Hepatic stellate cells—the pericytes in the liver

Hepatic stellate cells (HSCs) are pericytes of liver in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule. HSCs comprise specialized functions such as vitamin A storage, hemodynamic functions, support of liver regeneration, and immunoregulation. In pathological conditions, HSCs transform to an activated myofibroblasts-like phenotype, start to proliferate, and de novo express several proinflammatory and profibrogenic genes. These processes are particularly important in the development of cirrhosis, portal hypertension, and hepatocellular cancer. This review highlights recent findings in understanding the biology of HSCs and discusses the physiological functions of HSCs and the role of activated HSCs in pathophysiology and disease.     

Centrosomes in the DNA damage response—the hub outside the centre

Here, we review how DNA damage affects the centrosome and how centrosomes communicate with the DNA damage response (DDR) apparatus. We discuss how several proteins of the DDR are found at centrosomes, including the ATM, ATR, CHK1 and CHK2 kinases, the BRCA1 ubiquitin ligase complex and several members of the poly(ADP-ribose) polymerase family. Stereotypical centrosome organisation, in which two centriole barrels are orthogonally arranged in a roughly toroidal pericentriolar material (PCM), is strongly affected by exposure to DNA-damaging agents. We describe the genetic dependencies and mechanisms for how the centrioles lose their close association, and the PCM both expands and distorts after DNA damage. Another consequence of genotoxic stress is that centrosomes undergo duplication outside the normal cell cycle stage, meaning that centrosome amplification is commonly seen after DNA damage. We discuss several potential mechanisms for how centrosome numbers become dysregulated after DNA damage and explore the links between the DDR and the PLK1- and separase-dependent mechanisms that drive centriole separation and reduplication. We also describe how centrosome components, such as centrin2, are directly involved in responding to DNA damage. This review outlines current questions on the involvement of centrosomes in the DDR.     

HLA-DP — part of the concert

The inductive event in the immune response is the recognition of peptides bound to human major histocompatibility complex (MHC)-encoded HLA molecules by T cells. Here, Christian Meyer, Jürgen May and Leonhard Schnittger discuss some important aspects of HLA-DP molecules.     

Autonomic neuropathy—in its many guises—as the initial manifestation of the antiphospholipid syndrome

Autonomic disorders have previously been described in association with the antiphospholipid syndrome. The present study aimed to determine the clinical phenotype of patients in whom autonomic dysfunction was the initial manifestation of the antiphospholipid syndrome and to evaluate for autonomic neuropathy in these patients. This was a retrospective study of 22 patients evaluated at the University of Colorado who were found to have a disorder of the autonomic nervous system as the initial manifestation of antiphospholipid syndrome. All patients had persistent antiphospholipid antibody positivity and all patients who underwent skin biopsy were found to have reduced sweat gland nerve fiber density suggestive of an autonomic neuropathy. All patients underwent an extensive evaluation to rule out other causes for their autonomic dysfunction. Patients presented with multiple different autonomic disorders, including postural tachycardia syndrome, gastrointestinal dysmotility, and complex regional pain syndrome. Despite most having low-titer IgM antiphospholipid antibodies, 13 of the 22 patients (59%) suffered one or more thrombotic event, but pregnancy morbidity was minimal. Prothrombin-associated antibodies were helpful in confirming the diagnosis of antiphospholipid syndrome. We conclude that autonomic neuropathy may occur in association with antiphospholipid antibodies and may be the initial manifestation of the syndrome. Increased awareness of this association is important, because it is associated with a significant thrombotic risk and a high degree of disability. In addition, anecdotal experience has suggested that antithrombotic therapy and intravenous immunoglobulin therapy may result in significant clinical improvement in these patients.

Open image in new window

     

Immunomagnetic cell sorting—pushing the limits

Efficient cell separation is a prerequisite to the functional analysis of specialised cell types within complex biological systems. High gradient magnetic cell sorting (MACS) has become increasingly popular as the method of choice for cell separation for various applications. It combines high sensitivity and high purity as well as increased recovery and viability of isolated cell populations compared to other methods. Magnetic cell sorting is particularly useful for isolation of rare cells from heterogeneous cell populations. The recent development of MACS-MultiSort eliminated the last drawback of magnetic cell sorting, namely the restriction to a single parameter. The option to sort for multiple parameters has now been added to the advantages of this method. Additionally, technologies have been developed for isolating live cells according to secreted products or for analysing and separating cells expressing antigens at very low density. These new techniques add new parameters for cytometric analysis and together with efficient magnetic separation they provide new perspectives for research, as well as for the diagnosis and therapy of many diseases. Here we discuss some of these advanced methods, their potential and their limitations.     

Autoimmune diseases — at the molecular level

Autoimmunity and autoimmune diseases are the focus of intensive research using the concepts and tools of immunology, molecular genetics and cell biology. A group of scientists recently gathered to discuss recent developments in organ-specific and systemic autoimmune diseases in both human and animal models. In this article, we hope to convey some of the excitement and enthusiasm evident at the meeting which placed emphasis on work at the molecular level.     

Dracunculiasis—the saddle is virtually ended

Dracunculiasis is a preventable parasitic disease that for many years has affected poor communities without a safe portable water supply. Transmission is basically limited among the nomadic in remote rural settings. Most countries, including Asia, are declared free from the Guinea worm disease restraining the burden of transmission to Africa especially Sudan, Ghana, Mali, Nigeria and Niger. This review focuses mainly on the progress made so far by the Global Guinea Worm Eradication Programme championed by the Carter Center, Centers for Disease Control and Prevention, World Health Organisation, The United Nations Children’s Fund and the individual efforts of endemic nations through their National Guinea Worm Eradication Programme aimed towards total global Guinea worm eradication.     

Is the Y chromosome disappearing?—Both sides of the argument

On August 31, 2011 at the 18th International Chromosome Conference in Manchester, Jenny Graves took on Jenn Hughes to debate the demise (or otherwise) of the mammalian Y chromosome. Sex chromosome evolution is an example of convergence; there are numerous examples of XY and ZW systems with varying degrees of differentiation and isolated examples of the Y disappearing in some lineages. It is agreed that the Y was once genetically identical to its partner and that the present-day human sex chromosomes retain only traces of their shared ancestry. The euchromatic portion of the male-specific region of the Y is ~1/6 of the size of the X and has only ~1/12 the number of genes. The big question however is whether this degradation will continue or whether it has reached a point of equilibrium. Jenny Graves argued that the Y chromosome is subject to higher rates of variation and inefficient selection and that Ys (and Ws) degrade inexorably. She argued that there is evidence that the Y in other mammals has undergone lineage-specific degradation and already disappeared in some rodent lineages. She also pointed out that there is practically nothing left of the original human Y and the added part of the human Y is degrading rapidly. Jenn Hughes on the other hand argued that the Y has not disappeared yet and it has been around for hundreds of millions of years. She stated that it has shown that it can outsmart genetic decay in the absence of “normal” recombination and that most of its genes on the human Y exhibit signs of purifying selection. She noted that it has added at least eight different genes, many of which have subsequently expanded in copy number, and that it has not lost any genes since the human and chimpanzee diverged ~6 million years ago. The issue was put to the vote with an exact 50/50 split among the opinion of the audience; an interesting (though perhaps not entirely unexpected) skew however was noted in the sex ratio of those for and against the notion.     

Calcitonin — A Drug of the Past or for the Future?

Postmenopausal osteoporosis results from a continuous imbalance between bone resorption and bone formation, favoring bone resorption. An increasing number of treatments for osteoporosis are in development and on the market. A range of differences and similarities are found between these treatment options, and these need to be carefully evaluated before the initiation of treatment. This article summarizes data from in vitro and animal studies, as well as clinical trials, on the effect of calcitonin on bone turnover.Calcitonin was found to exert its antiresorptive effects via directly reducing osteoclastic resorption, and thus leads to an increase in bone mineral density and bone strength. Furthermore, calcitonin appears to mainly target the most active osteoclasts, and in contrast to most other antiresorptive agents it does not reduce the number of osteoclasts. Finally, in humans, while attenuating resorption, calcitonin treatment does not interfere markedly with bone formation, in contrast to other currently available antiresorptive agents. Thus, we speculate that calcitonin treatment will lead to a continuously positive bone balance in contrast with other antiresorptive agents currently on the market and thereby, in a physiologic manner, result in improved bone quality.Calcitonin is currently only available in injectable and nasal formulations. An oral formulation may, however, improve patient acceptance and compliance. Currently, several different routes are being pursued to identify an optimal oral formulation, of which the technology based on 5-CNAC is the most advanced. There are promising clinical data available for this formulation from both osteoarthritis and osteoporosis clinical trials, although the antifracture efficacy is not yet known.     

Inflammasomes and the microbiota—partners in the preservation of mucosal homeostasis

Seminars in Immunopathology - Inflammasomes are multiprotein complexes that serve as signaling platforms initiating innate immune responses. These structures are assembled upon a large array of...     

Effect of Constant Illumination on the Function of the Hypothalamic—Pituitary—Adrenal Axis in Nonhuman Primates

Bulletin of Experimental Biology and Medicine - We studied the effect of constant illumination on the effects of administration of arginine vasopressin (AVP), one of the most important regulators...     

Evidence for the Use of Intravenous Immunoglobulins—A Review of the Literature

Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel of immunologists and internists with experience in IVIg therapy reviewed the medical literature for published data concerning treatment with IVIg. The quality of evidence was assessed, and a summary of the available relevant literature in each disease was given. To our knowledge, this is the first all-inclusive comprehensive review, developed to assist the clinician when considering the use of IVIg in autoimmune diseases, immune deficiencies, and other conditions.