected both in atopic dermatitis and in allergic contact dermatitis lesions. We found scattered CD30⁺ cells in only one of six formalin-fixed paraffin-embedded acute atopic dermatitis biopsies, but in all of the respective snap-frozen specimens, possibly because CD30 expression on atopic dermatitis infiltrating cells is weak and sensitive to formalin fixation and paraffin embedding. CD30CD3 and CD30CD4 double staining identified CD30⁺ cells to be helper T lymphocytes. No significant CD30 expression (either in paraffin-embedded or in frozen material) could be found in subacute/chronic atopic dermatitis lesions or in any of the specimens of allergic contact dermatitis. The results suggest a specific regulatory function of CD30⁺ T cells in acute atopic dermatitis. With respect to the view that CD30 is a marker for Th2 cells, our observations confirm previous findings that Th2 cells predominate in the infiltrate particularly of acute atopic dermatitis. CD30 expression in acute atopic dermatitis but not in acute allergic contact dermatitis might be helpful in the histological differentiation of these disorders and in the further characterization of atopy patch testing. Received: 1 April 1998 / Received after revision: 28 May 1998 / Accepted: 3 July 1998     

Características epidemiológicas de los pacientes con lupus eritematoso cutáneo

Introduction and objectivesLupus erythematosus is a chronic autoimmune inflammatory disease with a wide clinical spectrum and variable clinical course. Few studies have analyzed the characteristics of patients with only cutaneous lupus erythematosus (CLE). The aim of this study was to describe the epidemiological, clinical, and immunological characteristics of a series of patients diagnosed with CLE.Patients and methodsAn analysis was performed of the data from all patients over 18 years of age with a diagnosis of CLE and seen between January 1, 2007 and December 31, 2011 in a tertiary hospital.Results and conclusionsOne hundred- one patients were included in the study. The mean age at diagnosis was 40 years and 84% were women. Subacute forms of presentation were observed in 94% of patients. The chronic discoid forms were localized to the head and neck in 79% of cases, whereas the subacute forms were on the trunk in 97% of cases. Patients with acute forms were positive for antinuclear, anti-DNA, anti-smooth muscle, and anti-RNP (ribonucleoprotein) antibodies, whereas anti-Ro and anti-La antibodies predominated in patients with subacute forms. Seventeen patients presented more than 1 subtype of CLE. Fifteen (88%) of these patients received immunosuppressor treatment versus 44 (52%) of the other 84 patients with only 1 subtype of CLE. Patients with distinct subtypes of CLE present different clinical and immunological characteristics. Oral immunosuppressants are often needed to control the disease in a large proportion of patients with different subtypes of CLE.     

Histopathologic findings in lupus erythematosus tumidus: review of 80 patients

BACKGROUND: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. OBJECTIVE: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. METHODS: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). RESULTS: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. CONCLUSION: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE.     

Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden

Background Studies reporting the incidence of isolated cutaneous lupus erythematosus (CLE) are rare. Objectives To examine in a population‐based cohort study the incidence of CLE and its subsets in Sweden. The short‐term probability of receiving an additional diagnosis of systemic lupus erythematosus (SLE) is also assessed. Methods A population‐based open cohort study including all patients with CLE [International Classification of Diseases (ICD) code, ICD‐10: L93] in Sweden, 2005–2007. Patients (n = 1088) were identified in the Swedish National Patient Register. Results The incidence of CLE was 4·0/100 000; the female/male ratio was 3 : 1. Mean age at disease onset was 54 years. The most common subset was discoid lupus erythematosus (DLE) (80%, n = 868). A quarter of the patients (24%, n = 260) were already diagnosed with SLE at the time they were diagnosed with CLE. During the whole observation period (2005–2007), an additional 18% (n = 107) were diagnosed with SLE, the probability of receiving an additional SLE diagnosis being highest for the subacute CLE (SCLE) subset. Conclusions This is the first nationwide epidemiological study on CLE. We found the incidence of CLE to be about equal to that of SLE, and found a higher short‐term probability for receiving an additional diagnosis with SLE than previously described for CLE. Subsets other than DLE and SCLE were rarely reported in our system; an update of the ICD codes for this diagnostic group could increase reporting of these more unusual cases. Our study clarifies that monitoring and follow‐up are called for in this patient group due to the risk for SLE, and underscores the need for clear criteria for risk assessment in the large group of patients with CLE who also fulfil criteria for SLE.     

The expression of human leukocyte antigen-DR and CD25 on circulating T cells in cutaneous lupus erythematosus and correlation with disease activity

BACKGROUND: Lupus erythematosus (LE) is a chronic autoimmune disease with a broad clinical spectrum reaching from primarily cutaneous manifestations [cutaneous LE (CLE)] up to systemic disease [systemic LE (SLE)]. In patients with SLE, the expression of activation markers on circulating T cells reflects disease activity. Here, we investigated whether this also holds true for patients with CLE. PATIENTS AND METHODS: The expression of the activation markers human leukocyte antigen (HLA)-DR and CD25 on circulating T lymphocytes was measured by flow cytometry in 24 patients suffering from different types of active CLE. Simultaneously, the disease activity was assessed clinically using a CLE activity index. Eighteen healthy donors were analyzed for control purposes. RESULTS: HLA-DR was expressed on a significantly elevated percentage of both CD4+ and CD8+ circulating T cells in active CLE patients when compared with healthy controls. The percentage of HLA-DR-expressing T lymphocytes closely correlated with the disease activity. Interestingly, in disseminated scarring chronic discoid LE, a significantly increased percentage of CD25+ cells was observed only in the subset of skin-homing cutaneous lymphocyte antigen (CLA)+CD4+ and CD8+ T cells. CONCLUSION: Our results provide evidence that activation markers on peripheral blood T cells might help to objectively assess the disease activity in CLE. Furthermore, a significant population of CD25+CLA+CD8+ T cells can only be detected in a subgroup of patients with disseminated scarring CLE and might reflect the systemic expansion of activated cytotoxic T lymphocytes involved in destruction of epidermal tissue.     

Adult-onset infective dermatitis associated with HTLV-I. Clinical and immunopathological aspects of two cases

Infective dermatitis associated with HTLV-I (IDH) is a chronic, infected childhood eczema. Two adult-onset cases of IDH were studied, one of which was associated with HAM/TSP. The patients were submitted to dermatological, neurological and pathological examination. Immunohistochemical studies were made using CD3, CD4, CD8, CD20, CD79a, and CD57 antibodies. Cytotoxic granules were investigated using granzyme B, perforin, and TIA. The patients presented infected erythematous, scaly lesions with mild itching and a good response to sulfamethoxazole/ trimethoprim. A differential diagnosis with atopic dermatitis (AD) and seborrheic dermatitis (SD) was made, based on: the distinctive morphology and distribution of the lesions, presence of exudative and infected lesions, and mild pruritus. The inflammatory infiltrate was composed predominantly of CD8+ lymphocytes that did not present cytotoxic granules. We concluded that IDH can begin in adulthood and may be associated with HAM/TSP. The immunohistochemical findings were different from those observed in AD and SD.     

Vitamin D deficiency in patients with cutaneous lupus erythematosus is prevalent throughout the year

Background Vitamin D mediates immunomodulatory functions and its deficiency has been associated with an increased prevalence of immunological diseases including systemic lupus erythematosus (SLE). Chronic discoid or subacute cutaneous lupus erythematosus (CLE) are ultraviolet (UV)‐triggered skin diseases. As vitamin D is mostly UV‐derived and not from nutrition, its deficiency is frequent especially during the UV‐deprived winter months. Objective To compare the vitamin D status of patients with CLE with patients with type I allergy and healthy individuals during the summer or winter months. Methods The vitamin D status of patients with CLE (n = 41) was compared with patients with type I allergy (n = 24), healthy individuals (n = 25) and a reference pool (n = 1951) by means of concentrations of circulating storage metabolite 25‐hydroxyvitamin D in the summer and winter. Results Serum 25‐hydroxyvitamin D concentrations were lower during the winter in the reference population, and type I allergic and healthy individuals (29·2–35·5 nmol L^?1) compared with the summer months (56·3–89·8 nmol L^?1) and paralleled by the prevalence of vitamin D deficiency (serum 25‐hydroxyvitamin D < 50 nmol L^?1; winter: 70·8–73·4%, summer: 34·9–39·4%). In contrast, vitamin D deficiency in patients with CLE was prevalent throughout the year (summer: 85·7%, winter: 97·1%). In patients with CLE with concomitant prednisolone treatment, the 25‐hydroxyvitamin D serum levels were comparable with (mean daily intake 877 IU) or without vitamin D supplementation during summer or winter (P = 0·75 and P = 0·14, respectively). Conclusions  Our data identify vitamin D deficiency in patients with CLE throughout the year and indicate that monitoring and correcting the vitamin D status should be considered to prevent bone demineralization and fractures and to modulate beneficially immunological dysfunction.     

Ultraviolet light protection by a sunscreen prevents interferon‐driven skin inflammation in cutaneous lupus erythematosus

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad‐spectrum sunscreen to prevent UV‐induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV‐dependent activation of interferon (IFN)‐driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad‐spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen‐treated and sunscreen‐untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c‐ and CD123‐positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV‐irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68‐positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN‐driven inflammatory response in CLE.     

Identification of TIA-1+ and granzyme B+ cytotoxic T cells in lichen sclerosus et atrophicus

BACKGROUND: The onset and persistence of cutaneous lichen sclerosus et atrophicus (LSA) are linked to the presence of an inflammatory infiltrate of CD3+ T cells that includes CD4+ and CD8+ cells. The functional relevance of the presence of these cells is unknown. OBJECTIVE: The study intended to quantify resting and activated cytotoxic T cells in LSA lesions. METHODS: Twenty patients with active LSA were studied. Skin-infiltrating T cells were immunohistologically characterized with antibodies against CD3, CD8, T-cell-restricted intracellular antigen (TIA-1) and granzyme B (GrB). TIA-1 labels cytotoxic granules of resting and activated T cells, whereas GrB designates activated cytotoxic T lymphocytes (CTL). RESULTS: In all cases, numerous T cells were consistently found expressing cytotoxic granules. The results indicated a high number of infiltrating CD8+ TIA+ T cells. Furthermore, a notable number of GrB+ activated CTL associated with hydropic degeneration of the basal cell layer were found within the dermal infiltrate and at the dermoepidermal interface. CONCLUSION: This study shows that a high proportion of skin-infiltrating T cells in LSA has a potential cytotoxic function. The results indicate that hydropic degeneration of basal keratinocytes may at least partially be mediated by CTL-dependent mechanisms. Our data also indicate that a cell-mediated immune response may play an important role in the pathogenesis of the disease.     

Role of the chemokine receptor CCR4 and its ligand thymus- and activation-regulated chemokine/CCL17 for lymphocyte recruitment in cutaneous lupus erythematosus

Skin-infiltrating T lymphocytes are thought to play a major role in the pathogenesis of cutaneous lupus erythematosus (CLE). In this study, we investigated the role of the chemokine receptor 4 (CCR4) and its ligand thymus- and activation-regulated chemokine (TARC/CCL17) for the recruitment of T cells in inflamed skin of patients with CLE. We found significant numbers of CCR4+ T lymphocytes in the skin of all patients with CLE. Interestingly, a subset of patients with disseminated scarring skin involvement were characterized by both lesional and circulating CD8+ T cells expressing CCR4. Destruction of epidermal and adnexal structures was histomorphologically associated with CCR4+ cytotoxic T cells invading basal layers of the epidermis where keratinocytes showed apoptotic death. The CCR4 ligand TARC/CCL17 was strongly expressed in skin lesions and elevated in the serum of CLE patients. The functional relevance of lymphocytic CCR4 expression could be confirmed by TARC/CCL17-specific in vitro migration assays. Our investigations suggest that CCR4 and TARC/CCL17 play a role in the pathophysiology of CLE. In particular, cytotoxic CD8+ T cells expressing CCR4 appear to be involved in scarring subtypes of CLE.     

Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis

BACKGROUND: Infiltration of the skin by pathogenic T cells is regarded as a key factor in the development of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. OBJECTIVES: To investigate whether T cells containing cytotoxic proteins may contribute to the generation of skin inflammation in these skin diseases. METHODS: Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD (n = 8) and psoriasis (n = 6), and from non-atopic controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by immunohistochemistry. RESULTS: A significant enhancement of perforin and granzyme B expression was observed in lesional AD skin as compared with normal skin, non-lesional AD skin and psoriasis. Expression of these cytotoxic proteins was also increased in psoriasis as compared with normal skin and non-lesional psoriatic skin. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells located in the perivascular infiltrate. In AD increased numbers of positive cells were also observed focally at sites of spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. CONCLUSIONS: Our data suggest that cytotoxic CD4+ and CD8+ T cells containing perforin and granzyme B may play an integral part in eliciting cutaneous inflammation in AD.     

The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets

BACKGROUND: Plasmacytoid dendritic cells and type I interferons (IFNs) are supposed to play a central proinflammatory role in the pathogenesis of cutaneous lupus erythematosus (LE). The IFN-inducible chemokines CXCL9 and CXCL10 are involved in recruiting CXCR3+ effector lymphocytes from the peripheral blood into skin lesions of LE. We hypothesized that the expression pattern of IFN-inducible proteins reflects the characteristic distribution of the inflammatory infiltrate in different subsets of cutaneous LE. OBJECTIVES: To test this hypothesis in patients with LE. METHODS: Lesional skin biopsies taken from patients with different subsets of LE [chronic discoid LE (CDLE), n = 12; subacute cutaneous LE (SCLE), n = 5; LE tumidus (LET), n = 4; LE profundus (LEP), n = 6] were investigated by immunohistochemistry using monoclonal antibodies to the lymphocyte surface markers CD3, CD4, CD8, CD20 and CD68, the cytotoxic proteins Tia1 and granzyme B, the chemokine receptor CXCR3, the specifically type I IFN-inducible protein myxovirus protein A (MxA) and the chemokines CXCL9 and CXCL10. RESULTS: The expression pattern of MxA followed the distribution of the inflammatory infiltrate typically seen in the investigated cutaneous LE subsets. In CDLE and SCLE, expression was focused in the epidermis and upper dermis, while in LET a perivascular and in LEP a subcutaneous pattern was found. Similar findings were obtained for CXCL9 and CXCL10. CONCLUSIONS: Our results demonstrate a close morphological association between the expression pattern of IFN-inducible proteins and the distribution of CXCR3+ CD3+ lymphocytes in all investigated subsets of cutaneous LE. This supports the importance of an IFN-driven inflammation in this condition. Infiltrating lymphocytes carrying CXCL10 in their granules might amplify the lesional inflammation and be responsible for the chronic course of this disease.