CONTENTS
Review
- The Paradigms of Causality and Treatment for Autoimmune Disease
Irun R. Cohen, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, IsraelAbstract. A key concept in medicine is that rational therapy rests on accurate diagnosis; quite simply, therapy that is not tuned to the cause of the disease will not cure the patient. I do not mean to say that effective treatments cannot emerge from faulty diagnoses. In truth, much of our therapeutic ensemble is composed of drugs developed as a result of chance observation, random, screening, intuition, or pre-scientific tradition. Nevertheless, the way to effective therapy is best paved by understanding. Effects are inherent in their causes; so if we want to cure autoimmune diseases using the scientific method, we are obliged to inquire into their causes. By reducing the discordant complexity of the disease to the single cause that underlies it, we can hope to learn the most efficient way to manipulate the disease process. How do we identify a cause when we see one? Quite simply, a single cause is that which is both necessary and sufficient to produce the effect. Here, I explore the general paradigm of autoimmune causality, using multiple sclerosis as a specific example.
Keywords: autoimmune disease; therapy; causality; multiple sclerosis; diabetes..betes..
- Uncovering the Differences between T Cell Tolerance and Immunity
Anthony T. Vella, Department of Microbiology, Oregon State University, Corvallis, Oregon, USAAbstract. In the last two decades T cell function has been analyzed in vitro from many different angles with a great deal of attention dedicated to the basic requirements of activation. During this time a compendium of information has been collected and has proven to be invaluable. Paradoxically very little is known about T cell activation and function in vivo. In the last decade a number of models have been developed which allow the tracking of Ag-activated T cells in vivo and these studies have been instrumental in advancing the field of T cell biology. In particular, a new and emerging paradigm of T cell immunity is evolving.
Keywords: T cell activation; immunity; immune memory.memory.
- The Physiological Role of Regulatory T Cells in the Prevention of Autoimmunity: Generation, Specificity and Mode of Action
Benedict Seddon, Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UKAbstract. Until recently, the traditional view was that tolerance to self antigens was maintained by a combination of physical deletion intrathymically and functional deletion in the periphery of autoreactive T cells. There is now, however, abundant evidence that the normal T cell repertoire contains overtly autoreactive T cells whose pathogenic potential is held in check by the activity of a distinct subset of peripheral T cells, so called regulatory or suppressor T cells. This article examines data from one model of rodent autoimmunity, where autoimmune pathology develops following thymectomy and irradiation of normal laboratory rats, which characterise the development and function of these so called regulatory T cells.
Keywords: regulatory T cells; autoimmunity prevention.ention.
- Epitope Spreading: a Mechanism for Progression of Autoimmune Disease
Vincent K. Tuohy (1, 2) and R. Philip Kinkel (2); (1) Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA, (2) Mellen Center for Multiple Sclerosis Research and Treatment, Department of Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USAAbstract. Autoimmune diseases are typically characterized by a persistent inflammatory self-recognition process that ultimately leads to chronic progressive disability. Over the past several years we have addressed the fundamental question of why autoimmune diseases are chronic. Our working hypothesis in these studies has been that autoimmunity involves a continuous acquisition of new self-recognition events, thereby providing an inflammatory steady-state that leads to chronicity. This acquired T cell neoautoreactivity is commonly referred to as epitope spreading. By studying mulitple sclerosis (MS) and its related animal model, experimental autoimmune encephalomyelitis (EAE), we have found that chronic progression of autoimmune disease is invariably linked to the development of any epitope-spreading process that manifests as a cascade of inflammatory T cell neoautoreactivities to a sequential series of predictable new target self-antigens. However, our most recent observations indicated that the emergence of epitope spreading is accompanied by a concurrent regression of the established primary autoreactivity associated with disease onset. Thus, our studies indicate that progression of autoimmune disease involves a shifting of T cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during progression to chronicity. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an „epitope du jour” and „moving target” perspective.
Keywords: autoimmunity; EAE/MS; T cell; myelin; demyelination.nation.
- A Role of NF-kB and the Proteasome in Autoimmunity
Takuma Hayashi and Denise Faustman, Immunobilogy Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USAAbstract. Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic b cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear facktor-kB (NF-kB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor a (TNF-a). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
Keywords: type 1 diabetes; proteasome, LMP2; apoptosis; NOD mose; NF-kB. NF-kB.
- Complement Regulatory Proteins and Autoimmunity
Mitsuhiro Kawano, Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, JapanAbstract. To discriminate self from nonself is an essential issue in the immune system. Autologous cells are protected against complement-mediated cell injury by the self-recognition mechanism using complement regulatory proteins composed of complement receptor type 1 (CR1, CD35), membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF, CD55) and homologous restriction factor (protectin, CD59). Recently, the upregulation of these molecules has been widely shown in inflammatory tissues and organs affected by autoimmune disease, and in vitro assays have revealed that immune complexes or several cytokines, including interferon g, tumor necrosis factor a, interferon 1b and transforming growth factor b can upregulate these molecules. In contrast, it has been found that expression of these complement regulatory proteins is markedly decreased on autologous cells undergoing apoptosis. These findings suggest that complement regulatory proteins have dual roles at inflammatory sites: enhancement of cellular resistance to complement attack and acceleration of clearance of cells injurious to the organism due to complement-mediated mechanisms. To assist the former function, a therapeutic approach using recombinant soluble complement regulatory proteins may provide one promising strategy for the treatment of autoimmune diseases.
Keywords: membrane cofactor protein (CD46); decay accelerating factor (CD55); homologous restriction factor (CD59); complement receptor type 1 (CD35).(CD35).
- PATHOGENIC IMMUNITY IN THEILER’S VIRUS-INDUCED DEMYELINATING DISEASE: A VIRAL MODEL FOR MULTIPLE SCLEROSIS
Byung S. Kim (1), Joann P. Palma (1), Atsushi Inoue (2) and Chang-Sung Koh (2); (1) Departments of Microbiology-Immunology and Pathology, Northwestern University Medical School, Chicago, IL 60611 and (2) Third Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390, JapanAbstract. Multiple sclerosis involves inflammatory immune responses in the central nervous system and is considered as an autoimmune disease potentially associated with viral infection. The majority of experimental models rely heavily on the autoimmune components since similar diseases can be induced following immunization with various myelin antigens. A very attractive alternative model is the Theiler’s murine encephalomyelitis virus-induced demyelinating disease. This disease is primarily a CD4+ T cell-mediated, inflammatory demyelinating disease, induced following viral infection. Virus-specific inflammatory Th1 cell responses, rather than cytotoxic T lymphocyte response, play a critical role in the pathogenic immune responses. The major pathogenic epitopes have been identified and these are correlated with a Th1 type response to the epitopes following viral infection. In addition, the initial virus-specific immune response is followed by the autoimmune responses to myelin antigens. Assessment of cytokines produced locally in the CNS during the course of disease suggests involvement of inflammatory cytokines in the disease. Furthermore, the manipulation of inflammatory cytokine levels by administration of either recombinant cytokines or antibodies to the cytokines strongly influences the induction and/or progression of disease, supporting the importance of these inflammatory cytokines in this virus-induced demyelinating disease.
Keywords: multiple sclerosis; Theiler’s virus; demyelinating disease.isease.
- Evidence that Fas and FasL Contribute to the Pathogenesis of Experimental Autoimmune Encephalomyelitis
Bonnie N. Dittel, Section of Immunobiology, Yale School of Medicine, New Haven, CT 06520-8011, USAAbstract. The well established and characterized animal model for the human demyelinating autoimmune disease mulitple sclerosis (MS) is known as experimental autoimmune encephalomyelitis (EAE). EAE is clinically characterized by focal areas of inflammation and demyelination and an infiltrate composed of large numers of lymphocytes and macrophages, often found in a perivascular localization but also throughout the central nervous system (CNS). Active immunization of mice with several different protein components of myelin, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), are capable of eliciting an immune response resulting in the quintessential symptoms of EAE: ascending paralysis involving the tail and then the limbs. Depending on this mouse strain and myelin antigen utilized, the disease course can be acute or chronic relapsing, characterized by a rapid onset of hind limb weakness that commonly progresses to paralysis, followed by spontaneous remission starting 7-10 days after the initial appearance of symptoms. EAE can also be induced passively by the adoptive transfer of in vitro activated CD4+ T cell clones or lines, typically of the Th1 phenotype, into irradiated susceptible recipients. The mechanisms involved in the cellular pathogenesis leading to paralysis and demyelination have been extensively studied and are primarily mediated by CD4+ T cells of the Th1 phenotype, with specificity for myelin antigens. Following activation, Th1 CD4 T cells produce in abundance the inflammatory cytokine TNF-a, IFN-g and lymphotoxin-a (LT-a, also known as TNF-b). IFN-g production is highly correlated with encephalitogenicity and may contribute to disease by up-regulation of adhesion molecules on endothelial cells, facilitating migration of lymphocytes into the CNS; by induction of MHC class I and MHC class II molecules on astrocytes, microglial cells and brain endothelium, facilitating Ag presentation in the CNS; and by activation of macrophages, leading to production of nitric oxide, a potent cytotoxic molecule. TNF-a and LT-a are both members of the TNF family of molecules and cause cell death by apoptosis following interaction with their counter-receptors, the TNFR1 and TNF2, leading to a cascade of proteolytic events culminating in the blebbing of the cytoplasmic membrane, nuclear condensation and DNA fragmentation. Consequently, the production of TNF-a and LT-a by Th1 clones has been correlated with encephalitogenic potential and Abs to both prevents EAE upon transfer of encephalitogenic clones. Even though substantial evidence exists for the role of inflammatory cytokines in the pathogenesis of EAE, other mechanisms of myelin destruction are thought to exist. To date, many reports have implicated a role for the cell death-inducing ligand pair Fas and Fas ligand (FasL)
Keywords: Fas; Fas ligand; experimental autoimmune encephalomyelitis.elitis.
- The Role of Cytokines in Experimental Autoimmune Encephalomyelitis
Estelle Bettelli and Lindsay B. Nicholson, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USAAbstract. Experimental autoimmune encephalomyelitis (EAE) is an animal model of the demyelinating disease multiple sclerosis. In EAE cytokines play a critical role in defining the Th1 or Th2 nature of the autoantigen directed immune response, and in propagating and regulating inflammation within the central nervous system. In this review we summarize some of the recent developments in the field of cytokine research that relate to this model of human disease, focusing principally on disease induced with the autoantigens myelin proteolipid protein and myelin oligodendrocyte protein.
Keywords: experimental autoimmune encephalomyelitis; cytokines; proteolipid protein; myelin oligodenodrocyte protein; review.review.
- Involvement of Apoptotic Protease Cascade for Tissue Destruction in Sjögren’s Syndrome
Yoshio Hayashi, Kumiko Yayagi and Norio Haneji, Department of Pathology, Tokushima University School of Dentistry, 3 Kuramotocho, Tokushima 770, JapanAbstract. Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry mouth and dry eye due to insufficient secretion. Although it has been assumed that a combination of immunologic, genetic and environmental factors may play a key role on the development of autoimmune lesion in the salivary and lacrimal gland, little is known about the disease pathogenesis. We have identified the 120 KD a-fodrin as an important autoantigen on the development of SS in both animal model and SS patients, but the mechanism of a-fodrin cleavage leading to tissue destruction in SS remains unclear. Tissue-infiltrating CD4+ T cells purified from the salivary glands bear a large proportion of Fas ligand and the salivary gland duct cells possess apoptotic receptor Fas. Anti-Fas antibody-induced apoptotic salivary gland cells results in specific a-fodrin cleavage to the 120 KD fragment in vitro. Preincubation with a combination of calpain and caspase inhibitor peptides could be responsible for inhibition of the 120 KD a-fodrin cleavage. Thus, an increase in apoptotic protease activities may be involved in tha progression of a-fodrin proteolysis and tissue destruction in the development of SS.
Keywords: Sjögrens’s syndrome; autoantigen; protease; apoptosis.ptosis.
- Is Lack of Peripheral Tolerance Induction a Cause for Diabetes in the Non-Obese Diabetic Mouse?
Torben Lund, Department of Immunology, Windeyer Institute for Medical Sciences, and Jessica Strid, Immunobiology Unit, Institute of Child Health, University College London, London, UKAbstract. The nonobese diabetic (NOD) mouse is a spontaneous animal model for type 1 diabetes characterized by a selective destruction of the insulin producing b-cells in the pancreas. As in humans, the disease is controlled by several susceptibility genes some of which maps to the major histocompatibility complex on chromosome 17. However environmental factors contributes also to the development of the disease in the NOD mouse presumably through controlling the balance between the Th1 and Th2 response in the animal. Recent observations have shown that the NOD mouse has abnormalities in the development of bone marrow-derived antigen presenting cells. These include the most potent activators of naive T cells, the dendritic cells, which exist in at least two different sub-populations; DC1 cells responsible for activation of Th1 cells and DC2 cells that produce Th2 cells. In addition to activate na?ve T cells, the dendritic cells are also involved in generating central and peripheral tolerance to self-molecules. In this process DC2 cells appear to be more important for development of peripheral tolerance than DC1 cells. Further to abnormalities in development of bone marrow-derived antigen presenting cells, the NOD mouse has also a defect in the thymic selection of T cells leading to a higher concentration of autoreactive T cells. We speculate that the NOD mouse may develop an imbalance in the two subset of dendritic cells with a skewing towards DC1 cells; thus having a reduced ability to generate peripheral tolerance to a number of autoantigens.
Keywords: peripheral tolerance; non-obese diabetic (NOD) mouse; antigen-presenting cellsg cells
- Neuro-Endocrine-Immune Axis in Human Rheumatoid Arthritis
Tsuyoshi Sakane and Noboru Suzuki, Department of Immunology and Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, JapanAbstract. We present an overview of the role of neuro-endocrine-immune mechanisms in the pathophysilogical responses of patients with rheumatoid arthritis (RA). In patients with RA proinflammatory cytokines secreted by synovial cells provoke local inflammation in the joints and, simultaneously, initiate a systemic acute phase response. Thus, profund changes of the neuro-endocrine-immune axis could take place in the patients. Defects in the hypothalamus-pituitary-adrenal axis have been observed in patients with RA. Prolactin levels are often elevated and a abnormal sex hormone levels have been described in RA patients. Defective neural regulation of inflammation involving neuropeptides at least partly plays a pathogenic role in RA.We and others have found that participants of the neuro-endocrine-immune interactions, such as hormones, neurotransmitters and neuropeptides, modulate RA synovial cell functions and that they are actually produced by, and their receptors are expressed on, cells within the inflammatory joint compartment. Thus, neuropeptides and hormones not only affect a systemic acute phase response of RA patients, but also modulate local inflammation directly in RA joints. These results suggest that defects in regulatory processes, which are fundamental to RA, may lie in the immune system, the nervous system, the endocrine system or the interactions of these. A better understanding of neuro-endocrine-immune interactions holds the promise of new approaches to the treatment of RA with the use of hormones, neurotransmitters, neuropeptides and/or their antagonists.
Keywords: neuro-endocrine-immune interactions; rheumatoid arthritis, synovial cells; hupothalamus-pituitary-adrenal axis; inflammation.mation.
- The Role of T Cells in Rheumatoid Arthritis
Cornelia M. Weyand, Ewa Bryl and Jörg J. Goronzy, Division of Rheumatology, Mayo Foundation, Rochester, MN 55905, USA
Abstract. In rheumatoid arthritis (RA), T cells infiltrate into the synovial membrane where they initiate and maintain activation of macrophages and synovial fibroblasts, transforming them into tissue-destructive effector cells. The diversity of the disease process and the formation of complex lymphoid microstructures indicates that multiple T cell activation pathways are involved. This model is supported by the association of distinct disease patterns with different variants and combinations of HLA class II molecules. T cell pathology in RA, however, is not limited to the joint. Affected patients have major abnormalities in the T cell pool with a marked contraction in T cell receptor diversity and an outgrowth of large clonal populations. Clonally expanded CD4+ T cells lose expression of the CD28 molecule and gain expression of perforin and granzyme. Consequently, the functional profile of expanded CD4+CD28null T cells is fundamentally changed and is shifted towards tissue-injurious capabilities. CD4+CD28null T cells are particularly important in patients with extraarticular manifestations of RA, where they may have a direct role in vascular injury. Understanding the mechanisms underlying the loss of T cell diversity and the emergence of pro-inflammatory CD4+CD28- T cell clonotypes may have implications for other autoimmune syndromes.
Keywords: HLA; autoimmunity; cytokines, synovitis; oligoclonality; CD4+CD28null.