Immunopathogenesis of primary biliary cirrhosis: an old wives' tale

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the autoimmune destruction of the small intrahepatic bile ducts. The disease has an unpredictable clinical course, but may progress to fibrosis and cirrhosis. Although medical treatment with urseodeoxycholic acid is largely successful, some patients may progress to liver failure requiring liver transplantation. PBC is characterised by the presence of disease specific anti-mitochondrial (AMA) antibodies, which are pathognomonic for PBC development. The disease demonstrates an overwhelming female preponderance and virtually all women with PBC present in middle age. The reasons for this are unknown; however several environmental and immunological factors may be involved. As the immune systems ages, it become less self tolerant, and mounts a weaker response to pathogens, possibly leading to cross reactivity or molecular mimicry. Some individuals display immunological changes which encourage the development of autoimmune disease. Risk factors implicated in PBC include recurrent urinary tract infection in females, as well as an increased prevalence of reproductive complications. These risk factors may work in concert with and possibly even accelerate, immune system ageing, contributing to PBC development. This review will examine the changes that occur in the immune system with ageing, paying particular attention to those changes which contribute to the development of autoimmune disease with increasing age. The review also discusses risk factors which may account for the increased female predominance of PBC, such as recurrent UTI and oestrogens.     

Glycolysis — new concepts in an old pathway

Summary A survey of the existing data on the interactions of glycolytic enzymes with the cellular structure in mammalian tissues has substantiated the occurrence of an extensive degree of such associations in all tissues and during all stages of development. Furthermore, a considerable specificity was evident between the individual multiple forms of the enzymes in relation to these associations.In reviewing these data, a model has been developed which proposes that the glycolytic sequence is best described as consisting of a number of segments in vivo, each segment formed by a cluster of isozymes, many of which can interact with the actin containing filaments of the cytomatrix. The novel features of this segmentation and compartmentation have been described, and evidence has been provided that these phenomena collectively play a key role in meeting the different types of energy requirement in the cytoplasm of divergent cell types, with the wide selection of isozymes in this system offering the potential for increased flexibility and control in this important area of metabolism.     

Mutants with aberrant numbers of gametic cells shed new light on old questions

In contrast to animals, plant gametes form in distinct haploid generations, termed gametophytes. The female gametophyte of Arabidopsis consists of two gametic cells, the egg and central cell, which are flanked by accessory cells. The gametic cells differ with respect to morphology, molecular attributes and, importantly, their fate: whereas the egg cell, upon fertilisation, gives rise to the embryo, the central cell forms the endosperm. To ensure correct endosperm formation, not only the egg cell but also the central cell has to fuse with a sperm cell. The respective sperm cell pair is delivered by a single pollen tube. In some plant species, the two male gametes appear to express a different bias towards the female gametes. Such a preference consequently determines their respective contribution to either embryo or endosperm development. In Arabidopsis and many other species the sperm cells are indistinguishable and it has been discussed whether they possess an inherent preference for either of the female gametes. The recent isolation of mutants that form an aberrant number of either male or female gametes stimulates discussion, albeit with different results. Furthermore, some data indicate that the central cell is competent to initiate endosperm formation without a paternal contribution. These data support the theory that the endosperm is of gametophytic rather than sporophytic origin.     

A new weapon against an old target

High expression of folate receptors is characteristic for the effector cell population of synovial macrophages in synovial inflammation. A new drug conjugate, EC0746, targets the folate inhibitor aminopterin to folate receptors. In vitro studies show that this conjugate acts antiproliferatively and inhibits cytokine production by macrophage cell lines. Moreover, it shows strong anti-arthritic effects in the rat model of adjuvant-induced arthritis in vivo. Toxicity of aminopterin was reduced 40-fold by using equimolar doses of the drug conjugate. In conclusion, this new treatment approach has the potential to further improve the most successful principle of folate inhibition in the treatment of arthritis.     

A new view of an old pore

Despite reports suggesting a potential role in membrane fusion, the V(0) subunit of the (+)H/ATPase has remained an unlikely candidate for the fusion pore. In this issue of Cell, Hiesinger and coworkers (Hiesinger et al., 2005) present a forward genetic screen that reveals it to be necessary for synaptic vesicle fusion, independent of its role in vesicle acidification.     

Dopamine: an old target in a new therapy

Dopamine, a molecule of joy and emotions, plays vital role in regulation cancer growth and tumor angiogenesis. Dopamine secrets from neural cells in brain and peripheral cells as well. Peripheral dopamine is associated with tumorigenic events. Recent publication [Sarkar et al. Int. J. Cancer: doi:10.1002/ijc.29414, 2014] suggests that dopamine can be an ideal substitute as an anti-vascular endothelial growth factor A (VEGF-A) agent for the treatment tumor angiogenesis as dopamine is less expensive, minimum side-effect and more sensitive than other drugs. The studies also found that dopamine prevent the 5FU-induced neutropenia in tumor-bearing mice. Collectively, these pre-clinical studies claim that dopamine could be a novel therapy for managing cancer growth and chemotherapy related disorder.