oleoylanilide and Syndrome

Topics: Adult; Aged; Alcohol Drinking; Anilides; Animals; Case-Control Studies; Causality; Chi-Square Distribution; Child; Female; Humans; Lung Neoplasms; Male; Myocardial Ischemia; Oleic Acids; Risk; Risk Factors; Sex Factors; Smoking; Syndrome; Time Factors

The toxic oil syndrome is an exogenously-induced autoimmune disease in humans, which is believed to be due to the accidental ingestion of oleic acid anilides. In a previously established murine model anilides-treated A/J mice developed a wasting disease after 1 week. Anilides-treated B10.S mice showed after 6 weeks a hyperimmunglobulinemia with autoantibody production, but no clinical symptoms. We now compared in vitro the effects of anilides on splenocytes and T cells in A/J and B10.S mice. Splenocyte proliferation was similar in both strains. After in vivo treatment of mice with anilides and in vitro restimulation, splenocytes of sick A/J mice showed a significant increase in splenocyte proliferation. Splenocytes from B10.S mice, however, had a suppressed baseline response and did not proliferate on restimulation. Adherent cells were necessary to induce proliferation in A/J mice-derived T cells. Apoptosis in splenocytes was significantly elevated in anilides-treated A/J and in B10.S mice as compared to saline-treated controls. These data show that anilides are able to affect the immune system in a strain-dependent way and may therefore take part in inducing the disease seen in humans and mice.

Topics: Anilides; Animals; Apoptosis; Autoimmune Diseases; Cell Adhesion; Cell Count; Cell Division; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Food Contamination; Male; Mice; Oleic Acids; Plant Oils; Rapeseed Oil; Species Specificity; Spleen; Syndrome; T-Lymphocytes

The toxic oil syndrome (TOS) represents an exogenously induced autoimmune disease with acute or chronic symptoms similar to systemic lupus erythematosus or scleroderma. When genetically different mouse strains were exposed to oleic acid anilide (OAA), it was possible to mimic the different syndrome manifestations. The aim of the present study was to examine the role of NF-kappaB/Rel transcription factors in the development of the severe acute wasting disease observed in A/J mice. Within a week of OAA exposure, the A/J, but not B10.S strain, displayed weight loss, cachexia, apathy, reduced activity, and breathing difficulties. In affected A/J mice we observed a marked increase in NF-kappaB activation (p50/p65 dimers) both in splenic T cells and peritoneal macrophages as well as in tissue from aorta and gut. Incubation of splenocytes with OAA in vitro induced a dose-dependent removal of IkappaB-alpha, accompanied by NF-kappaB activation, whereas Sp-1 binding was not affected. Furthermore, we demonstrated the increased expression of the two NF-kappaB target genes IL-6 and IL-1beta in OAA-exposed mice and a transient OAA-induced accumulation of TNFalpha in vitro. This is the first report which implicates NF-kappaB/Rel in acute forms of chemically induced autoimmune-like disease and may serve as a paradigm for the involvement of this transcriptional system in acute processes associated with autoimmunity, suggesting possible avenues of therapeutic intervention.

Topics: Acute Disease; Anilides; Animals; Autoimmune Diseases; Blotting, Western; DNA-Binding Proteins; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; I-kappa B Proteins; Macrophages, Peritoneal; Mice; Mice, Inbred A; NF-kappa B; NF-kappa B p50 Subunit; NF-KappaB Inhibitor alpha; Oleic Acids; Organ Specificity; Plant Oils; Ribonucleases; Spleen; Syndrome; T-Lymphocytes; Transcription Factor RelA

The toxic oil syndrome (TOS), a multisystemic disease, that occurred in Spain in 1981, was caused by the ingestion of rapeseed oil denatured with 2% aniline. Due to the clinical course of the disease, immunopathological mechanisms have been suspected but a direct connection was never demonstrated. To analyse this possibility, we determined several immunological parameters in the sera of patients with TOS and without the disease, using a case-control design: total immunoglobulins, IgG and IgE antibodies against different toxic agents (oleylanilide, aniline, linoleyl-anilide, and 3-phenylaminopropane-1-2-diol), autoantibodies, cytokines (IL-4, IL-6, TNF, GM-CSF) and soluble receptors (sCD23 and sIL-2R). We detected high levels of sIL-2R in TOS patients compared to controls (P < 0.0001). A higher levels of sCD23 and IgE were also found. In addition, the response to oleyl-anilide of peripheral blood lymphocytes from TOS patients was studied and a significant proliferative response in 30% of TOS patients versus 5% controls was observed. Our data support the implication of the immune system in the acute phase of TOS, with a possible activation of T-cells and release of cytokines, that could explain some of the clinical findings in this phase of the disease.

Topics: Anilides; Autoantibodies; Brassica; Case-Control Studies; Fatty Acids, Monounsaturated; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulins; Lymphocyte Activation; Oleic Acids; Plant Oils; Rapeseed Oil; Receptors, IgE; Receptors, Interleukin-2; Syndrome; T-Lymphocytes

The toxic oil syndrome is characterized by IgE elevation and eosinophilia, as well as scleroderma-like skin manifestations and other symptoms of autoimmune disease. Fatty acid anilides, found in large amounts in adulterated cooking oil, were suspected to be the etiologic agent in this disease. The capacity of oleic acid anilide to induce features of autoimmunity in vivo was investigated. B10.S mice were continuously treated i.p. with oleic acid anilide for 6 wk by using osmotic pumps. A significant increase in IgE and IgM serum levels was observed after 1 to 3 wk; subsequently five of six mice developed IgG1 levels 3.5- to 10-fold higher than the controls. Anilide-treated mice developed splenomegaly with a 2.1- and a 3.5-fold increase in IgM- and IgG-bearing splenocytes, respectively, and a 5.6- and 29-fold elevation in functional IgM- and IgG-secreting cells, respectively. Increased serum levels of predominantly IgM antibodies to histone, denatured DNA, and DNP as well as rheumatoid factor were detected. In vivo expression in the spleen of 10 cytokine genes was also examined, and mRNA encoding IL-1 beta and IL-6 were significantly elevated in splenocytes of anilide-treated mice. The enhanced Ig production suggests that anilide induced a cytokine-mediated polyclonal activation of B cells. Elicitation of IgM antibodies to denatured forms of autoantigens indicates that anilide treatment partially broke autoimmune tolerance in these mice. Anilide-treated mice may be a useful animal model for further exploring the mechanism and pathogenesis of systemic autoimmunity in the toxic oil syndrome.

Topics: Anilides; Antibodies, Antinuclear; Autoantibodies; Autoimmune Diseases; Brassica; Cytokines; Fatty Acids, Monounsaturated; Gene Expression; Histones; Immunoglobulin Isotypes; Lymphocyte Subsets; Oleic Acids; Plant Oils; Rapeseed Oil; Rheumatoid Factor; RNA, Messenger; Syndrome

Topics: Anilides; Animals; Arachidonic Acid; Arachidonic Acids; Brassica; Fatty Acids; Fatty Acids, Monounsaturated; Foodborne Diseases; Glutathione; Lipid Peroxides; Male; Oils; Oleic Acids; Plant Oils; Rapeseed Oil; Rats; Rats, Inbred Strains; Syndrome

Fatty acid anilides, the major xenobiotic found in the cooking oils responsible for the Spanish toxic oil syndrome, are immunogenic for rabbits as ascertained by a skin test reaction, the characterization of specific antibodies against anilides and the immunofluorescent detection of 'anilide dependent antigens' in tissue slices from treated animals.

Topics: Anilides; Animals; Antibodies; Brain; Brassica; Drug Hypersensitivity; Epitopes; Fatty Acids, Monounsaturated; Fluorescent Antibody Technique; Food Contamination; Immunization; Immunosorbent Techniques; Linoleic Acids; Liposomes; Muscles; Neuromuscular Diseases; Oils; Oleic Acids; Plant Oils; Rabbits; Rapeseed Oil; Skin Tests; Syndrome