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Current Immunology Reviews (v.3, #1)


Editorial by David Lo (pp. 1-1).
We begin another year much as the last, but with continued momentum. As we noted in last year's comments, our goal is to provide review articles that furnish new perspectives to bridge the gap between basic immunology and clinical application. Our particular focus is to arrange reviews covering specific application of research in basic mechanisms to the understanding of complex clinical diseases, and to highlight areas in which studies in other biomedical topics have major significance to basic and clinical immunology mechanisms. The article in this first issue of our third year illustrates these goals emphatically! I will begin by highlighting two articles that start with the cutting edge research in basic immune mechanisms and then go all the way to bridging the gap toward direct application to clinical medicine. The article by Alber and Kamradt on the most recently described Th17 subset shows how new discoveries in basic cellular immunology have direct application in elucidating clinical disease mechanisms. Similarly, the article by La Motte-Mohs, Awong and Zuniga-Pflucker shows the development of a model of the most fundamental lymphocyte developmental pathway - T lymphocyte differentiation - might be exploited for the production of lymphocytes in vitro for clinical applications. Also in this issue are the articles that impart essential mechanistic information on host response and disease pathogenesis. Gomez et al. provide us with new information on how the signal transduction mechanism changes become evident in aging immune systems. Santos et al. give us some interesting insights into how the different roles of dendritic cells can have a profound impact on the nature of immune responses in response to mycobacterium, and subsequent clinical disease. Jacobs et al. also provide us with important information on various mechanisms associated with dendritic cells in both innate and adaptive immunity. Finally, molecular mechanisms of pathogenesis are elucidated in articles by De Bruyne et al., who summarizes some important interactions between myeloma cells and stromal cells in the bone marrow, and Ying et al., who presents interesting details on how Chlamydia has been able to override basic cell mechanisms in the regulation of cell survival and death during infection. Thus, our journal is in full stride, providing an important forum for articles presenting critical information on molecular mechanisms of pathogenesis in immune mediated diseases and host response. We are grateful for the impressive contributions from our authors, and we encourage continued support from our readers and contributors.

Regulation of Protective and Pathogenic Th17 Responses by Gottfried Alber, Thomas Kamradt (pp. 3-16).
The recent description of a T helper lymphocyte subset (Th17) that is characterized by the production of IL-17, TNF-α , IL-6, IL-22, and GM-CSF has substantially influenced current concepts of the pathogenesis of inflammatory diseases such as arthritis or encephalitis. Contrasting with the prevailing dogma that held IFN-γ producing Th1 cells responsible for the pathogenesis of most organ-specific autoimmune diseases it had been noted for some time that IFN-γ-/- mice were more susceptible to arthritis and encephalitis than their wild-type, littermates and that IL-12 was dispensable for disease induction. Recently it has become clear, that Th17 cells are of central importance for the pathogenesis of inflammatory diseases. The differentiation of naive Th cells into Th17 is triggered by antigen recognition in the presence of both IL-6 and TGF-β . IL-23, a heterodimeric cytokine which shares the p40 chain with IL-12 is an important survival factor for Th17 whereas IL-27, another member of the IL-12 family strongly inhibits Th17 production. Here we review the protective and pathogenic functions of Th17 in host defense and inflammatory diseases.

Dendritic Cells: More Than Just Adaptive Immunity Inducers? by Nathalie Jacobs, Jacques Boniver, Pascale Hubert, Philippe Delvenne (pp. 17-22).
Dendritic cells (DC) are well known for their capacity to induce immune responses and there is also accumulating evidence of their ability to interact with various cell types of the innate system, such as NK, NKT or TCRγδ cells. These interactions are bi-directional, mediated by soluble or cell surface molecules and have been mainly described in the context of immune responses to infectious agents and tumors. NK, NKT or TCRγδ cells induce the maturation of DC, as shown by the increased expression of CD86, IL12 production and priming of T cell responses. On the other hand, mature DC have the ability to activate NK, NKT or TCRγδ cells for sustained innate immune responses and activated NK cells may kill immature DC. In addition, DC and NK or TCRγδ cells share similar functions such as cytotoxic and antitumor activity, interferon production and antigen presentation capacity.

Signal Transduction of the Aging Innate Immune System by Christian Gomez, Vanessa Nomellini, Eric Boehmer, Elizabeth Kovacs (pp. 23-30).
Aging is associated with defects in the cells of the innate immune system, in both their function and number. During the last decade, new evidence has revealed impairment in the early stages of the activation processes that trigger innate immune cells. In this review, the impact of aging on signal transduction in macrophages (MΦs), as pivotal representatives of innate immunity, is presented. Emphasis is put on the classical intracellular pathways of MΦ activation in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). The critical analysis of the literature reveals that, when intracellular signaling defects occur, the ability of MΦ s to respond appropriately is significantly compromised. Taken together, these observations may help explain why aged individuals have inflammatory and immune defects that range from decreased capacity to fight infections to delayed healing of dermal wounds. Gaining an understanding of the nature of the defects in innate immune cells, such as MΦ s, may shed light on the development of therapeutic strategies aimed at restoring innate immune function in aged individuals so they can better combat infectious challenges.

Host-Cell Survival and Death During Chlamydia Infection by Songmin Ying, Matthew Pettengill, David Ojcius, Georg Hacker (pp. 31-40).
Different Chlamydia trachomatis strains are responsible for prevalent bacterial sexually-transmitted disease and represent the leading cause of preventable blindness worldwide. Factors that predispose individuals to disease and mechanisms by which chlamydiae cause inflammation and tissue damage remain unclear. Results from recent studies indicate that prolonged survival and subsequent death of infected cells and their effect on immune effector cells during chlamydial infection may be important in determining the outcome. Survival of infected cells is favored at early times of infection through inhibition of the mitochondrial pathway of apoptosis. Death at later times displays features of both apoptosis and necrosis, but pro-apoptotic caspases are not involved. Most studies on chlamydial modulation of host-cell death until now have been performed in cell lines. The consequences for pathogenesis and the immune response will require animal models of chlamydial infection, preferably mice with targeted deletions of genes that play a role in cell survival and death.

Myeloma Cells and Their Interactions With the Bone Marrow Endothelial Cells by Elke De Bruyne, Eline Menu, Els Van Valckenborgh, Hendrik De Raeve, Ben Van Camp, Ivan Van Riet, Karin Vanderkerken (pp. 41-55).
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by a monoclonal proliferation of plasma cells in the bone marrow (BM), secretion of paraprotein in serum, development of osteolytic bone lesions and angiogenesis in the BM. In the BM, MM cells receive signals to survive and proliferate due to the existence of functional, mutual interactions between the MM cells and the BM stromal cells. This stroma not only offers protection against apoptosis and leads to growth stimulation, but also has a role in the clinical very relevant drug resistance. As such, it became clear that the BM stroma can also become a therapeutical target in addition to the MM cells. In the past, the BM fibroblasts were considered to be the main stromal cells that interact with the MM cells. However, since the observation of a myeloma associated angiogenesis in patients and in the 5TMM mouse model, it became clear that the endothelial cells (EC) are also an important participant of the BM stromal cells. BMEC are involved in the specific homing of MM cells and are a source of paracrine growth factors. In this review, the interaction between BMEC and MM cells will be discussed.

In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells by Ross La Motte-Mohs, Geneve Awong, Juan Carlos Zuniga-Pflucker (pp. 57-75).
T cells develop within the unique microenvironment provided by the thymus. T cell differentiation involves a series of commitment events and developmental checkpoints including T cell receptor (TCR) gene recombination and positive/negative selection of developing thymocytes to yield functionally mature T cells. These events occur in a sequential, temporal and spatial fashion, as developing thymocytes migrate through the thymus. In vitro studies to yield insights into human T cell development have classically employed the fetal thymic organ culture (FTOC) model system. This approach relies on the seeding of human hematopoietic stem cells (HSCs) and/or their progeny into host thymic lobes or thymic fragments, typically of mouse origin. Recently, a novel in vitro approach that makes use of the OP9 bone marrow stromal cell line expressing the Notch receptor ligand Delta-like-1 (OP9-DL1) effectively supported the generation of large numbers of human progenitor T cells from HSCs. In this review, we outline several in vitro systems employed for the generation and study of human T cells. Particular emphasis is dedicated to the OP9-DL1 coculture system. Finally, given the number of progenitor T cells that can be generated in vitro, we discuss the potential implications for the treatment of immune-related diseases such as cancer, immunedeficiency, and autoimmunity.

Current Understanding of the Role of Dendritic Cells and Their Co-Stimulatory Molecules in Generating Efficient T Cell Responses in Lepromatous Leprosy by Dilvani Santos, Alice Miranda, Philip Suffys, Carlos Rodrigues, Saulo Bourguignon, Helena Castro (pp. 77-85).
Leprosy is a chronic infectious disease caused by Mycobacterium leprae that needs continued vigilance, particularly for detection and treatment of hidden and undiagnosed cases. Cell-mediated immunity in leprosy has been identified as a key mechanism for the understanding of this disease. The dendritic cell (DC) is the most potent professional antigenpresenting cell and recently has been the focus of much interest as the main initiator of naive T-cell responses to several antigens. For rational use of DCs in adjuvant therapy of lepromatous leprosy, the patterns of synthesis and secretion of cytokines by DCs during some mycobacterial infections must be better understood. Therefore, the aim of this review is to illustrate some of the cellular events involved in the immune recognition of the antigens during leprosy and the role of antigen- presenting cell (DC) and their co-stimulatory molecules, such as DC-SIGN, CD-40, B7-1 and B7-2, in generating efficient T-cell responses.
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