Objective. To investigate whether smoking and HLA-DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline-modified proteins.Methods. In a case-control study involving patients with recent-onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk factor (smoking), major susceptibility genes included in the SE of HLA-DR, and the presence of the most specific autoimmunity known for RA (i.e., antibodies to proteins modified by citrullination). Immunostaining for citrullinated proteins in cells from bronchoalveolar lavage fluid was used to investigate whether smoking is associated with citrullination in the lungs.Results. Previous smoking was dose-dependently associated with occurrence of anticitrulline antibodies in RA patients. The presence of SE genes was a risk factor only for anticitrulline-positive RA, and not for anticitrulline-negative RA. A major geneenvironment interaction between smoking and HLA-DR SE genes was evident for anticitrulline-positive RA, but not for anticitrulline-negative RA, and the combination of smoking history and the presence of double copies of HLA-DR SE genes increased the risk for RA 21-fold compared with the risk among nonsmokers carrying no SE genes. Positive immunostaining for citrullinated proteins was recorded in bronchoalveolar lavage cells from smokers but not in those from nonsmokers.Conclusion. We identified an environmental factor, smoking, that in the context of HLA-DR SE genes may trigger RA-specific immune reactions to citrullinated proteins. These data thus suggest an etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity, all restricted to a distinct subset of RA.
Objective. High mobility group box chromosomal protein 1 (HMGB-1) is a ubiquitous chromatin component expressed in nucleated mammalian cells. It has recently and unexpectedly been demonstrated that stimulated live mononuclear phagocytes secrete HMGB-1, which then acts as a potent factor that causes inflammation and protease activation. Macrophages play pivotal roles in the pathogenesis of arthritis. The aim of this study was to determine whether synovial macrophage expression of HMGB-1 is altered in human and experimental synovitis.Methods. Intraarticular tissue specimens were obtained from healthy Lewis rats, Lewis rats with Mycobacterium tuberculosis-induced adjuvant arthritis, and from patients with rheumatoid arthritis (RA). Specimens were immunohistochemically stained for cellular HMGB-1. Extracellular HMGB-1 levels were assessed in synovial fluid samples from RA patients by Western blotting.Results. Immunostaining of specimens from normal rats showed that HMGB-1 was primarily confined to the nucleus of synoviocytes and chondrocytes, with occasional cytoplasmic staining and no extracellular matrix deposition. In contrast, inflammatory synovial tissue from rats with experimental arthritis as well as from humans with RA showed a distinctly different HMGB-1 staining pattern. Nuclear HMGB-1 expression was accompanied by a cytoplasmic staining in many mononuclear cells, with a macrophage-like appearance and an extracellular matrix deposition. Analysis of synovial fluid samples from RA patients further confirmed the extracellular presence of HMGB-1; 14 of 15 samples had HMGB-1 concentrations of 1.8-10.4 g/ml.Conclusion. The proinflammatory mediator HMGB-1 was abundantly expressed as a nuclear, cytoplasmic, and extracellular component in synovial tissues from RA patients and from rats with experimental arthritis. These findings suggest a pathogenetic role for HMGB-1 in synovitis and indicate a new potential therapeutic target molecule.High mobility group box chromosomal protein 1 (HMGB-1; previously called high mobility group 1 [HMG-1] or amphoterin) is an intranuclear factor that facilitates protein interactions with chromatin (1). Hmgb1 knockout mice die shortly after birth because of hypoglycemia secondary to insufficient glucocorticoid receptor expression, which is under HMGB-1-mediated transcriptional control (2). HMGB-1 is ubiquitously present in the nucleus of almost all mammalian cells and is highly conserved between species (3). Beyond this intranuclear role, it has recently been discovered that HMGB-1 is secreted by certain cells, including activated monocytes and macrophages, and plays important roles in inflammation and tumor metastasis (4,5). The molecule is a late mediator of endotoxin lethality in mice and
Objective. To study cytokine expression in muscle tissues of patients with inflammatory myopathies and to compare the profiles of patients with polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM). Methods. We performed indirect immunohistochemistry studies of muscle tissue sections with a panel of 16 different cytokine‐specific monoclonal antibodies, directed against interleukin‐1α, (IL‐1α), IL‐1β, IL‐1 receptor antagonist (IL‐1ra), IL‐2, IL‐3, IL‐4, IL‐6, IL‐8, IL‐10, IL‐13, interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), granulocyte‐macrophage colonystimulating factor (GM‐CSF), transforming growth factor β1 (TGFß1), TGFß2, and TGFß3 in 5 untreated patients each with PM, DM, and IBM and in 4 normal controls. Fresh frozen muscle tissue sections were fixed in formaldehyde before the procedure. The use of saponin as a detergent to permeabilize the cell membranes enabled identification of intracellular cytokine production. Results. The most prominent finding was the expression of IL‐1α observed in all patients but in none of the normal controls. In all patients with PM, DM, and IBM, IL‐1α was expressed in endothelial cells of capillaries, arterioles, and venules in areas surrounded by inflammatory cells, and also in areas with no or scarce inflammatory cells in both endomysium and perimysium. Furthermore, IL‐1α was also expressed in mononuclear inflammatory cells in all 15 cases. IL‐1β was observed in inflammatory cells in 10 of the 15 patients but, in contrast to IL‐1α, it was not expressed in blood vessel walls. TGFß1, TGFß2, and TGFß3 were strongly positive in all 15 patients, but only scattered cells were positive in the normal controls. The remaining cytokines were observed only in relatively few cells and only in occasional patients (although the patients were selected for the presence of large infiltrates), and in none of the controls. The patterns were similar in PM, DM, and IBM. Conclusion. Cytokine expression in muscle tissue of patients with inflammatory myopathy is dominated by IL‐1α, IL‐1β, and TGFß1–3. The predominant IL‐1α expression in the blood vessels indicates an importance of the endothelial cells in the inflammatory process in PM, IBM, and DM. A sustained, local release of T cell‐derived cytokines may not be a requirement for tissue injury in the inflammatory myopathies. There does not appear to be a qualitative difference in cytokine expression patterns in PM, IBM, and DM.
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