B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non-PD-1-Mediated Pathway.

It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4(+) T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated TH17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

Comparing shift-autocorrelation with cepstrum for detection of burst pulses in impulsive noise.

The recently introduced shift method is applied to detect and characterize burst-pulse vocalizations produced by marine mammals. To this end, burst pulses are modeled as sequences of click-like events that are repeated after a certain inter-click interval (ICI). The shift method is used to first emphasize events that repeat within an input signal. Afterwards, the ICI can be estimated. A qualitative comparison of the method is made against classical cepstrum using real data. The detection performance is measured using random trials of simulated data with impulsive noise. It is shown that although the cepstrum outperforms in Gaussian noise at low signal-to-noise ratio, the shift method performs significantly better in impulsive noise.

Expression of endomucin, a novel endothelial sialomucin, in normal and diseased human skin.

Endomucin is an endothelial sialomucin that was recently identified with the help of monoclonal antibodies raised against mouse endothelial cells. Cloning of human endomucin allowed us to generate monoclonal antibodies against soluble recombinant forms of human endomucin. In this study, we investigated the expression of this novel molecule in human skin under different conditions, using the monoclonal antibodies. In normal human skin, endomucin was detected for the monoclonal antibody L6H10 by immunoblotting, and immunohistologic analysis of wax-embedded sections revealed that this glycoprotein is expressed on capillaries, venules, and lymphatic vessels. Interestingly, staining of arterial endothelium was either weak or focal using the monoclonal antibodies against endomucin. In situ hybridization of normal human skin confirmed the expression pattern on the messenger RNA level obtained above. We further analyzed the expression of endomucin in skin biopsy specimens from patients with inflammatory skin diseases, such as atopic dermatitis, psoriasis, lichen planus, cutaneous lupus erythematosus, and T cell lymphoma as well as with vascular skin tumors, such as hemangioma, pyogenic granuloma, angiolipoma, Kaposi's sarcoma, and angiosarcoma. We found endomucin expressed on the endothelium of each tissue, concluding that this novel molecule is a new endothelial-specific marker in the study of normal and diseased human skin.

Effects of blood transportation on human peripheral mononuclear cell yield, phenotype and function: implications for immune cell biobanking.

Human biospecimen collection, processing and preservation are rapidly emerging subjects providing essential support to clinical as well as basic researchers. Unlike collection of other biospecimens (e.g. DNA and serum), biobanking of viable immune cells, such as peripheral blood mononuclear cells (PBMC) and/or isolated immune cell subsets is still in its infancy. While certain aspects of processing and freezing conditions have been studied in the past years, little is known about the effect of blood transportation on immune cell survival, phenotype and specific functions. However, especially for multicentric and cooperative projects it is vital to precisely know those effects. In this study we investigated the effect of blood shipping and pre-processing delay on immune cell phenotype and function both on cellular and subcellular levels. Peripheral blood was collected from healthy volunteers (n = 9): at a distal location (shipped overnight) and in the central laboratory (processed immediately). PBMC were processed in the central laboratory and analyzed post-cryopreservation. We analyzed yield, major immune subset distribution, proliferative capacity of T cells, cytokine pattern and T-cell receptor signal transduction. Results show that overnight transportation of blood samples does not globally compromise T- cell subsets as they largely retain their phenotype and proliferative capacity. However, NK and B cell frequencies, the production of certain PBMC-derived cytokines and IL-6 mediated cytokine signaling pathway are altered due to transportation. Various control experiments have been carried out to compare issues related to shipping versus pre-processing delay on site. Our results suggest the implementation of appropriate controls when using multicenter logistics for blood transportation aiming at subsequent isolation of viable immune cells, e.g. in multicenter clinical trials or studies analyzing immune cells/subsets. One important conclusion might be that despite changes due to overnight shipment, highly standardized central processing (and analysis) could be superior to multicentric de-central processing with more difficult standardization.