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Current Immunology Reviews (v.2, #2)
Regulation of Apoptosis by Gram-Positive Bacteria: Mechanistic Diversity and Consequences for Immunity by Glen Ulett, Elisabeth Adderson (pp. 119-141).
Apoptosis, or programmed cell death (PCD), is an important physiological mechanism, through which the human immune system regulates homeostasis and responds to diverse forms of cellular damage. PCD may also be involved in immune counteraction to microbial infection. Over the past decade, the amount of research on bacteriainduced PCD has grown tremendously, and the implications of this mechanism on immunity are being elucidated. Some pathogenic bacteria actively trigger the suicide response in critical lineages of leukocytes that orchestrate both the innate and adaptive immune responses; other bacteria proactively prevent PCD to benefit their own survival and persistence. Currently, the microbial virulence factors, which represent the keys to unlocking the suicide response in host cells, are a primary focus of this field. In this review, we discuss these bacterial "apoptosis regulatory molecules" and the apoptotic events they either trigger or prevent, the host target cells of this regulatory activity, and the possible ramifications for immunity to infection. Gram-positive pathogens including Staphylococcus, Streptococcus, Bacillus, Listeria, and Clostridia species are discussed as important agents of human infection that modulate PCD pathways in eukaryotic cells.
Physiological and Non-Redundant Functions of PKC Isotypes in T Lymphocytes by Nikolaus Thuille, Thomas Gruber, Christa Pfeifhofer, Natascha Hermann-Kleiter, Christina Lutz-Nicoladoni, Thomas Letschka, Veronika Kollmann, Michael Leitges, Gottfried Baier (pp. 143-156).
This review is about the physiological and non-redundant functions of the PKC gene products in hematopoietic cells, particularly T cells. In spite of the large amount of information on PKC functions in various cell types and tissues, the characterization of the isotype selective functions of the entire PKC family in lymphoid cell lineages is far from complete. Given the established important role of PKCθ as regulator of T cell fate and knowing that several other PKC isotypes are also expressed in T cells at a high level, we here summarize the physiological and non-redundant functions of PKCα, β, δ, ε,ζ and θ isotypes in T cells (with emphasis on the ongoing mouse genetic studies). Their known and/or suspected cellular regulation, effector pathways as well as physiological functions are discussed. While PKCβ,ε, δ and appear to be dispensable during cellular activation of primary CD3+ T cells, PKCα and PKCθ take critical parts in signaling pathways that are necessary for full antigen receptor mediated T cell activation and T lymphocyte immunity.
Defining a Role for Mucosal Immunity in the Prevention and Pathogenesis of Respiratory Allergic Diseases by Anthony Horner (pp. 157-167).
While it has long been recognized that the mucosal and systemic immune systems function semiindependently, until fairly recently, understanding of aeroallergen hypersensitivities derived principally from studies of systemic immune regulation. Nonetheless, tolerance and hypersensitivities to airborne allergens are likely to be driven primarily, if not exclusively, by immunological events taking place within the lungs and their associated lymphoid tissues. Therefore, this review will focus on the role of the airways in the prevention, development, and treatment of respiratory allergic diseases. I will first consider how the immunological immaturity of infancy may contribute to the genesis of respiratory allergic diseases. Current understanding of the mechanisms that promote airway allergen tolerance and those that mediate CD4 cell differentiation will then be discussed. Subsequent sections will review how airway exposures to allergens and man made and natural adjuvants influence local immune homeostasis and host risk for developing respiratory allergic diseases. Finally, I will consider how interventions that target airway immunity might be utilized for the prevention and treatment of aeroallergen hypersensitivities.
Molecular Advances Toward the Understanding of the Patho-Biology of Idiopathic Myelofibrosis by Anna Migliaccio, Alessandro Vannucchi, Giovanni Migliaccio, Ronald Hoffman (pp. 169-186).
Chronic idiopathic myelofibrosis (IM) is a chronic myeloproliferative disorder characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis, marrow fibrosis, osteosclerosis, marrow neo-vascularization, abnormal stem/progenitor cell trafficking and extramedullary hematopoiesis. The disease may eventually evolve into acute leukemia. This Philadelphia chromosome negative disorder is thought to originate from a somatic mutation at the level of the multipotent hematopoietic stem cell, the most visible consequence of which is a profound hyperplasia associated with increased proliferation but abnormal differentiation of the megakaryocytes (MKs). The pathobiology of the disease, however, involves not only abnormal hematopoietic stem/progenitor cells functions, but also a defective marrow microenvironment. The molecular nature of the genetic defect in IM and how this defect might induce so many pleiotropic consequences remains unknown. Many of the features of the human disease can be reproduced in mice by genetic alterations that induce MK abnormalities similar to those found in patients. Unfortunately, none of the mutations causing the disease in mice has been detected in the human disease. These animal models, however, allow one to dissect the patho-biological pathway that establishes the complex features of IM. Furthermore, these models also shed light on the cross-talk between stem/progenitor cells and microenvironment in normal hematopoiesis.
IL-2 Receptor Targeted Immunomodulatory Biologics: The Past, Present, and Future by Deanna Franke, Haval Shirwan (pp. 187-208).
The interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) system plays a central role in both the innate and adaptive arms of the immune response. Of major importance is the function of IL-2/IL-2R in the activation, differentiation, expansion, and maintenance of T cells that are critical to adaptive immunity. Clinically, the IL-2/IL-2R axis has been linked to the development and persistence of hematopoietic malignancies, autoimmune disorders, and allograft rejection. As such, the IL-2/IL-2R system has been extensively studied and exploited for T-cell directed immunotherapy. Several immunomodulatory approaches targeting this receptor system have been developed that include antibody-based ligands and radioisotopes, as well as immunoglobulin and cytokine chimeric biologics, which contain toxins and apoptosis-inducing proteins. While some of these biologics are already in clinical practice others are either in transition to the clinic or under development. We herein review the effectiveness and limitations of these biologics and discuss new strategies that could minimize the limitations and improve on the efficacy of IL-2R-targeted immunotherapy.