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Current Immunology Reviews (v.2, #1)


Editorial by David Lo (pp. 1-1).
One of the most challenging tasks in biomedical research is keeping up with the immense literature in immunology. Recent years have shown that the traditional definition of immunology is no longer sufficient to encompass the relevant areas of study, making the task even more difficult, especially to the new investigator. Many (indeed it may be argued all) of the greatest recent advances in cellular immunology have come from areas not traditionally studied by immunologists (until now!). For example, immunology has had the benefit of cell biology in the elucidation of lymphocyte activation and the access to insights from protein structural chemistry to explain T cell receptor - MHC interactions. The situation is no simpler for those wishing to do the most medically relevant studies on immune development and function. Indeed, not all immunologists have the time to benefit from a medical education. While the mouse model, in all its forms including transgenic and knockout strains, has been a traditional focus of much basic immunology, there are considerable species differences between mouse and human. Mouse models of human disease unfortunately frequently fail to provide a faithful representation of clinical pathophysiology. Thus, a strong argument could be made that basic immunology research would greatly benefit from some clear guides as to the most relevant features of human clinical immunology and pathophysiology. Conversely, clinical research would similarly benefit from clear explanations of the latest advances in molecular immunology in a context that links molecular mechanisms to medical physiology. It is for these reasons we hope to provide researchers with a new source of review articles to bridge the gap between basic immunology and clinical application. Moreover, in addition to providing reviews covering specific application of research in basic mechanisms to the understanding of complex clinical diseases, we hope to highlight areas in which studies in other biomedical topics have major significance to basic and clinical immunology mechanisms. In this issue, to kick off the second year of the publication of Current Immunology Reviews, we include several articles that provide us with important insights into the clinical application of basic immunology research. I would highlight in particular a few articles in areas of study not considered mainstream immunology yet with profound consequence in immune responses in normal and disease settings. The article by Cloez-Tayarani (page 27) presents an interesting overview of the important effects of serotonin - mainly viewed as a neurotransmitter - on immune function. Similarly, Kuipers and van den Elsen (page 55) provide some insights into the possible important effects of statins in immune mediated diseases such as Multiple Sclerosis. This last paper also highlights the importance of understanding basic cell biology mechanisms in the context of immune responses. To this point, we also have papers by Atfield, Liu, and Penninger (page 73) on the molecular mechanisms involved in T cell anergy, an especially comprehensive overview by Baumruker and Billich (page 101) on the biochemistry of sphingolipids in cell signaling, and from Brunner and Wirth (page 3) a review of the important role of the B cell transcription factor BOB.1/OBF.1 in B cell function. The practical clinical applications of basic immunology research are presented in three articles. In the article by Galindo et al. (page 13), the immune response to Aeromonas virulence factors is examined, with important lessons in host response to infectious agents. Salek-Ardakani et al. (page 37) present a compelling argument for the use of the OX40:OX40L axis as a target for therapeutics in a variety of immune mediated inflammatory conditions. Finally, Cascalho and Platt (page 65) present a cautionary tale on the immunologic barriers to replacement of damaged organs. With these articles we continue an impressive series of publications with reviews bridging the gap between basic immunology research and their application to standard-of-care clinical medicine. We invite our readers to continue to offer their outstanding articles on these topics.

BOB.1/OBF.1 - A Critical Regulator of B Cell Function by Cornelia Brunner, Thomas Wirth (pp. 3-12).
The transcriptional coactivator BOB.1/OBF.1 binds as a ternary complex with the transcription factors Oct-1 and Oct-2 to DNA and induces octamer-dependent transcription. BOB.1/OBF.1 was shown to be necessary at multiple stages of B cell development, in the bone marrow as well as at late stages in secondary lymphoid organs. Bone marrow B cells from BOB.1/OBF.1-deficient mice show increased apoptosis accompanied with decreased expression levels of the anti-apoptotic protein Bcl2. Although transgenic B cell-specific expression of Bcl2 rescued the numbers and maturation of BOB.1/OBF.1-deficient B cells in the bone marrow as well as in peripheral lymphoid organs, the B cell function was still severely impaired. The most prominent characteristic of BOB.1/OBF.1 knock-out mice is the complete failure to form germinal centers upon immunization with thymic-dependent antigens and consequently a massive defect in production of secondary Ig isotypes. In addition, the marginal zone B cell compartment, first line defence against blood born antigens, is virtually absent in BOB.1/OBF.1 -/- animals. A large number of genes specifically expressed in B cells contain octamer motifs in their regulatory regions, but only a small number of BOB.1/OBF.1 dependent genes are described yet. To understand the molecular basis of BOB.1/OBF.1 function in B cell development we and others searched for BOB.1/OBF.1 target genes. A large number of BOB.1/OBF.1-dependent genes were identified, which are involved in different aspects of lymphocyte development and signaling, supporting the critical regulatory role of BOB.1/OBF.1 for lymphocyte function. Here we summarize recent developments highlighting the central role that BOB.1/OBF.1 plays in B lymphocytes.

Host Immune Responses to Aeromonas Virulence Factors by Cristi Galindo, Jian Sha, Amin Fadl, Lakshmi Pillai, Ashok Chopra (pp. 13-26).
Aeromonas species are emerging human pathogens, which produce an array of virulence factors and cause diseases ranging from gastroenteritis to systemic infections. These bacteria can be found in food and water and grow well and produce toxins at refrigeration temperatures, which greatly increase the risk of food poisoning. A detailed understanding of host responses to Aeromonas virulence factors is paramount to developing better treatment strategies. One of the important virulence factors of Aeromonas is the cytotoxic enterotoxin, Act, which induces potent inflammatory responses in host cells and is lethal when injected intravenously into mice. Microarray analyses of Act-treated host cells by our laboratory revealed that Act induced host cell signaling and apoptosis of macrophages and colonic epithelial cells. We furthered showed that Act production is regulated by glucose inhibited division gene A (gidA) and an iron-regulated ferric uptake regulatory (fur) gene. In addition to Act, our laboratory recently discovered new virulence factors/mechanisms, including the plasminogen-activating enzyme enolase and a type III secretion system, which contribute to Aeromonas-associated diseases. Current knowledge concerning host responses to these and other Aeromonas virulence factors is discussed.

Serotonin as a Modulator of Immune Function: An Overview by Isabelle Cloez-Tayarani (pp. 27-35).
The CNS and immune system interact in a reciprocal manner through a wide variety of common mediators including neurotransmitters and cytokines. Among the former, serotonin (5-Hydroxytryptamine = 5-HT) plays a major role in the control of neuronal activity. It may also control the level of cytokines and lymphocyte proliferation. 5-HT is synthesized and released in the circulation by enterochromaffin cells from gastric and intestinal mucosa. Under inflammatory conditions such as thrombosis and ischemia, the activated platelets release 5-HT at the site of inflammation and lead to an increase in its local concentration. In addition to its possible interaction with blood cells, 5-HT may also interact with the inflamed tissue macrophages through its various receptors. Accordingly, 5-HT transporters and 5-HT receptor subtypes have been characterized in different blood cells. This review provides an overview of reported data on the regulatory role of 5-HT on the activity of peripheral blood cells. Such role includes both immunostimulatory and immunoinhibitory effects based on 5-HT concentration and its cellular target. In the light of recent data, this review also speculates on the intracellular processes (i.e. MAP kinases), which are activated by 5-HT suggesting neuromodulatory function.

OX40:OX40L Axis: Emerging Targets for Immunotherapy of Human Disease by Shahram Salek-Ardakani, Aihua Song, Ian Humphreys, Michael Croft (pp. 37-53).
Recent advances in our understanding of the mechanisms through which T cells are activated have led to new therapeutic approaches in the treatment of immunological disorders. An emerging target for selective immune intervention has been the manipulation of T cell costimulatory pathways. Impressive results in animal models have shown that the tumor-necrosis-factor receptor (TNFR) family member, OX40 (CD134), and its binding partner OX40L, are key costimulatory molecules involved in the regulation of many T cell mediated immune disorders. In this review we will highlight these new findings with a particular emphasis on their potential implications for immunotherapy of human disease.

Putative Immune Regulatory Role of Statins by Hedwich Kuipers, Peter van den Elsen (pp. 55-64).
Statins, which are mainly used for treatment of hypercholesterolemia because of their lipid-lowering effects, may also display many immunomodulatory properties. Statins interfere in the mevalonate pathway through inhibition of HMG-CoA reductase activity and thereby affect isoprenylation of proteins and cholesterol biosynthesis. Besides lowering blood cholesterol levels, statins inhibit the production of pro-inflammatory cytokines and reduce membrane expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this review we discuss the putative immunomodulatory role of statins and the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several cell types, emphasizing on the disruption of cholesterol-containing microdomains, or lipid rafts, which transport and concentrate MHC-II molecules to the cell surface. Because glycosylphosphatidylinositol (GPI)-linked proteins are in general characteristic components of biochemically defined lipid rafts, and rely for transport and function at the cell surface on the integrity of these cholesterol-containing vesicles, we argue that statins, by disrupting these vesicles, also affect the expression of other immunoregulatory molecules. In addition, we also argue that statins inhibit the activation and intracellular transport of various proteins by interfering in protein isoprenylation. The interference in these processes results in reduced expression and function of membrane-bound molecules, which play important roles in the initiation and effector function of the immune response. Finally, we discuss the potential role of statins in the treatment of neuroinflammatory diseases.

The Immunologic Barriers to Replacing Damaged Organs by Marilia Cascalho, Jeffrey Platt (pp. 65-72).
The recent years have brought breathtaking advances in the biomedical sciences and biomedical engineering. These advances offer the promise that diseases responsible for most disability and early death may soon be addressed by replacing damaged organs with bio-engineered substitutes. Application of these technologies, however, is impeded by the immune response directed against foreign cells and tissues. Here we consider the potentiality and the limitations of these new technologies and how the technologies might be combined to generate novel approaches to organ replacement that overcome immunological barriers to success.

The Biochemical Mechanisms of T-Cell Anergy by Alexandre Atfield, Peter Liu, Josef Penninger (pp. 73-99).
T-cells are thought to play important roles in the coordination and development of immune responses in both health and disease. A key checkpoint in the prevention of inappropriate activation of T-cells is the requirement for costimulation by professional APCs via receptors such as CD28. Several in vivo and in vitro methods of experimental anergy induction have been developed and are in popular use today. However, the biochemical events that determine Tcell fate following the application of activating vs. anergizing stimuli remain poorly understood. We present a survey of T-cell signal transduction in productive encounters with antigen-presenting cells, as well as the molecular mechanisms that are thought to alter these signaling pathways in T-cell anergy and the conceptual and experimental context in which this understanding has been developed. A strong possibility is that the program of anergy induction involves the upregulation of one or more 'anergy factors' and over the years, several possible mechanisms of T-cell anergy have been proposed. Amongst these, E3 ubiquitin ligases such as Cbl-b, Itch and GRAIL have recently emerged as being essential players in T-cell tolerance, as well as host survival.

Sphingolipids in Cell Signaling: Their Function as Receptor Ligands, Second Messengers, and Raft Constituents by Thomas Baumruker, Andreas Billich (pp. 101-118).
Sphingolipids have lately been recognized as important signaling molecules with an unexpected multitude of actions and mechanisms. While we are currently just uncovering the tip of the iceberg, the available data give us an unprecedented understanding of how membrane rearrangements translate into the generation of intracellular lipid signaling molecules and further into secreted bioactive lipids. Furthermore, new concepts such as the rheostat of sphingolipids show that fundamental principles in signaling also do apply to this class of molecules. The plethora of sphingolipids as well as sphingolipid modifying enzymes seem to comprise many novel, attractive, and pharmaceutically exploitable targets beyond sphingolipidoses, in applications ranging from autoimmune diseases and neurodegenerative conditions to cancer. In this review, we summarize the mechanistic triad of action of sphingolipids as membrane/raft components, intracellular signaling molecules and secreted mediators.
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