Ernst Schering Research Foundation workshop最新文献

The human parvovirus B19 (PVB19), an erythrovirus causing diverse clinical manifestations ranging from asymptomatic or mild to more severe outcomes such as hydrops fetalis, is the only currently known human pathogenic parvovirus. Recently, PVB19 has been identified as a causative agent of pediatric and adult inflammatory cardiac diseases. The first hints for a possible etiopathogenetic role of the PVB19 infection and the development of cardiac dysfunction were demonstrated by molecular biology methods such as in situ hybridization (ISH) and polymerase chain reaction (PCR). In this regard, PVB19-associated inflammatory cardiomyopathy is characterized by infection of endothelial cells of small intracardiac arterioles and venules, which may be associated with endothelial dysfunction, impairment of myocardial microcirculation, and penetration of inflammatory cells in the myocardium.

There are few systems which enable adult tissue stem cells to be studied. However, the gastrointestinal tract with its high degree of polarity, well-defined cell migratory pathways, and dynamic cell replacement is a model tissue providing unique opportunities for stem cell study. Lineage tracking indicates that all cell replacement originates at well-defined stem cell positions, with an associated slower cell cycle. Radiobiological studies suggest a hierarchical stem cell compartment (actual and potential stem cells). Actual stem cells have an intolerance of genotoxic damage and die via apoptosis. Stem cells also selectively sort the old and new DNA strands at division, retaining the replication error free strands in the stem cell daughter. High genotoxic sensitivity and selective sorting of old and new DNA strands, provides extremely effective protective mechanisms against both replication and random errors. This provides a new explanation for the low cancer risk in the small intestine.

This review addresses the issue of histone deacetylase (HDAC) inhibitors as developed for the treatment of cancer and for the investigation of the inhibition of inflammation. The review focuses on both in vitro and in vivo models of inflammation and autoimmunity. Of particular interest is the inhibition of pro-inflammatory cytokines. Although the reduction in cytokines appears paradoxical at first, upon examination, some genes that are anti-inflammatory are upregulated by inhibition of HDAC. Whether skin diseases will be affected by inhibitors of HDAC remains to be tested.

Chronic heart failure (CHF) represents a major public health burden in developed countries. The introduction of new treatments has helped to improve its prognosis in recent years. However, it is still not possible to directly target the immunological aspects of the disease. In fact, chronic immune activation with the up-regulation of pro-inflammatory substances in the plasma remains an important feature of the disease, independently of its aetiology. Autoimmune mechanisms play a significant role in a subgroup of patients with dilated cardiomyopathy. The interplay between the two systems has not been established so far. This review briefly summarizes immune and autoimmune mechanisms in CHF.

T cell homeostasis is required for normal immune responses and prevention of pathological responses. Transforming growth factor beta (TGFbeta) plays an essential role in that regulation. Owing to its broad expression and inhibitory effects on multiple immune cell types, TGFbeta regulation is complex. Through recent advances in cell-specific targeting of TGFbeta signaling in vivo, the role of TGFbeta in T cell regulation is emerging. We demonstrated here a critical role for TGFbeta in regulating effector vs regulatory T cell homeostasis.

One of the most dramatic chromatin remodelling events takes place during mammalian spermatogenesis involving massive incorporation of somatic and testis-specific histone variants, as well as generalized histone modifications before their replacement by new DNA packaging proteins. Our data suggest that the induced histone acetylation occurring after meiosis may direct the first steps of genome compaction. Indeed, a double bromodomain-containing protein expressed in postmeiotic cells, Brdt, shows the extraordinary capacity to specifically condense acetylated chromatin in vivo and in vitro. In elongating spermatids, Brdt widely co-localizes with acetylated histones before accumulating in condensed chromatin domains. These domains preferentially maintain their acetylation status until late spermatogenesis. Based on these data, we propose that Brdt mediates a general histone acetylation-induced chromatin compaction and also maintains differential acetylation of specific regions, and is therefore involved in organizing the spermatozoon's genome.

Embryonic stem cells (ESCs), derivatives of cells of early mammalian embryos, have proven to be one of the most powerful tools in developmental and stem cell biology. When injected into embryos, ESCs can contribute to tissues derived from all three germ layers and to the germline. Prior studies have successfully shown that ESCs can recapitulate features of embryonic development by spontaneously forming somatic lineages in culture. Amazingly, recently it has been shown that mouse ESCs can also give rise to primordial germ cells (PGCs) in culture that are capable of undergoing meiosis and forming both male and female gametes. While the full potential of these ES-derived germ cells and gametes remains to be demonstrated, these discoveries provide a new approach for studying reproductive biology and medicine.

Inflammatory cardiomyopathy defined as myocarditis associated with cardiac dysfunction, represents a main cause of heart failure. Despite the improvement of diagnostic techniques, a specific standardized treatment of myocarditis is not yet available. The immunohistochemical detection of myocardial HLA up-regulation has been demonstrated useful in the identification of a sub-group of autoimmune inflammatory dilated cardiomyopathy (DCM) in part susceptible to immunosuppression. Recently, in a retrospective study, we defined the virologic and immunologic profile of responders and non-responders to immunosuppressive therapy of active lymphocytic myocarditis and chronic heart failure in patients who had failed to benefit from conventional supportive treatment. Non-responders were characterized by high prevalence (85%) of viral genomes in the myocardium and no detectable cardiac autoantibodies in the serum. Conversely, 90% of responders were positive for autoantibodies, while only 3 (15%) of them presented viral particles at PCR analysis on frozen endomyocardial tissue. With regard to the type of virus involved in non-responders, enterovirus, adenovirus, or their combination was associated with the worst clinical outcome. Hepatitis C virus (HCV) was the only viral agent of our series associated with detectable cardiac autoantibodies, suggesting a relevant immunomediated mechanism of damage by HCV and explaining the relief of myocardial inflammation after immunosuppressive treatment. The assessment of virologic and immunologic features of patients with biopsy-proven inflammatory cardiomyopathy may allow us to identify a specific treatment leading to recovery of cardiac function.

Lysosomal proteinases are involved in two critical stages of MHC class II-mediated antigen presentation, i.e., degradation of invariant chain, a chaperone molecule critical for MHC class II assembly and transport, and generation of class II-binding peptides in the endocytic compartment. We found that two lysosomal cysteine proteinases, cathepsins S and L, were found to be differentially expressed in different types of "professional" and "nonprofessional" antigen presenting cells, including B cells, macrophages, specialized thymic epithelium, intestinal epithelium, and dendritic cells. In this chapter, our recent studies on the role of cathepsin S and L in MHC class II-mediated antigen processing and presentation in these cells types are highlighted.