Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the introduction of the bm12 mutation into NZB mice results in animals that spontaneously produce high titer IgG autoantibodies to dsDNA. The observation that NZB.H-2bm12 develop lupus although NZB.H-2b control mice do not, provides a unique system to study the role of Th cells in the production of antibodies to dsDNA. We have isolated, in the absence of a known stimulating autoantigen, a series of seven autoreactive T cell clones that provide help in vitro for the production of IgG anti-dsDNA antibodies by syngeneic B cells. The data on these seven cloned T cell lines was compared to two cloned T cell lines specific for keyhole limpet hemocyanin. The seven cloned T cell lines, coined clones 19D, 23G, 410F, 410H, C1, C15, and C52 all show significant help in vitro for production of IgM and IgG antibodies to ssDNA and dsDNA; antibody levels increased 7- to 30-fold compared to cultures without T cells. Clones C1, C15, and C52 were furthered studied and were shown to provide help for IgM antihistone and anti-OVA responses but provided significantly less help for IgG antibodies. In contrast, keyhole limpet hemocyanin-specific cloned T cell lines TK2 and TK5 provided help for IgM antibodies to ssDNA, dsDNA, and histone, but failed to significantly increase IgG antibodies to ssDNA, dsDNA, or histone. The cloned T cell lines were restricted to H-2bm12 and proliferated only in response to APC from NZB.H-2bm12 and B6.C-H-2bm12 but not NZB.H-2b or NZB.H-2d mice; their in vitro helper activity was inhibited by antibodies to class II. All cloned T cell lines expressed Thy-1, CD5, and TCR-alpha/beta. Three of the seven clones used TCR-V beta 4. However, the V beta expression of the four remaining autoreactive T cell clones could not be determined. All of the autoreactive cloned T cell lines produce significant IL-4 but no detectable IL-2 or IFN-gamma. We believe that HPLC-purified peptides eluted from I-Abm12 molecules from APC can potentially provide insight on the putative autoantigen.
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PMID:Generation and characterization of cloned T helper cell lines for anti-DNA responses in NZB.H-2bm12 mice. 146 Feb 94

Cells from the spleens of non-immunized mice were cultured in horizontal tubes, rotating very slowly around their long axis. Under these conditions, the flux speed gradient of the cell suspension near the tube walls greatly increased the chances of cells coming into contact with one another. Mixed clusters of B, T and APC cells were soon found adhering firmly to the walls of the tube; cluster formation leveled off after about 3 h. The clustered cells were easily separated from those remaining in suspension and constituted a particular cell compartment comprising a maximum of 20-30% of the total. B cells from this compartment, cultured in complete medium for 48 h, almost exclusively produced IgM antibodies. Antibodies reacting with self antigens were so numerous in the culture medium that it is likely all IgM were self antibodies. That the clusters obtained under these conditions constituted a compartment of autoimmune cells is supported by previous work which showed that 20-30% of spleen cells secrete IgM antibodies almost exclusively. Cluster formation as a function of age was compared in NZB mice which are used as a model of lupus erythematosus, and in BALB/c mice which never manifest self-immune pathology. The number of cells found in clusters per whole spleen increased exponentially with age in NZB mice and linearly in BALB/c mice. The production of autoimmune antibodies as a function of age also increased exponentially for NZB mice and linearly in BALB/c mice, which provides further striking support for the hypothesis that the clusters formed constitute the autoimmune comportment.
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PMID:Relationship between the synthesis of autoimmune antibodies and the formation of clusters of B, T and APC cells during the syngeneic mixed lymphocyte reaction in BALB/c and NZB mice: a technique for isolation of the spleen autoimmune compartment of non-immunized pathogen-free mice. 214 64

The role of IL-4 in the cellular interactions leading to the induction of CTL tolerance to H-2b alloantigens and to the development of a lupus-like autoimmune disease in BALB/c mice after neonatal injection with (C57BL/6 x BALB/c)F1 cells was investigated in vivo by using an anti-IL-4 mAb. Treatment of F1 cell-injected BALB/c mice with 15 mg of anti-IL-4 mAb was shown to interfere with tolerance induction, as assessed by the high percentages of H-2b target cell lysis and the very low or undetectable levels of B cell chimerism markers observed in these mice. Treatment with 4.5 mg of anti-IL-4 mAb interfered with tolerance induction only in one-third of F1 cell-injected BALB/c mice, but that dose induces specific modulations of the autoimmune manifestations in all mice, leading to the nearly complete prevention of the disease. In particular, the production of anti-ssDNA IgG1 and of total IgG1 and IgE antibodies was seriously affected by the treatment, as well as the proliferation and membrane Ia and K expression of F1 donor splenic cells and thymic APC. Treatment of F1 cell-injected BALB/c mice between 24 and 48 h of life with 0.5 mg of anti-IL-4 mAb did not interfere with tolerance induction, but had similar effects on the autoimmune syndrome as treatment with 4.5 mg. These results suggest that, after F1 cell injection of newborn mice, IL-4 plays an important role in the cellular interactions leading to the induction of tolerance to the corresponding alloantigens and to the development of the associated autoimmune syndrome.
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PMID:In vivo effects of anti-IL-4 monoclonal antibody on neonatal induction of tolerance and on an associated autoimmune syndrome. 221 49

Male BXSB mice develop lupus-like disease and die early in life (4 to 5 mo) whereas female mice do not. Others have demonstrated that CD4+ cells from male mice support B cell resistance to tolerance induction to human gamma-globulin (HGG). In this study, male and female mice tolerized at 2 mo of age with deaggregated HGG and subsequently immunized with HGG in comparison with mice immunized only were tested for anti-HGG Ab responses. CD4+ cells from draining lymph nodes of these mice were tested in culture for proliferation and production of cytokine mRNA and protein in response to HGG plus APC. Tolerized male but not female mice produced anti-HGG Abs of both the IgG1 and IgG2a isotypes. HGG-stimulated CD4+ cells from immunized male and female mice that were not tolerized produced IL-2, IL-4, IL-5, IFN-gamma, and TNF-beta mRNA as well as IL-2 and IL-4 protein, whereas tolerized, immunized mice of both sexes failed to proliferate or produce either IL-2 or IL-4 or express any cytokine mRNA in response to HGG in vitro. A resistance in tolerance induction in male mice, as determined by anti-HGG Abs, was also observed at 3 mo of age. Although a resistance to tolerance was also seen in terms of proliferation in the 3-mo-old males, production of IL-2 or IL-4 protein was still not observed. Thus, all T cell subsets identified by cytokine expression profiles were tolerized not only from females but also from males, of which the latter appeared to show some resistance to tolerance induction.
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PMID:In vivo tolerance induction and associated cytokine production by subsets of murine CD4+ T cells. 753 93

Anticardiolipin antibodies (aCL) or lupus anticoagulants (LA) have been found to exert an inhibitory action upon the activation and function of protein C, a natural coagulation inhibitor. Recently an in vitro phenomenon called resistance to activated protein C (APC resistance) has been described as the most frequent cause of hereditary thrombophilia. In order to see whether a positive association of APC resistance with aCL exists we examined plasma of 162 consecutive outpatients referred for thrombophilia screening. Further, the IgG fraction was isolated from plasma of two aCL-positive and LA-negative patients and of two aCL-negative healthy subjects by means of protein A affinity chromatography. Each of these isolates was mixed with normal plasma, and the APC resistance was assayed; 25/162 (15.4%) patients had confirmed abnormal APC resistance. Only 1/25 (4.0%) APC resistance-positive patients and 11/137 (8.0%) APC resistance-negative patients had positive IgG- and/or IgM-aCL (p = 0.5, nonsignificant). In the in vitro test system the APC resistance ratio remained unaffected after addition of normal IgG or aCL-IgG fraction in the tested normal plasma and did not deviate from the range of buffer controls. These data do not suggest any association of aCL with abnormal APC resistance. aCL-IgG fractions from aCL-positive and LA-negative plasmas do not interfere with the APC resistance test system in vitro in low concentration.
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PMID:Anticardiolipin antibodies do not seem to be associated with APC resistance in vivo or in vitro. 757 27

The influence of antibodies against phospholipids (PLa) on APC response was investigated in 155 women with a history of thromboembolism and/or repeated foetal losses. PLa were determined as antibodies against cardiolipin (CLa) and phosphatidyl serine (PSa) and as lupus anticoagulant (LA) tested by dilute Russell's Viper Venom time and by the Textarin/Ecarin ratio. APC-response was studied by a clotting (aPTT-based) and by an amidolytic (factor IXa-X-based) assay. A reduced response to APC (APC-resistance) was found in 49% of 65 PLa-positive and in 13% of 90 PLa-negative samples (chi 2 = 23.9; p < 0.5 x 10(-4)). It was more common in the samples with LA, as compared to CLa+PSa positive (58% vs. 30%, not significant). The presence of the mutation causing Arg506-Gln substitution in coagulation factor V was investigated in 84 samples. The occurrence of the mutation in APC-resistant patients with CLa+PSa or with LA in one of the two assays was similar to those without PLa (84% and 100%, respectively). In the absence of APC resistance, the occurrence of the mutation was similar in the samples with and without PLa (14% vs. 11%). Samples with LA, determined by both tests used, comprised a special group where the frequency of the mutation in the APC resistant samples was significantly reduced (p < 0.01). In the latter samples, the pathogenic mechanism of APC resistance may be connected with the influence on phospholipid membranes.
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PMID:Studies on phospholipid antibodies, APC-resistance and associated mutation in the coagulation factor V gene. 763 Dec 99

This review has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The most common of the hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the most common acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore, these are the defects which should first be searched for in an individual with unexplained thrombosis. If these more common defects are not found, the rarer defects, including HC-II, plasminogen, or TPA deficiency, dysfibrinogenemia, elevated PAI-1, or heterozygous homocystinemia should be looked for. The incidence of activated protein C co-factor deficiency (APC resistance) is not yet clear but may also represent a common defect. PAI-1 defects may, with time, be shown to be common. Finding these defects has important implications for therapy for the individual patient and for the institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein(a) or defects of extrinsic (tissue factor) pathway inhibitor (EPI, TFPI), may be associated with enhanced risks for thrombosis.
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PMID:Blood protein defects associated with thrombosis. Laboratory assessment. 778 Dec 75

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.
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PMID:Mechanisms of autoimmunity in type I diabetes. 844 41

Seventy-eight women with a history of thromboembolism were studied for cardiolipin antibodies (CLa), lupus anticoagulant activity (LA) and resistance to activated protein C (APC-resistance). Elevated CLa were found in 15 (19%) and LA in 15 women (19%), respectively. Twenty-six patients (33%) were APC-resistant, 17 of them had LA and/or CLa. No correlation was observed between the LA coefficient, CLa level and the extent of APC-resistance. The study shows the difference in the nature of phospholipid antibodies (PLa) and APC-resistance: cause-dependent for APC-resistance and time-dependent for the LA activity. APC-resistance was commoner in thrombosis triggered by endogenous (pregnancy, delivery) than by exogenous (oral contraceptives, surgery) factors (P < 0.05). The incidence of PLa was not connected to the cause of thrombosis. Time-dependent changes in the PLa spectrum manifested by a reduction of isolated LA frequency five years after thrombosis (P < 0.05). The response of APC seemed to show no variation with time passed after thrombosis. The co-existence of PLa and APC-resistance in 22% of thrombophilic women may stress the role of phospholipids in the blood coagulation process.
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PMID:Phospholipid antibodies and resistance to activated protein C in women with thrombophilia. 858 7


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