Clonal expansion of T cell specificities in the synovial fluid of patients has been taken as evidence for a local stimulation of T cells. By studying the T cell receptor (TCR) repertoire of CD4± T cells in the synovial and peripheral blood compartments of patients with early rheumatoid arthritis (RA), we have identified clonally expanded CD4 + populations. Expanded clonotypes were present in the peripheral blood and the synovial fluid but were not preferentially accumulated in the joint. Dominant single clonotypes could not be isolated from CD4+ cells of HLA-DRB1 *04+ normal individuals. Clonal expansion involved several distinct clonotypes with a preference for Vf633, V1314', and VJ817'CD4+ T cells. A fraction of clonally related T cells expressed IL-2 receptors, indicating recent activation. The frequencies of clonally expanded V/317+CD4+ T cells fluctuated widely over a period of one year. Independent variations in the frequencies of two distinct clonotypes in the same patient indicated that different mechanisms, and not stimulation by a single arthritogenic antigen, were involved in clonal proliferation. These data support the concept that RA patients have a grossly imbalanced TCR repertoire. Clonal expansion may result from intrinsic defects in T cell generation and regulation.The dominance of expanded clonotypes in the periphery emphasizes the systemic nature of RA and suggests that T cell proliferation occurs outside of the joint. (J. Clin. Invest. 1994. 94
Properties of the metal ion binding sites of Zn-transcription factor IIIA (TFIIIA) were investigated to understand the potential of this type of zinc finger to undergo reactions that remove Zn 2+ from the protein. Zn-TFIIIA was purified from E. coli containing the cloned sequence for Xenopus laevis oocyte TFIIIA and its stoichiometry of bound Zn 2+ was shown to depend on the details of the isolation process. The average dissociation constant of Zn 2+ in Zn-TFIIIIA was 10 −7 . The dissociation constant for Zn-F3, the third finger from the N-terminus of TFIIIA, was 1.0 × 10 −8 . The reactivity of Zn-TFIIIA with a series of metal binding ligands, including 2-carboxy-2′-hydroxy-5′-sulfoformazylbenzene (zincon), 4-(2-pyridylazo)-resorcinol (PAR), and 3-ethoxy-2-oxo-butyraldehyde-bis-(N 4 -dimethylthiosemicarbazone) (H 2 KTSM 2 ) revealed similar kinetics. The reactivity of PAR with Zn-TFIIIA declined substantially when the protein was bound to the internal control region (ICR) of the 5S ribosomal DNA. Both Cd 2+ and Pb 2+ disrupt TFIIIA binding to its cognate DNA sequence. The Pb 2+ dissociation constant of Pb-F3 was measured as 2.5 × 10 −8 . According to NMR spectroscopy, F3 does not fold into a regular conformation in the presence of Pb 2+ .
SUMMARYOver 40 years of studies on platelet-derived growth factors (PDGFs) and their receptors, the molecular mechanisms and functional roles of PDGFs in the development of embryos and human diseases, especially in cancer, are gradually being unravelled. PDGF-BB was approved by the United States Food and Drug Administration for promoting wound healing, while imatinib, which selectively inhibits tyrosine kinase activity of PDGF receptors (PDGFR), has been prescribed to treat patients with gastrointestinal stromal tumor and chronic eosinophilic leukaemia. However, much less often have these drugs been studied in relation to cardiovascular diseases. This brief review mainly describes the role of PDGF signalling in cardiovascular pathogenesis such as atherosclerosis, pulmonary arterial hypertension, diabetes, angiogenesis and inflammation with an emphasis on how PDGFs function in these situations and what components might serve as potential therapeutic targets against cardio-metabolic dysfunction.
Type 2 diabetes mellitus is a type of metabolic disorder characterized by hyperglycaemia with multiple serious complications, such as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy, and diabetic foot. Platelet-derived growth factors are growth factors that regulate cell growth and division, playing a critical role in diabetes and its harmful complications. This review focused on the cellular mechanism of platelet-derived growth factors and their receptors on diabetes development. Furthermore, we raise some proper therapeutic molecular targets for the treatment of diabetes and its complications.
High‐fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD‐fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a+DX5– tissue‐resident NK (trNK) cells. Obesity‐induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD‐fed mice. OPN treatment enhances the expression of ER stress markers, including p‐PERK, p‐eIF2, ATF4, and CHOP in both murine liver tissues and HL‐7702, a human liver cell line. Pretreatment of HL‐7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity‐induced hepatic ER stress, and IR through OPN production.
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