Sabine Zahn

Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis.

Background.  Dermatomyositis (DM) is an autoimmune disease of unknown origin affecting skin and muscles. Infiltrating autoreactive T lymphocytes are thought to play an important pathogenetic role, but it is unclear which mechanisms are involved in the recruitment of these cells. Recent studies provided evidence that a type I interferon (IFN)‐driven immune response, including the recruitment of T cells via IP10/CXCR3 interactions, might be important for the generation of skin lesions of cutaneous lupus erythematosus (CLE), an autoimmune disease that shares some clinical and histopathological features with DM. We hypothesized that a similar mechanism might also be involved in the pathogenesis of DM skin lesions.

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.

Evidence for a Pathophysiological Role of Keratinocyte-Derived Type III Interferon (IFNλ) in Cutaneous Lupus Erythematosus

Type I IFNs (IFNα/β) have been shown to have a central role in the pathophysiology of lupus erythematosus (LE). The recently discovered type III IFNs (IFNλ1/IL29, IFNλ2/IL28a, IFNλ3/IL28b) share several functional similarities with type I IFNs, particularly in antiviral immunity. As IFNλs act primarily on epithelial cells, we investigated whether type III IFNs might also have a role in the pathogenesis of cutaneous LE (CLE). Our investigations demonstrate that IFNλ and the IFNλ receptor were strongly expressed in the epidermis of CLE skin lesions and related autoimmune diseases (lichen planus and dermatomyositis). Significantly enhanced IFNλ1 could be measured in the serum of CLE patients with active skin lesions. Functional analyses revealed that human keratinocytes are able to produce high levels of IFNλ1 but only low amounts of IFNα/β/γ in response to immunostimulatory nuclear acids, suggesting that IFNλ is a major IFN produced by these cells. Exposure of human keratinocytes to IFNλ1 induced the expression of several proinflammatory cytokines, including CXCL9 (CXC-motiv ligand 9), which drive the recruitment of immune cells and are associated with the formation of CLE skin lesions. Our results provide evidence for a role of type III IFNs in not only antiviral immunity but also autoimmune diseases of the skin.

Impaired Th1 responses in mice deficient in Epstein-Barr virus-induced gene 3 and challenged with physiological doses of Leishmania major.

Protection against Leishmania major is dependent on IL‐12 release from L. major‐infected dendritic cells (DC) that induce IFN‐γ‐producing Th1/Tc1 cells. IL‐27, a novel member of the IL‐12 family, is a heterodimer composed of p28 and IL‐12p40‐related Epstein‐Barr virus‐induced gene 3 (EBI3), and was shown to be produced by DC. In this study, we utilized EBI3‐deficient mice to investigate the role of IL‐27 in leishmaniasis using physiological low‐dose infections that mimic natural transmissions. Lesions in EBI3–/– mice were significantly larger between weeks 3 and 10 post infection, reaching up to approximately threefold increased lesion volumes compared to wild types. In parallel, dermal lesions of EBI3–/– mice contained greater parasite numbers, reaching a peak load that was 2‐log higher than in C57BL/6 mice. However, lesions in EBI3–/– and wild‐type mice resolved after 12 weeks. At early time points, the antigen‐specific cytokine response in EBI3–/– lymph nodes showed increased levels of IL‐4, IL‐10 and IL‐13 and decreased IFN‐γ production. IL‐27 production was restricted to the DC population, since the majority of EBI3 expression in lymph nodes of infected mice was found in CD11c+ cells. In conclusion, our data show that DC‐derived IL‐27 is critical for the timely initiation of efficient anti‐parasite Th1 immunity early in infections.

Type I interferon-associated cytotoxic inflammation in cutaneous lupus erythematosus

Inappropriate activation of innate immune mechanisms, in particular of the type I interferon (IFN) system, is regarded to play an important role in the pathogenesis of lupus erythematosus (LE). Type I IFN serum levels have been shown to correlate with the disease activity in systemic LE and additionally play a proinflammatory role in the development of LE skin lesions. Recent studies demonstrated a close morphological association between the expression pattern of IFN-inducible chemokines (MxA, CXCL10) and typical histological features of cutaneous LE. These and other studies suggest that a complex network of IFN-associated cytokines, chemokines and adhesion molecules orchestrates and promotes tissue injury observed in LE skin.

Pathogenesis of cutaneous lupus erythematosus: common and different features in distinct subsets

The term ‘cutaneous lupus erythematosus’ (CLE) comprises several related autoimmune skin disorders, defined as ‘specific’ skin manifestations of lupus erythematosus (LE). The spectrum of clinical presentation of CLE is wide, reaching from mild erythema to disseminated scarring skin lesions. There is increasing knowledge concerning the pathogenesis of LE skin lesions and it has been shown that a complex network of cutaneous cytokines, chemokines and adhesion molecules orchestrate and promote tissue injury observed in LE skin lesions. However, a complete understanding of the diverse pathophysiological mechanisms in the different CLE subsets does not exist. Here we review the main pathological features described in CLE patients against the background of the clinical diversity of different CLE subtypes. Lupus (2010) 19, 1020—1028.

Dendritic Cell-Derived IL-12p40 Homodimer Contributes to Susceptibility in Cutaneous Leishmaniasis in BALB/c Mice

Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1αβ, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. Detailed analyses by Western blot and ELISA revealed that one-tenth of IL-12p40 detected in DC supernatants was released as the IL-12 antagonist IL-12p40 homodimer (IL-12p80). BALB/c DC released ∼2-fold more IL-12p80 than C57BL/6 DC both in vitro and in vivo. Local injection of IL-12p80 during the first 3 days after infection resulted in increased lesion volumes for several weeks in both L. major-infected BALB/c or C57BL/6 mice, in higher lesional parasite burdens, and decreased Th1-cytokine production. Finally, IL-12p40-transgenic C57BL/6 mice characterized by overexpression of p40 showed increased levels of serum IL-12p80 and enhanced disease susceptibility. Thus, in addition to IL-1αβ, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome.

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.

Interferon‐α stimulates TRAIL expression in human keratinocytes and peripheral blood mononuclear cells: implications for the pathogenesis of cutaneous lupus erythematosus

Summary Background  The tumour necrosis factor‐related apoptosis‐inducing ligand TRAIL has been shown to participate in the pathogenesis of systemic lupus erythematosus (SLE). The accumulation of apoptotic cell debris has been hypothesized to induce this autoimmune inflammation, and TRAIL may trigger this programmed cell death. Furthermore, TRAIL is among the interferon (IFN)‐regulated genes which are typically expressed in the peripheral blood of patients with acute SLE.

Transcriptional profiling identifies an interferon‐associated host immune response in invasive squamous cell carcinoma of the skin

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the 2 most common types of nonmelanoma skin cancer. Both derive from keratinocytes but show a distinct biological behavior. Here we present transcriptional profiling data of a large cohort of tumor patients (SCC, n = 42; BCC, n = 114). Differentially expressed genes reflect known features of SCC and BCC including the typical cytokeratin pattern as well as upregulation of characteristic cell proliferation genes. Additionally, we found increased expression of interferon (IFN)‐regulated genes (including IFI27, IFI30, Mx1, IRF1 and CXCL9) in SCC, and to a lower extent in BCC. The expression of IFN‐regulated genes correlated with the extent of the lesional immune‐cell infiltrate. Immunohistological examinations confirmed the expression of IFN‐regulated genes in association with a CXCR3+ cytotoxic inflammatory infiltrate on the protein level. Of note, a small subset of SCC samples with low expression of IFN‐regulated genes included most organ transplant recipients receiving immunosuppressive medication. Collectively, our findings support the concept that IFN‐associated host responses play an important role in tumor immunosurveillance in the skin.