salicylates and Antiphospholipid-Syndrome

The antiphospholipid syndrome (APS) commonly affects the central nervous system through mechanisms that may include small vessel pathology and activation of thrombin. Antiphospholipid antibodies (aPL) activate endothelial cells but the specific activation of brain vascular endothelial cells (BVEC) and the receptors and signaling pathways involved have not been fully characterized.. To examine whether aPL, the inflammatory stimulant lipopolysacharide (LPS) and thrombin activate BVECs through a Ras-dependent pathway.. Rat BVEC (G8) were grown to confluence on 24-well plates. IgG was purified from 8 APS patients on a protein G column. Phosphorylation of ERK in the BVEC was measured by immunoblot utilizing a specific antibody.. Significant phosphorylation of ERK was measured following exposure of the cells to LPS and thrombin and this was blocked by the Ras inhibitor farnesylthiosalicylate (FTS). aPL IgG (1:100 relative to serum) from 7/8 patients also induced phosphorylation of ERK.. Activation of the Ras-ERK pathway is an effect of both APS IgG and thrombin. This pathway is potentially amenable to drugs such as FTS and may serve as a therapeutic target in APS.

Topics: Animals; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Brain; Cell Line; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Farnesol; Female; Humans; Immunoglobulin G; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Male; Phosphorylation; ras Proteins; Rats; Salicylates; Thrombin

Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia.. To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/lpr mice) and in an induced model of APS.. Female Balb/C mice immunized once with beta2-glycoprotein I (beta2-GPI) in complete Freund's adjuvant (CFA) and female MRL/lpr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-beta2-GPI antibodies were measured by ELISA.. FTS treatment 3 times a week resulted in significant decreases of aPL and anti-beta2-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol.. Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.

Topics: Animals; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; beta 2-Glycoprotein I; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Farnesol; Female; Freund's Adjuvant; Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred MRL lpr; ras Proteins; Salicylates; Time Factors

Activation and proliferation of lymphocytes requires the active signal transducer Ras. Activation of lymphocytes, associated with autoimmunity, may therefore be modified by S-farnesylthiosalicylic acid (FTS), a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. The MRL/lpr mouse is a genetic model of a generalized autoimmune disease sharing many features and organ pathology with systemic lupus erythematosus (SLE) and the primary antiphospholipid syndrome (APS). The objective of the present study was to examine the effect of FTS on laboratory and clinical pathology in the MRL/lpr mouse. Female MRL/lpr (n = 50) and MRL/++ control (n = 35) mice were treated intraperitoneally with either FTS (5 mg/kg/day) or saline between 6 and 18 weeks of age. The mice were weighed, tested for proteinuria and lymphadenopathy, lymphocyte proliferation, antibodies, grip strength and behaviour in an open field. FTS treatment resulted in a 50% decrease in splenocyte proliferation to ConA, LPS and a disease specific antigen, beta(2)-glycoprotein-I, and in a significant decrease in serum antibody levels against cardiolipin and dsDNA. Proteinuria and grip strength were normalized and lymphadenopathy and postmortem lymph node and spleen weights were significantly reduced in FTS treated MRL/lpr mice. These findings indicate that modulation of Ras activation has a significant impact on the MRL/lpr model and may represent a new therapeutic approach for the treatment of systemic autoimmune diseases such as SLE and APS.

Topics: Animals; Antiphospholipid Syndrome; Autoantibodies; Autoimmune Diseases; Farnesol; Female; In Vitro Techniques; Lupus Erythematosus, Systemic; Lymphatic Diseases; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred MRL lpr; ras Proteins; Salicylates

Topics: Adult; Antiphospholipid Syndrome; Aspirin; Choroidal Neovascularization; Female; Fluorescein Angiography; Humans; Pre-Eclampsia; Pregnancy; Salicylates; Treatment Outcome; Visual Acuity

A case of a successful pregnancy is presented in a woman with anti-phospholipid syndrome and habitual abortions. She was treated with heparin-salicyl therapy during her pregnancy. No complications were noted. The significance of the presence of anti-phospholipid antibodies is stressed. The other therapeutic possibilities are discussed.

Topics: Abortion, Habitual; Adult; Antiphospholipid Syndrome; Female; Heparin; Humans; Lupus Coagulation Inhibitor; Pregnancy; Pregnancy Outcome; Salicylates