Self and non-self discrimination is needed for the existence rather than deletion of autoimmunity: the role of regulatory T cells in protective autoimmunity

Autoimmune T cells have been viewed for decades as an outcome of immune system malfunction, and specifically as a failure to distinguish between components of self and non-self. The need for discrimination between self and non-self as a way to avoid autoimmunity has been repeatedly debated over the years. Recent studies suggest that autoimmunity, at least in the nervous system, is the bodys defense mechanism against deviations from the normal. The ability to harness neuroprotective autoimmunity upon need is evidently allowed by naturally occurring CD4+CD25+ regulatory T cells, which are themselves controlled by brain-derived compounds. These findings challenge widely accepted concepts of the need for discrimination between self and non-self, as they suggest that while such discrimination is indeed required, it is needed not as a way to avoid an anti-self response but to ensure its proper regulation. Whereas a response to non-self can be self-limited by a decreased presence of the relevant antigen, the response to self needs a mechanism for strict control, such as that provided by the naturally occurring regulatory T cells.Received 8 June 2004; accepted 6 July 2004     

Natural peptide analgesics: the role of solution conformation

Endogenous opioids have been studied extensively since their discovery, in the hope of finding a perfect analgesic, devoid of the secondary effects of alkaloid opioids. However, the design of selective opioid agonists has proved very difficult. First, structural studies of peptides in general are hampered by their intrinsic flexibility. Second, the relationship between constitution and the so-called 'bioactive conformation' is far from obvious. Ideally, a direct structural study of the complex between a peptide and its receptor should answer both questions, but such a study is not possible, because opioid receptors are large membrane proteins, difficult to study by standard structural techniques. Thus, conformational studies of opioid peptides are still important for drug design and also for indirect receptor mapping. This review deals with conformational studies of natural opioid peptides in several solvents that mimic in part the different environments in which the peptides exert their action. None of the structural investigations yields a convincing bioactive conformation, but the global conformation of longer peptides in biomimetic environments can shed light on the interaction with receptors. Received 15 April 2001; received after revision 10 May 2001; accepted 11 May 2001     

Molecular aspects of pathogenesis in osteoarthritis: the role of inflammation

Arthritic diseases cause enormous burdens in terms of pain, crippling, and disability. Osteoarthritis (OA), the most common form of arthritis, is characterized by a slow progressive degeneration of articular cartilage. The exact etiology of OA is not known, but the degradation of cartilage matrix components is generally agreed to be due to an increased synthesis and activation of extracellular proteinases, mainly matrix metalloproteinases. Insufficient synthesis of new matrix macromolecules is also thought to be involved, possibly as a consequence of deficient stimulation by growth factors. Although OA is defined as a noninflammatory arthropathy, proinflammatory cytokines such as interleukin-1 have been implicated as important mediators in the disease. In response to interleukin-1, chondrocytes upregulate the production of nitric oxide and prostaglandin E₂, two factors that have been shown to induce a number of the cellular changes associated with OA. The generation of these key signal molecules depends on inducible enzymes and can be suppressed by pharmacological inhibitors.     

The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress

The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome integrity in humans. Received 31 October 2006; received after revision 4 January 2007; accepted 5 February 2007     

Towards an understanding of the role of glutamate in neurodegenerative disorders: energy metabolism and neuropathology

It is thought that impairment, of energy metabolism that results in deterioration of membrane function, leading to loss of the Mg²⁺ block on NMDA receptors, and allowing persistent activation of these receptors by glutamate, might be a cause of neuronal death in neurodegenerative disorders. Studies in rodents using mitochondrial respiratory chain toxins, such as aminooxyacetic acid, 1-methyl-4-phenylpyridinium, malonic acid and 3-nitropropionic acid, suggest that such processes may indeed be involved in neurotoxicity. Striatal and nigral degeneration induced by mitochondrial toxins in rodents resembles the neuropathology seen in humans suffering from Huntington's or Parkinson's disease, and can be prevented either by decortication or by NMDA receptor antagonists. Such experimental observations suggest that glutamate may be involved in neuronal death leading to neurodegenerative disorders in humans. If so, glutamate antagonists may offer a therapeutic approach for retarding the progression of these disabling disorders.     

Functionality of the TRPV subfamily of TRP ion channels: add mechano-TRP and osmo-TRP to the lexicon!

Transient receptor potential (TRP) ion channels have been identified as cellular sensors responding to diverse external and internal stimuli. This review will cover the TRPV subfamily that comprises vertebrate and invertebrate members. The six mammalian TRPV channels were demonstrated to function in thermosensation, mechanosensation, osmosensation and Ca²⁺ uptake. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic and chemical stimuli in C. elegans. We will focus here on the role that TRPV ion channels play in mechanosensation and a related sensory (sub-)modality, osmosensation. Received 2 May 2005; received after revision 30 July 2005; accepted 30 August 2005