Dendritic cells and cytokines in human inflammatory and autoimmune diseases
Introduction
The immune system is composed of a non-antigen-specific innate limb and an antigen-specific adaptive limb [1]. Innate immunity, borne by cells such as granulocytes and macrophages and proteins such as complement and cytokines, includes a variety of prompt reactions in response to infectious agents and other challenges. An excessive response results in inflammatory processes. The adaptive immunity, borne by lymphocytes, is acquired in weeks or months. It is characterized by an exquisite specificity for the eliciting antigen as well as memory, which allows a faster and stronger response upon re-exposure to the antigen. Adaptive responses can be immunogenic, leading to resistance to infections and possibly cancer, or tolerogenic avoiding response against self. Indeed, to efficiently protect us from invading microorganisms, the adaptive immune system must distinguish self from non-self as immune responses against self can create a wide repertoire of autoimmune diseases. Anti-self immune responses are prevented through a variety of mechanisms occurring at various levels during the development of the immune system [2]. Autoreactive lymphocytes can be deleted, rendered anergic or rendered suppressive [3], [4], [5]. Suppressor T cells, also called regulatory T cells, suppress autoreactive responses both in an antigen-specific and a non-antigen-specific fashion. These immunological events happen either in the primary lymphoid organs (bone marrow and thymus) and are thus collectively called “central tolerance” or in the periphery and are then called “peripheral tolerance”. Clinical autoimmunity arises as a result of an altered balance between the autoreactive cells and the regulatory mechanisms designed to counterbalance them.
DCs are specialized to capture and process antigens to present their peptides to lymphocytes. They are found in all tissues including blood and lymphoid organs [6], [7], [8], [9], [10], [11], [12]. In peripheral tissues, DCs are found in an immature stage specialized in the capture of antigens. In response to microbes, DCs undergo a complex process of maturation into antigen-presenting cells. This happens while the DCs migrate from the periphery into the draining lymph node through the lymphatics. In the steady state, DCs also migrate at a low rate without undergoing activation. Then they present self-antigens to lymphocytes in the absence of costimulation thereby leading to peripheral tolerance. Various mouse models have demonstrated that DCs bearing self-antigens are able to induce autoimmune diseases [13], [14], [15]. Furthermore alterations of DC homeostasis have been directly implicated in various human autoimmune diseases including type I diabetes, multiple sclerosis, and systemic lupus erythematosus (SLE) [16], [17].
Here we review our current understanding of dendritic cell function in tolerance and how cytokines interfere with these processes to generate autoimmunity.
Section snippets
Dendritic cell maturation
Dendritic cells (DCs) are a heterogeneous family of cells of haematopoietic origin that are specialized in the handling of antigens, i.e. those from infectious agents and self, and their presentation to lymphocytes. Though most of the current knowledge relates to the presentation of peptides to T cells in the context of MHC classes I and II molecules, DCs can present glycolipids and glycopeptides to T cells and NKT cells as well as polypeptides to B cells. DCs undergo a complex maturation
Cytokines, inflammation and autoimmunity
Cytokines represent critical mediators of the autoimmune process. They may represent products of DCs and/or induce the differentiation of immature DCs into mature DCs that can select autoreactive lymphocytes (Fig. 2).
Toll-like receptor (TLR) ligands and autoimmunity
Infections frequently precede the occurrence of either organ-specific or systemic autoimmune diseases. Molecular mimicry, however, cannot account for all the autoimmune responses that have been linked to infectious diseases. TLRs are key components of the innate immune system. These receptors activate multiple pathways of inflammation that eventually permit to eradicate invading pathogens [135]. Microbial-derived TLR ligands include a wide range of molecules with strong adjuvant activity that
High mobility group box 1 protein and SLE
High mobility group box 1 protein, an abundant nuclear protein displaying potent pro-inflammatory effects when released extracellularly, can mediate the activation of TLR9 by DNA-containing immune complexes through a mechanism involving the immunoglobulin superfamily member RAGE, which is the best-characterized receptor for HMGB1. Necrosis or tissue injury causes HMGB1 to be released from cells; it then binds to DNA-containing immune complexes in serum and then the resultant complexes regulate
Conclusions
Much progress has occurred in the understanding of the biological basis of autoimmunity in the past decade leading to identification of cytokines as the major regulators of immune homeostasis and the balance between tolerance and immunity. This permitted generation of new treatments with TNF and IL-1 antagonists on top (Table 1). TNF blockade is clinically useful in several autoimmune diseases. Blocking IL-1 effectively treats patients with juvenile arthritis, familial periodic fever syndromes
Acknowledgments
Supported by Baylor Health Care System Foundation, the Alliance for Lupus Research (VP), the Dana Foundation, Defense Advanced Research Planning Agency (JB), The National Institutes of Health (U19 AIO57234-02, P01 CA084512, R01 CA078846 to JB, R0-1 AR050770-01 and P50 ARO54083 to VP). JB holds the W.W. Caruth, Jr. Chair in Organ Transplantation Immunology. AKP holds the Michael A. Ramsay Chair for Cancer Immunology Research. We thank Dr. Michael Ramsay and Dr. William Duncan for their
Jacques Banchereau, PhD is the director of Baylor Institute for Immunology Research in Dallas and holds the W.W. Caruth, Jr. Chair in Organ Transplantation Immunology. He received his PhD in biochemistry from the University of Paris in 1980 and later served as director of the Schering Plough Laboratory for Immunological Research near Lyon, France, where he was among the first to discover how to grow human dendritic cells. Dr. Banchereau came to Baylor in 1996 to develop the Baylor Institute for
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Cited by (0)
Jacques Banchereau, PhD is the director of Baylor Institute for Immunology Research in Dallas and holds the W.W. Caruth, Jr. Chair in Organ Transplantation Immunology. He received his PhD in biochemistry from the University of Paris in 1980 and later served as director of the Schering Plough Laboratory for Immunological Research near Lyon, France, where he was among the first to discover how to grow human dendritic cells. Dr. Banchereau came to Baylor in 1996 to develop the Baylor Institute for Immunology Research. He is an adjunct professor of Microbiology and a member of the Cancer Immunobiology Center at The University of Texas Southwestern Medical Center. Dr. Banchereau also holds an adjunct professorship in biomedical studies at Baylor University Medical Center in Waco, TX. He has served on the National Institutes of Health's Experimental Immunology Study Section, Center for Scientific Review, in the area of Experimental Immunology. He has published more than 260 papers and 160 book chapters and reviews in major international journals. His research interests center around various areas of immunology and cancer including dendritic cells, novel cytokines and antibody-producing B lymphocytes.
Patrick Blanco, MD, PhD is currently an assistant professor in the Department of Immunology at the University of Bordeaux 2 and at the University Hospital of Bordeaux. He obtained his degree in medicine (1998) and in internal medicine (2001) at the University of Bordeaux “Victor Segalen”. He has worked in the laboratory of Professor Jacques Banchereau as a postdoctoral Fellow from 1999 to 2001 (Baylor Institute for Immunology Research, Dallas, TX, USA). His main field of interest is the study of the pathogenesis and treatment of autoimmune diseases. In particular, he was among the first to delineate the implication of dendritic cells and CD8+ T lymphocyte in the generation of the autoimmune response and tissue lesions in systemic lupus erythematosus.
Karolina Palucka, MD, PhD earned her MD in 1988 from Warsaw Medical Academy in Poland. She went on to complete her PhD in hematology and immunology in 1993 at the Karolinska Institute in Stockholm, Sweden. Dr. Palucka is an investigator at the Baylor Institute for Immunology Research in Dallas, where she began in 1998 as a senior research associate. She holds the Michael A.E. Ramsay Chair for Cancer Immunology Research. She also oversees the Flow Cytometry Core and the GMP Cell Core. In August 2005, she was appointed to an adjunct professorship in biomedical studies at Baylor, Waco. Dr. Palucka and her team focus on understanding how the human immune system works and how it may be manipulated to fight cancer. She also leads a project to develop a mouse model of the human immune system, which is being used to study human tumors and how they influence dendritic cell function. These ‘humanized’ mice are also being used to develop improved vaccine strategies.
Virginia Pascual, MD received her MD from Facultad de Medicina, Universidad Complutense in Madrid. Dr. Pascual joined the faculty at Baylor Institute for Immunology Research in 1999 as an Investigator. She has been an adjunct professor of biomedical studies at Baylor, Waco since August 2005. In her clinical practice, she specializes in pediatric rheumatology and her research focuses on understanding autoimmune diseases in children. Dr. Pascual's group discovered that interleukin-1 is a major cause of the joint inflammation in a type of juvenile arthritis and that blocking this cytokine alleviated symptoms. They have also elucidated the role of interferon-α in systemic lupus erythematosus (SLE). She is the principal investigator on an NIH P50 Center of Research Translation award that established a Center for Lupus Research at BIIR.