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      Critical Roles for Interleukin 1 and Tumor Necrosis Factor α in Antibody-induced Arthritis

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          Abstract

          In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)–α was also required, although seemingly less critically than IL-1, because a proportion of TNF-α–deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFα for bone destruction. The variability in the requirement for TNF-α, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.

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          Most cited references43

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          Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin.

          When stimulated with antigen, B cells are influenced by T cells to proliferate and differentiate into antibody-forming cells. Since it was reported that soluble factors could replace certain functions of helper T cells in the antibody response, several different kinds of lymphokines and monokines have been reported in B-cell growth and differentiation. Among these, human B-cell differentiation factor (BCDF or BSF-2) has been shown to induce the final maturation of B cells into immunoglobulin-secreting cells. BSF-2 was purified to homogeneity and its partial NH2-terminal amino-acid sequence was determined. These studies indicated that BSF-2 is functionally and structurally unlike other known proteins. Here, we report the molecular cloning, structural analysis and functional expression of the cDNA encoding human BSF-2. The primary sequence of BSF-2 deduced from the cDNA reveals that BSF-2 is a novel interleukin consisting of 184 amino acids.
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            Gp130 and the interleukin-6 family of cytokines.

            Receptors for most interleukins and cytokines that regulate immune and hematopoietic systems belong to the class I cytokine receptor family. These molecules form multichain receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective cytokines. In most cases, these functional receptor complexes share common signal transducing receptor components that are also in the class I cytokine receptor family, i.e. gp130, common beta, and common gamma molecules. Interleukin-6 and related cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction. Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130. Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews recent progress in the study of the interleukin-6 family of cytokines and gp130.
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              Organ-specific disease provoked by systemic autoimmunity.

              Rheumatoid arthritis (RA) is a chronic joint disease characterized by leukocyte invasion and synoviocyte activation followed by cartilage and bone destruction. Its etiology and pathogenesis are poorly understood. We describe a spontaneous mouse model of this syndrome, generated fortuitously by crossing a T cell receptor (TCR) transgenic line with the NOD strain. All offspring develop a joint disease highly reminiscent of RA in man. The trigger for the murine disorder is chance recognition of a NOD-derived major histocompatibility complex (MHC) class II molecule by the transgenic TCR; progression to arthritis involves CD4+ T, B, and probably myeloid cells. Thus, a joint-specific disease need not arise from response to a joint-specific antigen but can be precipitated by a breakdown in general mechanisms of self-tolerance resulting in systemic self-reactivity. We suggest that human RA develops by an analogous mechanism.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                1 July 2002
                : 196
                : 1
                : 77-85
                Affiliations
                [1 ]Section on Immunology and Immunogenetics, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
                [2 ]Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Medicale/Université Louis Pasteur, 67404 Strasbourg, France
                [3 ]Beth Israel Deaconess Medical Center and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA 02215
                [4 ]Service d'Anatomie et de Cytologie Pathologique, Hopital Beaujon, 92118 Clichy, France
                Author notes

                Address correspondence to Diane Mathis and Christophe Benoist, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: 617-264-2745; Fax: 617-264-2744; E-mail: cbdm@ 123456joslin.harvard.edu

                Article
                20020439
                10.1084/jem.20020439
                2194010
                12093872
                eb028859-f9a8-44b7-aee8-b9ad2d28e120
                Copyright © 2002, The Rockefeller University Press
                History
                : 19 March 2002
                : 25 April 2002
                : 14 May 2002
                Categories
                Article

                Medicine
                cytokine,inflammatory,transgenic,tnf,knockout
                Medicine
                cytokine, inflammatory, transgenic, tnf, knockout

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