Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-a* Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a growth factor for granulocytes and macrophages, is an activator of cells of the monocyte/macrophage lineage and induces HLA class I1 expression and cytokine synthesis in these target cells. Macrophage activation and class I1 expression are prominent features in rheumatoid arthritis (RA) joints, but the mechanism of their stimulation is not understood, since interferon-y, the major stimulus of class I1 expression, is not usually detectable at the protein level in synovial cell culture supernatants. We have, therefore, studied GM-CSF expression in cultures of cells derived from joints affected by F U and osteoarthritis (OA), and show that GM-CSF is produced spontaneously both by RA synovial cells and to a lesser extent by OA synovial cells in the absence of extrinsic stimuli. GM-CSFproduction continues for the 5-day duration of the culture period. Using neutralizing antibodies to tumor necrosis factor (TNF)-a we demonstrated that GM-CSF production in RA synovial cell cultures is dependent on the continued presence of active TNF-a. This result supports our concept that continued activation of the cytokine network is a marked feature of RA, and that TNF-a plays a pivotal role in this network, by regulating the production of other pro-inflammatory cytokines, such as interleukin 1, as demonstrated previously, and GM-CSE
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Cytokines are protein mediators involved in inflammation, the immune response, cell growth, repair and fibrosis. All of these processes are ongoing in active autoimmune diseases such as rheumatoid arthritis (RA), and so it would be expected that many cytokines would be actively produced in RA joints or Graves' disease (GD) thyroid glands. The cDNA cloning of cytokines has permitted the generation of pure recombinant molecules, and of newer more sensitive assays, and spurred the rapid development of knowledge in this field. Here we review the molecular strategies devised to study the possible role of cytokines in the pathogenesis of RA and GD, and describe some of the initial results. After 'cataloguing' the relative abundance of various cytokines, we sought to discover which cytokines are of major importance in pathogenesis. For that purpose we used neutralizing anti-cytokine antibodies and found that TNF alpha is one of the major signals regulating the production of IL-1 in the RA but not in the osteoarthritic (OA) joint. In order to further understand the dynamics of the cytokine network, the localization of the cytokine-producing cells by immunostaining and in situ hybridization has also been performed. The latter techniques are particularly valuable for attempting to establish the role of the target cell, such as thyroid epithelium, in the pathogenesis of disease. Cytokines act on cells via binding to high-affinity receptors. The last two years has been the cDNA cloning of many molecules encoding cytokine receptor chains, and it is now possible to begin to evaluate the other half of the cytokine pathway. Taken together, there are now exciting opportunities for the molecular dissection of the cytokine events occurring in auto-immune tissues.
The findings from this study indicate that although there are clearly common perspectives, the views of people with aphasia about services do not necessarily coincide with those of service providers. This is an important consideration when initiating consultation and highlights the need for clarity on the part of practitioners in identifying the aims and objectives of their services as far as people with aphasia are concerned.
A brother and sister of Pakistani origin suffered from sensorineural deafness, diabetes mellitus and a macrocytic anaemia. Their bone marrows showed megaloblastic erythropoiesis and contained many ringed sideroblasts. Electron microscope studies of the bone marrow revealed (1) iron-laden mitochondria in many erythroblasts, (2) non-specific abnormalities indicative of dyserythropoiesis in some erythroblasts, and (3) evidence of ineffective erythropoiesis. The deoxyuridine suppression test indicated that the megaloblastic changes were not caused by an impairment of the methylation of deoxyuridylate. Studies of nucleic acid synthesis in the bone marrow cells showed that the rate of incorporation of [3H]thymidine into DNA was increased and that the rates of incorporation of [14C]glycine and [14C]adenine into both DNA and RNA were essentially within the normal range. The anaemia did not respond to therapy with hydroxocobalamin, folic acid or pyridoxine but responded to 25 mg thiamine, daily, by mouth. In one of the cases a post-thiamine marrow aspirate showed a considerable improvement in both the megaloblastic and sideroblastic changes.
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