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...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 (ICDLE), 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 ICDLE 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.展开更多
Patients with Sé zary syndrome (SS) show clonal expansion in the peripheral blood of skin- homing CD4+ T- helper cells expressing cutaneous lymphocyte antigen (CLA). However, an increase of CLA+ CD4+ T cells can ...Patients with Sé zary syndrome (SS) show clonal expansion in the peripheral blood of skin- homing CD4+ T- helper cells expressing cutaneous lymphocyte antigen (CLA). However, an increase of CLA+ CD4+ T cells can also be observed in various inflammatory dermatoses. To facilitate early diagnosis and therapeutic monitoring of SS using flow cytometry, we evaluated the expression of CD7 and CD26 on the CLA+ CD4+ lymphocyte subset. Peripheral lymphocytes from 7 patients with SS, 16 patients with mycosis fungoides (MF) and 11 healthy controls were analysed by flow cytometry for the expression of CD4, CD7, CD26, CLA and CCR4. In addition, a longitudinal study was performed over 16 months in two patients with SS. Absence of CD7 and CD26 on CLA+ CD4+ T cells was highly specific for SS. Importantly, the absence of CD26 on CLA+ CD4+ T cells was very sensitive for SS, at 100% in our patient cohort. The number of CD26- CLA+ CD4+ T cells closely correlated with therapeutic interventions in the longitudinal analysis of two patients over more than 1 year. We conclude that the absence of CD26 expression on skin- homing CLA+ CD4+ T- helper cells is a very sensitive and highly specific parameter for early diagnosis and therapeutic monitoring of patients with SS.展开更多
Background: Pityriasis lichenoides (PL) is a rare cutaneous lymphoproliferative disorder of unknown origin. Malignant transitions of PL have been described, but are very rare. We recently observed the fatal course of ...Background: Pityriasis lichenoides (PL) is a rare cutaneous lymphoproliferative disorder of unknown origin. Malignant transitions of PL have been described, but are very rare. We recently observed the fatal course of a 26- year- old patient who presented with a clinical picture resembling PL but had cytotoxic CD8+ T- cell lymphoma of the skin (CxCTL). This case prompted us to reinvestigate the role of cytotoxic T lymphocytes in PL and its relationship to antiviral immunity. Methods: Skin biopsy specimens of 11 patients with PL and two biopsy specimens of CxCTL were included. In all, 5 biopsy specimens taken from healthy skin and 5 samples of varicella- zoster virus (VZV) skin lesions were analyzed for control purposes. The inflammatory infiltrate was characterized by immunohistochemistry using monoclonal antibodies against CD3, CD4, CD8, CD20, cutaneous lymphocyte- associated antigen (CLA), CCR4, CXCR3, GranzymeB, Tia- 1, andMxA. Flowcytometry was used to analyze the expression of chemokine receptors on peripheral blood mononuclear cells in CxCTL. Results: The CxCTL skin lesions were dominated by a dense infiltration of CD8+ cytotoxic lymphocytes with a skin- homing CLA+ CCR4+ phenotype. PL and VZV skin lesions were also characterized by a predominantly CD8+ T cellular infiltrate with strong expression of the cytotoxic molecules Granzyme B and Tia- 1 and the skin- homing molecules CLA and CCR4. Coexpression analyses confirmed that skin CLA+ CD8 + cytotoxic T cells are present in CxCTL, VZV, and PL skin lesions. Strong lesional production of the antiviral protein MxA, which is specifically induced by type I interferons, could be found in all investigated disorders. The study was based on histologic, immunohistologic, and flow cytometric analyses in a limited number of patients, because of the rareness of the investigated diseases. Conclusion: Our results revealed a striking similarity between the immunohistologic picture of malignant CxCTL, benign PL, and VZV skin lesions. Strong expression of the antiviral protein MxA in all disorders supports the view that a common antiviral immune response pattern leads to aberrant skin recruitment of CLA+ CCR4+ cytotoxic T lymphocytes in PL and CxCTL.展开更多
Introduction: Imiquimod (Aldara.) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies basal cell carc...Introduction: Imiquimod (Aldara.) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies basal cell carcinoma (BCC), Bowen’ s disease, actinic keratosis, and metastasis of malignant melanoma . Recently, it was discovered that imiquimod acts through the toll- like receptor (TLR) 7. We hypothesizethat TLR7- signaling strongly induces the production of interferon (IFN) α , which is able to enhance Th1- mediated cellular antiviral and antitumor immunity. Patients and methods: In the present study we analyzed the expression of MxA, a protein specifically induced by type I IFNs during topical imiquimod treatment in several patients suffering from different cutaneous malignancies (BCC, cutaneous metastasis of melanoma, and breast cancer), and characterized the inflammatory infiltrate, along with the expression of chemokine receptor CXCR3, by immunohistochemistry. Results: Treatment with the TLR7agonist imiquimod induced a significant lesional lymphocytic inflammation, associated with strong expression of MxA, indicating the induction of type I IFN signaling. The extent of lesional MxA staining closely correlated with the number of infiltrating T lymphocytes and the expression of the chemokine receptorCXCR3,characteristic for Th1- biased immuneresponses. Discussion: Our in vivo results suggest an important role for TLR7- induced production of type I IFN, which links innate and adaptive immunity and promotes specific Th1- biased cellular immune response capable of eliminating cutaneous malignancies. MxA appears to be a valuable parameter to demonstrate IFN- type I expression in imiquimod therapy.展开更多
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 th...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.展开更多
文摘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 (ICDLE), 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 ICDLE 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.
文摘Patients with Sé zary syndrome (SS) show clonal expansion in the peripheral blood of skin- homing CD4+ T- helper cells expressing cutaneous lymphocyte antigen (CLA). However, an increase of CLA+ CD4+ T cells can also be observed in various inflammatory dermatoses. To facilitate early diagnosis and therapeutic monitoring of SS using flow cytometry, we evaluated the expression of CD7 and CD26 on the CLA+ CD4+ lymphocyte subset. Peripheral lymphocytes from 7 patients with SS, 16 patients with mycosis fungoides (MF) and 11 healthy controls were analysed by flow cytometry for the expression of CD4, CD7, CD26, CLA and CCR4. In addition, a longitudinal study was performed over 16 months in two patients with SS. Absence of CD7 and CD26 on CLA+ CD4+ T cells was highly specific for SS. Importantly, the absence of CD26 on CLA+ CD4+ T cells was very sensitive for SS, at 100% in our patient cohort. The number of CD26- CLA+ CD4+ T cells closely correlated with therapeutic interventions in the longitudinal analysis of two patients over more than 1 year. We conclude that the absence of CD26 expression on skin- homing CLA+ CD4+ T- helper cells is a very sensitive and highly specific parameter for early diagnosis and therapeutic monitoring of patients with SS.
文摘Background: Pityriasis lichenoides (PL) is a rare cutaneous lymphoproliferative disorder of unknown origin. Malignant transitions of PL have been described, but are very rare. We recently observed the fatal course of a 26- year- old patient who presented with a clinical picture resembling PL but had cytotoxic CD8+ T- cell lymphoma of the skin (CxCTL). This case prompted us to reinvestigate the role of cytotoxic T lymphocytes in PL and its relationship to antiviral immunity. Methods: Skin biopsy specimens of 11 patients with PL and two biopsy specimens of CxCTL were included. In all, 5 biopsy specimens taken from healthy skin and 5 samples of varicella- zoster virus (VZV) skin lesions were analyzed for control purposes. The inflammatory infiltrate was characterized by immunohistochemistry using monoclonal antibodies against CD3, CD4, CD8, CD20, cutaneous lymphocyte- associated antigen (CLA), CCR4, CXCR3, GranzymeB, Tia- 1, andMxA. Flowcytometry was used to analyze the expression of chemokine receptors on peripheral blood mononuclear cells in CxCTL. Results: The CxCTL skin lesions were dominated by a dense infiltration of CD8+ cytotoxic lymphocytes with a skin- homing CLA+ CCR4+ phenotype. PL and VZV skin lesions were also characterized by a predominantly CD8+ T cellular infiltrate with strong expression of the cytotoxic molecules Granzyme B and Tia- 1 and the skin- homing molecules CLA and CCR4. Coexpression analyses confirmed that skin CLA+ CD8 + cytotoxic T cells are present in CxCTL, VZV, and PL skin lesions. Strong lesional production of the antiviral protein MxA, which is specifically induced by type I interferons, could be found in all investigated disorders. The study was based on histologic, immunohistologic, and flow cytometric analyses in a limited number of patients, because of the rareness of the investigated diseases. Conclusion: Our results revealed a striking similarity between the immunohistologic picture of malignant CxCTL, benign PL, and VZV skin lesions. Strong expression of the antiviral protein MxA in all disorders supports the view that a common antiviral immune response pattern leads to aberrant skin recruitment of CLA+ CCR4+ cytotoxic T lymphocytes in PL and CxCTL.
文摘Introduction: Imiquimod (Aldara.) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies basal cell carcinoma (BCC), Bowen’ s disease, actinic keratosis, and metastasis of malignant melanoma . Recently, it was discovered that imiquimod acts through the toll- like receptor (TLR) 7. We hypothesizethat TLR7- signaling strongly induces the production of interferon (IFN) α , which is able to enhance Th1- mediated cellular antiviral and antitumor immunity. Patients and methods: In the present study we analyzed the expression of MxA, a protein specifically induced by type I IFNs during topical imiquimod treatment in several patients suffering from different cutaneous malignancies (BCC, cutaneous metastasis of melanoma, and breast cancer), and characterized the inflammatory infiltrate, along with the expression of chemokine receptor CXCR3, by immunohistochemistry. Results: Treatment with the TLR7agonist imiquimod induced a significant lesional lymphocytic inflammation, associated with strong expression of MxA, indicating the induction of type I IFN signaling. The extent of lesional MxA staining closely correlated with the number of infiltrating T lymphocytes and the expression of the chemokine receptorCXCR3,characteristic for Th1- biased immuneresponses. Discussion: Our in vivo results suggest an important role for TLR7- induced production of type I IFN, which links innate and adaptive immunity and promotes specific Th1- biased cellular immune response capable of eliminating cutaneous malignancies. MxA appears to be a valuable parameter to demonstrate IFN- type I expression in imiquimod therapy.
文摘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.
