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.

IP10/CXCL10 - CXCR3 interaction: a potential self-recruiting mechanism for cytotoxic lymphocytes in lichen sclerosus et atrophicus.

Lichen sclerosus et atrophicus is a chronic inflammatory skin disease of unknown aetiology. Recent studies have indicated that autoimmune mechanisms might be involved in its pathogenesis and have suggested a role for autoreactive cytotoxic T-lymphocytes. Based on recent observations we now hypothesize that a type I interferon-driven inflammation might be involved in the pathogenesis of this disease. Lesional skin biopsies were analysed by immunohistochemistry (CD3, CD4, CD8, CD68, CD123, Tia1, Granzyme B, Myxovirus resistance A, IP10/CXCL10 and CXCR3). Sequential double staining was performed to analyse co-expression of Tia1 and CXCR3. Significant expression of Myxovirus resistance A was found, indicating type I interferon production. This expression was closely associated with the expression of the interferon-inducible protein IP10 and the recruitment of CXCR3+ cytotoxic T-lymphocytes. Plasmacytoid dendritic cells appeared to be a major source of type I interferon in lichen sclerosus et atrophicus. Interestingly, several infiltrating lymphocytes contained IP10 in their granules. This is the first study providing evidence that a type I interferon-associated recruitment of CXCR3+ cytotoxic T-lymphocytes is involved in the pathogenesis of lichen sclerosus et atrophicus. Infiltrating lymphocytes, containing IP10 in their granules, could provide an important self-perpetuating mechanism.

CXCR3-mediated recruitment of cytotoxic lymphocytes in lupus erythematosus profundus.

BACKGROUND: Lupus erythematosus profundus (LEP) is a rare variant lupus erythematosus with unclear etiology characterized by lobular panniculitis. Recently, we observed a case of LEP involving the lower right eyelid. Our immunohistological analyses of lesional skin biopsies revealed a type I IFN signature in the context of cytotoxic lobular panniculitis. OBJECTIVE: Since type I IFNs have been shown to be involved in other cutaneous LE subtypes, especially in chronic discoid LE, we hypothesized that a type I IFN driven immune response might play an important role in the pathogenesis of LEP. METHODS: In addition to the above case, 9 skin biopsies taken from 5 patients with LEP were analyzed for a type I interferon signature by immunohistochemistry. Furthermore, 8 skin biopsies taken from patients with active chronic discoid LE and 5 biopsies of healthy skin were included for control purposes. The inflammatory infiltrate was characterized using monoclonal antibodies specific for CD3, CD4, CD8, CD20, CD68, and CD123. Subsequently, we analyzed the expression the type I IFN Marker MxA, the cytotoxic molecules granzyme B and Tia1, the chemokine receptor CXCR3 and its ligand, the interferon inducible protein IP10/CXCL10. RESULTS: LEP skin lesions were characterized by a lobular panniculitis, dominated by cytotoxic CXCR3(+) lymphocytes. Strong MxA expression indicated extensive type I IFN production within the fat lobules. Numerous plasmacytoid dendritic cells appear to be the major source of type I IFNs. Lesional expression of IP10 links the type I IFN production and recruitment of CXCR3(+) lymphocytes. LIMITATIONS: The study was based on histological and immunohistological analyses in a limited number of patients, due to the rareness of the investigated disease. CONCLUSION: Our results demonstrate a type I IFN driven immune response in active LEP skin lesions. We suggest that this type I IFN driven inflammation is responsible for the recruitment of CXCR3(+) lymphocytes into fat lobules and enhance their cytotoxic capacity.

Alcohol intake modulates the genetic association between HDL cholesterol and the PPARgamma2 Pro12Ala polymorphism.

The peroxisome proliferator-activated receptor gamma (PPARgamma) Pro12Ala polymorphism affects plasma lipids, but to what extent alcohol intake interferes with this association remains unknown. We randomly recruited 251 nuclear families (433 parents and 493 offspring) in the framework of the European Project on Genes in Hypertension study and genotyped 926 participants in whom all serum lipid variables and information on alcohol consumption were available for PPARgamma2 Pro12Ala. Genotype-phenotype relations were assessed using generalized estimating equations (GEE) and a quantitative transmission disequilibrium test (QTDT). The Ala12 allele was more frequent in Novosibirsk (0.17) than in Cracow (0.12) and Mirano (0.11) (P < 0.01). Using GEE (P = 0.03) or QTDT (P = 0.007), Italian offspring carrying the Ala12 allele had higher serum HDL cholesterol than noncarriers. HDL cholesterol levels were on average 0.086 mmol/l (P = 0.001) higher in drinkers than in nondrinkers. Compared with Pro12 homozygotes, Ala12 allele carriers consuming alcohol had higher serum total and HDL cholesterol, with the opposite trend occurring in nondrinkers. This genotype-alcohol interaction was independent of the type of alcoholic beverage and more pronounced in moderate than in heavy drinkers. We conclude that alcohol intake modulates the relation between the PPARgamma2 Pro12Ala and HDL cholesterol level and that, therefore, the Pro12Ala polymorphism, pending confirmation of our findings, might affect cardiovascular prognosis.