Dendritic cells and cytokines in human inflammatory and autoimmune diseases

https://doi.org/10.1016/j.cytogfr.2007.10.004Get rights and content

Abstract

Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.

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

References (157)

  • M. Moser

    Dendritic cells in immunity and tolerance-do they display opposite functions?

    Immunity

    (2003)
  • J.S. Manavalan et al.

    High expression of ILT-3 and ILT-4 is a general feature of tolerogenic dendritic cells

    Transpl Immunol

    (2003)
  • N. Suciu-Foca et al.

    Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review

    Int Immunopharmacol

    (2005)
  • S. Fujita et al.

    Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

    Blood

    (2006)
  • K. Sato et al.

    Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse

    Immunity

    (2003)
  • M. Karin et al.

    Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer

    Cell

    (2006)
  • D.E. Smith et al.

    Four new members expand the interleukin-1 superfamily

    J Biol Chem

    (2000)
  • J. Schmitz et al.

    IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines

    Immunity

    (2005)
  • C.A. Dinarello

    Biologic basis for interleukin-1 in disease

    Blood

    (1996)
  • R.M. Steinman

    Cytokines amplify the function of accessory cells

    Immunol Lett

    (1988)
  • T. Kishimoto et al.

    Interleukin-6 family of cytokines and gp130

    Blood

    (1995)
  • M. Veldhoen et al.

    TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells

    Immunity

    (2006)
  • O. Kudo et al.

    Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism

    Bone

    (2003)
  • R. Keul et al.

    A possible role for soluble IL-6 receptor in the pathogenesis of systemic onset juvenile chronic arthritis

    Cytokine

    (1998)
  • H.H. Uhlig et al.

    Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology

    Immunity

    (2006)
  • M. Cargill et al.

    A large-scale genetic association study confirms IL-12B and leads to the identification of IL-23R as psoriasis-risk genes

    Am J Hum Genet

    (2007)
  • R.N. Germain

    An innately interesting decade of research in immunology

    Nat Med

    (2004)
  • R.M. Steinman et al.

    Tolerogenic dendritic cells

    Annu Rev Immunol

    (2003)
  • S. Sakaguchi

    Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self

    Nat Immunol

    (2005)
  • E.M. Shevach

    Regulatory/suppressor T cells in health and disease

    Arthritis Rheum

    (2004)
  • Q. Tang et al.

    Regulatory T-cell physiology and application to treat autoimmunity

    Immunol Rev

    (2006)
  • J. Banchereau et al.

    Dendritic cells and the control of immunity

    Nature

    (1998)
  • J. Banchereau et al.

    Immunobiology of dendritic cells

    Annu Rev Immunol

    (2000)
  • P. Guermonprez et al.

    Antigen presentation and T cell stimulation by dendritic cells

    Annu Rev Immunol

    (2002)
  • Y.J. Liu

    IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors

    Annu Rev Immunol

    (2005)
  • I. Mellman

    Antigen processing and presentation by dendritic cells: cell biological mechanisms

    Adv Exp Med Biol

    (2005)
  • K. Shortman et al.

    Steady-state and inflammatory dendritic-cell development

    Nat Rev Immunol

    (2007)
  • Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, et al. Dendritic cell subsets in health and disease. Immunol...
  • B.N. Dittel et al.

    Presentation of the self antigen myelin basic protein by dendritic cells leads to experimental autoimmune encephalomyelitis

    J Immunol

    (1999)
  • U. Eriksson et al.

    Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity

    Nat Med

    (2003)
  • A. Bondanza et al.

    Cutting edge: dissociation between autoimmune response and clinical disease after vaccination with dendritic cells

    J Immunol

    (2003)
  • C.A. Janeway et al.

    T-cell responses to Mls and to bacterial proteins that mimic its behavior

    Immunol Rev

    (1989)
  • R. Medzhitov et al.

    Decoding the patterns of self and nonself by the innate immune system

    Science

    (2002)
  • C.G. Figdor et al.

    C-type lectin receptors on dendritic cells and Langerhans cells

    Nat Rev Immunol

    (2002)
  • T.B. Geijtenbeek et al.

    Self- and nonself-recognition by C-type lectins on dendritic cells

    Annu Rev Immunol

    (2004)
  • J.P. Ting et al.

    CATERPILLER: a novel gene family important in immunity, cell death, and diseases

    Annu Rev Immunol

    (2005)
  • S. Gallucci et al.

    Natural adjuvants: endogenous activators of dendritic cells

    Nat Med

    (1999)
  • B. Sauter et al.

    Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells

    J Exp Med

    (2000)
  • S.Y. Seong et al.

    Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

    Nat Rev Immunol

    (2004)
  • P.K. Srivastava et al.

    Stress-induced proteins in immune response to cancer

    Curr Top Microbiol Immunol

    (1991)
  • Cited by (410)

    View all citing articles on Scopus

    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.

    View full text