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ABSTRACT: 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.
Food and Chemical Toxicology 02/2002; 40(1):19-24. · 3.00 Impact Factor
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ABSTRACT: Two groups of compounds, the fatty acid anilides and the mono- and diester of 3-phenylamino-1,2-propanediol (PAP) are suspected as aetiologic agents for the toxic oil syndrome (TOS). Intraperitoneal administration of oleoyl and linoleoyl anilides in mice caused severe weight loss followed by death in 50% of the animals and histopathological changes mainly to the lungs. Linoleic diester of PAP led to weight loss, haemorrhage, congestion and emphysema in the lungs and an increase in blood eosinophilia. Although not producing the full spectrum of symptoms the effects of the substances resemble the acute human disease. Possibly, the two groups of substances led together to the full spectrum of disease manifestations seen in TOS.
Archive für Toxikologie 12/1999; 73(8-9):493-5. · 4.67 Impact Factor
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ABSTRACT: 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.
Toxicology and Applied Pharmacology 07/1999; 157(3):213-21. · 4.45 Impact Factor
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ABSTRACT: Autoantibodies to CRP were reported previously in patients suffering from toxic oil syndrome. This syndrome resembles autoimmune diseases such as systemic lupus erythematosus (SLE) or systemic scleroderma. We therefore examined the prevalence of antibodies to CRP and other acute-phase proteins in autoimmune diseases, including SLE, subacute cutaneous lupus erythematosus (SCLE), systemic scleroderma (SSc), and primary biliary cirrhosis (PBC), as well as in bone marrow transplantation-induced chronic graft-versus-host disease and eosinophilia-myalgia syndrome. IgG antibodies to CRP were found in 78% of SLE and in 30% of SCLE patients, while 16% of patients with PBC were positive. In up to 45% of patients with SSc predominantly IgG antibodies to ceruloplasmin were detectable. Lack of systemic involvement as in discoid lupus erythematosus and localized scleroderma (morphea) correlated with low or absent antibody formation. However, no correlation was found between anti-acute-phase protein antibodies with liver disease or other organ involvement. Adsorption studies revealed that non-native epitopes on the CRP molecule, termed modified CRP, are the main target of antibodies. Chronic inflammatory tissue injury in systemic autoimmune disease might increase the presentation of cryptic epitopes of CRP to the threshold required for T cell activation.
Clinical & Experimental Immunology 10/1998; 113(3):327-32. · 3.36 Impact Factor
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ABSTRACT: A 53 year old man presented with a giant variant of granuloma faciale, closely resembling rhinophyma. Therapeutic approaches with cryosurgery and dapsone were unsuccessful. Surgical reconstruction of the nasal skin resulted in an excellent and long lasting effect. We give a short overview of this relatively rare disease, describe an unusual manifestation and discuss the therapeutic possibilities. Surgical procedures seem to offer the best results, despite the inflammatory pathogenesis of the disease.
Der Hautarzt 07/1998; 49(6):496-8. · 0.58 Impact Factor
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ABSTRACT: The toxic oil syndrome (TOS) was caused by the ingestion of an adulterated rapeseed oil containing oleic acid anilide (OAA). It was characterized by lethal symptoms in the acute phase and by symptoms of idiopathic autoimmune diseases in the chronic phase. The pathogenetic mechanisms remain unclear. In a murine model of TOS we demonstrate strain-dependent effects on the immune system after treatment with OAA intraperitoneally. While C57BL/6 (H-2b) mice develop a polyclonal B cell activation without disease symptoms, most A/J (H-2a) mice suffer an acute lethal wasting disease. These differences are reflected in the splenic cytokine gene expression and secretion and in the Ig production. Increased IgE serum levels and reduced TNF-beta mRNA suggest a Th2 cell response in C57BL/6 mice. In A/J mice, splenocytes express IL-1alpha, IL-10, and IFN-gamma mRNA in vivo and secrete high levels of TNF-alpha in vitro. These observations resemble the human condition in TOS with development of either an acute lethal disease or a chronic autoimmune-like disease. As in other chemical-induced reactions genetic susceptibility seems to be important.
Toxicology and Applied Pharmacology 03/1998; 148(2):222-8. · 4.45 Impact Factor
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The Lancet 02/1997; 349(9044):29. · 38.28 Impact Factor
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ABSTRACT: Chronic graft-versus-host disease after bone marrow transplantation presents, in a few cases, as mild to severe scleroderma-like changes. Patients with chronic graft-versus-host disease with and without sclerodermatous skin changes were analysed for antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANoA) and the results correlated with disease symptoms and histocompatibility locus antigen (HLA) pattern. Nineteen patients with chronic graft-versus-host disease and scleroderma-like skin changes, 18 with chronic graft-versus-host disease without scleroderma, and 17 controls on immunosuppressive treatment were screened for ANA and ANoA using enzyme-linked immunosorbent assay, immunodiffusion and immunoblot techniques. Four patients with severe scleroderma had antibodies to topoisomerase I, two had antibodies against PM-Scl, both characteristic serological findings in idiopathic systemic scleroderma. One patient had La/SSB antibodies and, in three cases, antibodies to the nucleolar antigen C23 (nucleolin) could be identified. A possible correlation between antinucleolin antibodies and disease activity was observed. HLA-A1, -B1, and -B2 were found significantly more often in patients with scleroderma-like symptoms in comparison to patients without scleroderma-like symptoms. Chronic graft-versus-host disease with scleroderma-like manifestations can be associated with the occurrence of ANA specific for idiopathic scleroderma. The development of scleroderma after bone marrow transplantation might have a HLA-linked genetic background.
British Journal of Dermatology 06/1996; 134(5):848-54. · 3.67 Impact Factor
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S A Bell
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ABSTRACT: The toxic oil syndrome (TOS) is a chemically induced autoimmune-like reaction in humans. The etiologic agent(s) have so far not clearly been identified. A short overview is given on this disease which is associated with a unique antibody specificity to cryptic epitopes of C-reactive protein in affected patients. In addition a murine model for TOS is described which suggests that genetic susceptibility might play a role in inducing a similar syndrome in mice. These differences are reflected in the immunological alterations and cytokine production caused by the toxicant.
Molecular Biology Reports 02/1996; 23(3-4):261-3. · 2.93 Impact Factor
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ABSTRACT: Toxic oil syndrome (TOS) was caused by the consumption of rapeseed oil contaminated with derivatives of aniline. Many persons who survived the acute phase developed a puzzling, multi-year chronic disease considered to be inflammatory or autoimmune in nature. In attempting to characterize their autoantibodies, we found that 74% of TOS patients with chronic disease had IgG antibodies to C-reactive protein (CRP). This activity was detectable only when CRP was chemically or physically denatured and behaved like a previously described antibody produced by immunization with the CRP monomer. Significant antibody reactivities to other acute phase proteins, especially alpha 1-antitrypsin and fibrinogen (P < 0.025) and ceruloplasmin (P < 0.05) were also observed. IgG antibodies to cryptic epitopes in CRP and other major serum proteins that increase during the acute phase response may reflect an earlier toxin-mediated insult to the liver that included abnormal biosynthesis of and/or damage to acute phase proteins.
Journal of Autoimmunity 05/1995; 8(2):293-303. · 7.37 Impact Factor
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ABSTRACT: IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.
Journal of Clinical Investigation 08/1992; 90(1):165-73. · 15.39 Impact Factor
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ABSTRACT: 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.
The Journal of Immunology 07/1992; 148(11):3369-76. · 5.79 Impact Factor
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ABSTRACT: The term tinea axillaris has been used only a few times in the literature. In this paper we describe a male patient with widespread tinea corporis and unguium affecting also both axillary regions. Trichophyton verrucosum was isolated as the causative agent. The patient admitted to no direct contact with infected animals, but had lived in a rural area until a year before the infection became widespread. Topical treatment with glucocorticosteroids probably promoted propagation over large parts of his body and may have led to the infection of the axillary region, an unusual site for fungal infection. Treatment with itraconazole over 4 weeks led to complete clearing of all lesions on glabrous skin. Thereafter, itraconazole pulse therapy was used to treat the nail infection.
Mycoses 39(11-12):471-4. · 2.25 Impact Factor
