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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of Ro ribonucleoprotein are important in rheumatology, since anti-Ro antibodies are probably involved in the pathogenesis of congenital heart block and subacute cutaneous lupus erythematosus. In addition, the phosphorylation-dephosphorylation cycle modulates binding of ribonucleoproteins to RNA, a process that might affect the antigenicity and function of the Ro protein. The present study was designed to determine whether Ro can be phosphorylated by tyrosine kinase. To answer this question, synchronized HEp-2 cells were phosphorylated in vivo with exogenous 32P, and Ro ribonucleoprotein previously subjected to metabolic radiolabeling was immunoprecipitated by monoclonal anti-Ro antibodies and examined by SDS-PAGE and autoradiography. The main results were as follows: first, Ro ribonucleoprotein was phosphorylated in vivo; second, Ro was found to have phosphorylable tyrosine residues; third, tyrosine kinase participated in the phosphorylation of Ro; and fourth, phosphorylation did not change the recognition pattern of Ro by anti-Ro antibodies. In conclusion, Ro60 is phosphorylated by tyrosine kinase.
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PMID:Tyrosine kinase participates in phosphorylation of the Ro60 ribonucleoprotein. 954 Jan 17

Endothelial cells form a multifunctional cell lining that covers all of the inner surface of blood vessels and regulates several important physiological and pathological reactions. These include inflammation/immune reaction, blood vessel tonus, hemostasis/thrombosis, angiogenesis and so on. Thus, abnormalities of endothelial function may play crucial roles in the development of angitis syndrome, thrombosis/embolism, bleeding disseminated intravascular coagulation (DIC), and neovascularization in some pathological states including tumor growth and diabetic retinopathy. Research on endothelial cells now forms a new frontier termed 'Endotheliology'. Recent advances of the functional and structural aspects of endothelial cells are reviewed here mainly from the viewpoint of endothelial regulation of coagulation and the fibrinolytic system. First we show that the natural endothelial membrane protein thrombomodulin is localized not only on apical endothelial surface but also in caveolae. Since it has been reported that such factors involved in coagulation/fibrinolysis as tissue factor, tissue factor pathway inhibitor (TFPI), thrombin receptor and urokinase receptor are also localized in the caveolae, this membrane structure may act as a special component to regulate coagulation/fibrinolysis on the endothelial membrane surface. Next we demonstrate the signaling pathway of the thrombin receptor. Thrombin cleaves the N-terminus of the receptor as a substrate, exposing a new N-terminus. This newly exposed N-terminus acts as a ligand and activates platelets, endothelial cells and vascular smooth-muscle cells. We have identified that the signal from the thrombin receptor activates NF-kappaB through the activation of protein C kinase, tyrosine kinase and MAP kinase, and results in proliferation of the cells. We have also shown that the receptor is over-expressed on platelets from diabetes patients.
Lupus 1998
PMID:Biology of endothelium. 981 71

Systemic lupus erythematosus (SLE) is an autoimmune disease whose cause is poorly understood. Mice rendered deficient in specific genes have served as useful animal models in deciphering the genetic control of the disease [1]. We [2] and others [3, 4] previously demonstrated that mice deficient in the Src family tyrosine kinase Lyn developed a mild lupus-like disease with high survival rates. During the course of investigating the functional interaction of Src family kinases, we generated a mouse strain deficient in both Lyn and Fyn. The double-mutant mice died at relatively young ages and developed a severe lupus-like kidney disease. Unlike the double-mutant mice, single mutants deficient in either Lyn or Fyn lived longer and had distinct subsets of the symptoms found in the former. Lyn deficiency led to high levels of autoantibody production and glomerulonephritis, as previously reported [2--4], whereas loss of Fyn contributed to proteinuria by a B and T lymphocyte-independent mechanism. Our data suggest that the severe kidney disease in the double-mutant mice results from a combination of immunological and kidney-intrinsic defects. This new animal model may be informative about the causes of human SLE.
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PMID:Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. 1116 77

Receptors for prolactin (PRL-R) are expressed in normal leukocytes from rat and man. PRL signals through PRL-R associated Janus tyrosine kinase (Jak)-2 and signal transducers and activators of transcription (Stat). In addition, in human leukocytes PRL also activates the p38 MAP kinase pathway. PRL, at physiological concentrations, stimulates the expression of the interferon regulatory factor (IRF)-1 gene in rat spleen and bone marrow cells. In man, genes induced by PRL include several members of the 'suppressors of cytokine signaling' (SOCS) family and inducible nitric oxide synthase (iNOS; in mononuclear cells and in granulocytes) and IRF-1 (in granulocytes). Thus, in normal leukocytes, PRL induces the expression of several genes relevant to innate and acquired immune responses. Sex hormones, such as estrogen and PRL, have been implicated in the pathogenesis of murine and human SLE. Also defective signaling in leukocytes is a feature of the disease. What the origin is of aberrant signaling processes in SLE lymphocytes and how they relate to tolerance breakdown and immunopathology is still unknown. It is not unlikely that PRL is a player at some level. The exact contribution of PRL to immune responses in normal subjects and in SLE patients is not known. Further work should also indicate whether PRL might contribute to the onset or progression of the disease and assess the possible benefits of manipulating PRL concentrations in patients.
Lupus 2001
PMID:Effects of prolactin on signal transduction and gene expression: possible relevance for systemic lupus erythematosus. 1172 98

Mice lacking the membrane tyrosine kinase c-mer have been shown to have altered macro-phage cytokine production and defective phagocytosis of apoptotic cells despite normal phagocytosis of other particles. We show here that c-mer-deficient mice have impaired clearance of infused apoptotic cells and that they develop progressive lupus-like autoimmunity, with antibodies to chromatin, DNA, and IgG. The autoimmunity appears to be driven by endogenous antigens, with little polyclonal B cell activation. These mice should be an excellent model for studying the role of apoptotic debris as an immunogenic stimulus for systemic autoimmunity.
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PMID:Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. 1209 78

Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.
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PMID:Signaling mutations and autoimmunity. 1240 47

In the last few years it has become clear that in cells of the immune system, specialized microdomains present in the plasma membrane, called lipid rafts, have been found to play a central role in regulating signalling by immune receptors. Recent studies have looked at whether lipid rafts may be connected to the abnormalities in signalling seen in T lymphocytes isolated from patients with systemic lupus erythematosus (SLE). These early findings show that in SLE T cells, the expression and protein composition of lipid rafts is different when compared with normal T cells. These results also demonstrate changes in the function and localization of critical signalling molecules such as the LCK tyrosine kinase and the CD45 tyrosine phosphatase.
Lupus 2004
PMID:T-lymphocyte signalling in systemic lupus erythematosus: a lipid raft perspective. 1530 67

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45alpha, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a(-/-) mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a(-/-) T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45alpha in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45alpha, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.
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PMID:The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway. 1578 66

Autoantibody production and lymphadenopathy are common features of systemic autoimmune disease. Targeted or spontaneous mutations in the mouse germline have generated many autoimmune models with these features. Importantly, the models have provided evidence for the gene function in prevention of autoimmunity, suggesting an indispensable role for the gene in normal immune response and homeostasis. We describe here pathological and genetic characterizations of a new mutant strain of mice, the mutation of which spontaneously occurred in the Fas-deficient strain, MRL/Mp.Faslpr (MRL/lpr). MRL/lpr is known to stably exhibit systemic lupus erythematosus-like diseases. However, the mutant mice barely displayed autoimmune phenotypes, though the original defect in Fas expression was unchanged. Linkage analysis using (mutant MRL/lpr x C3H/lpr)F2 mice demonstrated a nucleotide insertion that caused loss of expression of small adaptor protein, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). SAP is known to be a downstream molecule of SLAM family receptors and to mediate the activation signal for tyrosine kinase Fyn. Recent studies have shown pleiotropic roles of SAP in T, B, and NK cell activations and NKT cell development. The present study will provide evidence for an essential role for SAP in the development of autoimmune diseases, autoantibodies, and lymphadenopathy in MRL/lpr lupus mice.
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PMID:A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice. 1636 33

Platelet-derived growth factor (PDGF) has been proved to play an important role in progressive glomerular disease of systemic lupus. The present study investigated the tyrosine kinase inhibitor of PDGF receptor, imatinib, as a novel therapeutic approach for the cure of lupus nephritis in New Zealand Black/White (NZB/W)F1 hybrid mice with established disease. Two groups of NZB/W mice (N=30 each group), starting at 5 months of age, were given by gavage vehicle or imatinib (50 mg/kg b.i.d). Fifteen mice for each group were used for the survival study. The remaining were killed at 8 months. Imatinib significantly (P=0.0022) ameliorated animal survival with respect to vehicle. The drug significantly delayed the onset of proteinuria (% proteinuric mice, 7 and 8 months: 33 and 47 vs vehicle, 80 and 87, P<0.05) and limited the impairment of renal function. Imatinib protected the kidney against glomerular hypercellularity and deposits, tubulointerstitial damage, and accumulation of F4/80-positive mononuclear cells and alpha-smooth actin-positive myofibroblasts. The abnormal transforming growth factor-beta mRNA expression in kidneys of lupus mice was reduced by imatinib. In conclusion, findings of amelioration of animal survival and renal manifestations in NZB/W lupus mice with established disease by imatinib suggests the possibility to explore whether imatinib may function as steroid-sparing drug in human lupus nephritis.
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PMID:Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease. 1668 13


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