Large molecular systems landscape uncovers T cell trapping in human skin cancer

Immune surveillance of tumour cells is an important function of CD8 T lymphocytes, which has failed in cancer for reasons still unknown in many respect but mainly related to cellular processes in the tumour microenvironment. Applying imaging cycler microscopy to analyse the immune contexture in a human skin cancer we could identify and map 7,000 distinct cell surface-associated multi-protein assemblies. The resulting combinatorial geometry-based high-functional resolution led to discovery of a mechanism of T cell trapping in the epidermis, which involves SPIKE, a network of suprabasal keratinocyte projections piercing and interconnecting CD8 T cells. It appears initiated by clusters of infrabasal T and dendritic cells connected via cell projections across a fractured basal lamina to suprabasal keratinocytes and T lymphocytes

Outpatient decolonization after recurrent skin infection with Panton-Valentine leukocidin (PVL)-producing S. aureus - The importance of treatment repetition

Background: Recurrent skin abscesses are often associated with Panton-Valentine leukocidin-producing strains of S. aureus (PVL-SA). Decolonization measures are required along with treatment of active infections to prevent re-infection and spreading. Even though most PVL-SA patients are treated as outpatients, there are few studies that assess the effectiveness of outpatient topical decolonization in PVL-SA patients. Methods: We assessed the results of topical decolonization of PVL-SA in a retrospective review of patient files and personal interviews. Successful decolonization was defined as the absence of any skin abscesses for at least 6 months after completion of the final decolonization treatment. Clinical and demographic data was assessed. An intention-to-treat protocol was used. Results: Our cohort consisted of 115 symptomatic patients, 66% from PVL-positive MSSA and 19% from PVL-positive MRSA. The remaining 16% consisted of symptomatic patients with close contact to PVL-SA positive index patients but without detection of PVL-SA. The majority of patients were female (66%). The median age was 29.87% of the patients lived in multiple person households. Our results showed a 48% reduction in symptomatic PVL-SA cases after the first decolonization treatment. The results also showed that the decrease continued with each repeated decolonization treatment and reached 89% following the 5th treatment. A built multivariable Cox proportional-hazards model showed that the absence of PVL-SA detection (OR 2.0) and living in single person households (OR 2.4) were associated with an independently increased chance of successful decolonization. Conclusion: In our cohort, topical decolonization was a successful preventive measure for reducing the risk of PVL-SA skin abscesses in the outpatient setting. Special attention should be given to patients living in multiple person households because these settings could confer a risk that decolonization will not be successful

Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children

Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures

Dominance of nonmalignant T-cell clones and distortion of the TCR repertoire in the peripheral blood of patients with cutaneous CD30+ lymphoproliferative disorders

Die Lymphomatoide Papulose (LyP) und das primär kutane anaplastische großzellige Lymphom (cALCL) gehören zum Spektrum der CD30+ lymphoproliferativen Erkrankungen (CLPD). Klinisch sind beide Entitäten, insbesondere die LyP, durch das ungewöhnliche Phänomen der spontanen klinischen Remissionen einzelner Hautläsionen gekennzeichnet. Besonders die LyP nimmt dabei oft einen chronisch rezidivierenden Verlauf über Jahrzehnte. In vorangegangenen Studien konnte gezeigt werden, dass dieser Gruppe der kutanen Lymphome eine klonale T-Zellpopulation zugrunde liegt. Auch nach mehreren Jahren der klinischen Remission konnte der zuvor bereits nachgewiesene T-Zell-Klon in neu auftretenden Hautveränderungen erneut detektiert werden. Bisher ist jedoch unklar, in welchem Kompartiment die klonalen T Zellen persistieren. Eine mögliche Hypothese ist, dass die malignen Zellen im peripheren Blut zirkulieren und sich von dort immer wieder neu in der Haut manifestieren. Um der Frage nachzugehen, ob die krankheitsverursachenden Zellen im peripheren Blut persistieren und von dort immer wieder in die Haut streuen, wurde eine systematische Analyse von insgesamt 126 Proben aus läsionaler Haut und korrespondierenden Blutproben von 31 Patienten durchgeführt. Dabei wurde ein besonderes Augenmerk auf die Entität der LyP gelegt. Neben einer hohen Detektionsrate klonaler TCR-γ-Genumlagerungen in der läsionalen Haut (84 %) zeigten die Daten einen unterschiedlichen T-Zell-Klon im peripheren Blut von 35 % und 86 % der Patienten mit LyP und ALCL. Bei keinem der 31 Patienten konnte der identische T-Zell-Klon in beiden Kompartimenten nachgewiesen werden. Die Immunoscope/TcLandscape Analyse zeigte weiterhin, dass die klonalen Expansionen im peripheren Blut mit einer Verschiebung der CDR3-Längenverteilung assoziiert sind. Die Abweichungen des TCR-Repertoires traten ferner früher und häufiger in Erscheinung als man es bei gesunden Individuen erwarten würde. Diese Ergebnisse lassen vermuten, dass die unerwartet hohe Detektionsrate einer klonalen T Zellpopulation im peripheren Blut von Patienten mit LyP evt. in Zusammenhang mit einer tumorantigenspezifischen T-Zellproliferation steht. Die genaue Bedeutung dieser nicht tumoridentischen klonalen T-Zellen bleibt jedoch zunächst ungeklärt.Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL) are part of the spectrum of CD30+ lymphoproliferative disorders (CLPD). Clinically LyP is characterized by spontaneous regression of single skin lesions. Despite the malignant appearing histology LyP has an excellent prognosis. Even after several years of clinical remission the identical clonal T-cell population can be detected in newly erupting skin lesions. This fact raised the question whether the malignant T-cell persist in the peripheral blood. In order to answer this question genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD were investigated for clonality. Blood samples were obtained at times of active disease and clinical remission. Detection of clonality was performed by combining TCR-gamma PCR with the Genescan method. Furthermore, in ten blood samples TCR repertoire analyses were performed by beta-variable complementarity-determining region 3 (CDR3) spectratyping. A clonal T-cell population could be detected in 36/43 (84%) of the investigated skin samples an in 35/83 (42%) blood samples. Comparison of skin and blood compartments demonstrated different clonal T-cell populations in all 31 patients, suggesting reactive clonal T-cell population in the peripheral blood. Furthermore, CDR3 spectratyping revealed that the not-tumor-identical clonal T-cell populations in the peripheral blood are associated with a restriction of the TCR repertoire, suggesting T-cell stimulation by an unknown antigen