Are there environmental forms of systemic autoimmune diseases?

A large number of drugs and an increasing number of environmental agents reportedly result in the appearance of a number of autoantibodies and in many instances in the appearance of a range of autoimmune clinical syndromes. The major disorders so recognized have marked resemblances to the autoimmune disease systemic lupus erythematosus. The commonly used term is drug-induced lupus; a better term is drug-related lupus. There is considerable interest at the present time in an increasing number of environmental agents. There have been two epidemics in recent years--one in Spain to a contaminant of rapeseed oil and one in the United States to a contaminant of l-tryptophan that caused an eosinophilic myositis. It is important for physicians and others involved in health care to recognize the potential associations of these diseases of unknown cause or causes.

Human autoantibodies recognizing a native macromolecular structure composed of Sm core proteins in U small nuclear RNP particles.

OBJECTIVE: Monoclonal antibody (mAb) F78 recognizes a heat-labile particle composed of Sm core proteins designated F78P. The objective of this study was to identify human autoantibodies recognizing the conformational structure of F78P. METHODS: Immunoblots using HeLa cell extracts without heating prior to sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used to identify autoantibodies recognizing F78P. To confirm reactivities with F78P, immunoprecipitates of mAb F78 were used as a substrate for immunoblots. To identify reactivities against the F78P structure in classic anti-Sm-positive sera, autoantibodies to individual Sm core proteins were absorbed with purified U1 small nuclear RNP before immunoblotting. RESULTS: We identified 2 sera that, like F78, recognized only F78P and not its component polypeptides. When classic anti-Sm antibodies were preabsorbed, the presence of F78-like, particle-specific antibodies was revealed in all of the anti-Sm-positive sera tested. CONCLUSION: Autoantibodies against the F78P structure were commonly present in sera from patients with systemic rheumatic diseases, often in combination with4=1998 M autoantibodies.

Genetic and immunologic studies of patients on procainamide.

Forty (40) patients with cardiac arrhythmias receiving procainamide (PA) therapy and 24 patients who were receiving other drugs for their cardiac disorders were investigated for class II HLA phenotypes and their DRB1*04 and DQB1*03 subtypes. Other genetic marker evaluations in the PA patients included: 1) class III MHC C4A and C4B null alleles of complement; and, 2) acetylation phenotype. Twenty (20) of the PA patients were also tested for the ability of their stimulated cells to secrete Interleukin-1 (IL-1 beta) and tumor necrosis factor (TNF alpha). We also examined the spontaneous production of these cytokines by peripheral blood leukocytes (PBL) from patients who were receiving chronic PA treatment. The results revealed no association of acetylation phenotypes with the class II HLA phenotypes nor class III MHC C4 allotypes in these patients. The results did show a significant increase in class III C4 complement allotypes in the PA patients when compared to the controls. The results also showed a significant increase in autoantibodies and DQw3 phenotypes in the PA patient group when compared to control populations. Results of spontaneous IL-1 and TNF production suggested there may be an association of select class II HLA phenotypes in some patients and this may be relevant to host responsiveness to PA treatment.

Association of osteonecrosis in systemic lupus erythematosus with abnormalities of fibrinolysis.

Patients with systemic lupus erythematosus (SLE) are at an increased risk of developing osteonecrosis (ON). Twenty-six patients with SLE were studied. Fifteen of these had ON and 11 did not. The latter were used as control subjects. Various coagulation analytes including antithrombin III (ATIII) activity, protein C activity, protein S activity, alpha 2-antiplasmin activity, anticardiolipin antibodies (aCL), plasminogen activator inhibitor (PAI-1) activity and tissue type plasminogen activator (tPA) antigen were measured using citrated plasma samples from the patients. A significant proportion (80%) of patients had at least one laboratory abnormality that has been associated with a thrombotic predisposition. ON was significantly associated with elevated levels of PAI-1 activity; it was also associated with elevated PAI-1/tPA ratio. There was no association between ON of SLE and abnormalities of the other measured coagulation analytes. These results suggest that defective fibrinolysis seems to be operative in the pathogenesis of ON associated with SLE. The defect appears to involve an imbalance between tPA and its inhibitor, PAI-1. This imbalance could represent an important risk factor in the pathogenesis of ON.

Accelerated atherosclerosis and coronary disease in SLE.

Atherosclerosis may represent a significant cause of death and morbidity in patients with systemic lupus erythematosus. Coronary involvement is more premature in lupus patients. We present the case of a young woman diagnosed with SLE at the age of 20 years who had a myocardial infarction at age 29 years. We review the mechanisms of atherosclerosis, the interrelations between atherosclerosis and autoimmunity, and between atherosclerosis and SLE. We also review the risk factors, influence of disease and treatment and the guidelines for management of accelerated atherosclerosis in lupus patients.

Reversible parotid enlargement and pseudo-Sjögren's syndrome secondary to hypertriglyceridemia.

We describe 2 patients with a Sjögren-like syndrome apparently secondary to hypertriglyceridemia. Both had bilateral parotitis in addition to musculoskeletal and sicca symptoms. Parotid gland histology revealed fatty infiltration with no inflammation. Therapy with dietary modification and triglyceride lowering drugs resulted in resolution of symptoms and parotid swelling in one patient. In the 2nd patient, hypertriglyceridemia was resistant to triglyceride lowering drugs, and parotid symptoms and swelling continued unabated. Our findings suggest aggressive treatment of hyperlipidemia in pseudo-Sjögren's syndrome may result in amelioration of musculoskeletal and parotid symptoms.

Triplex-DNA stabilization by hydralazine and the presence of anti-(triplex DNA) antibodies in patients treated with hydralazine.

Hydralazine is an antihypertensive drug that elicits andti-nuclear antibodies in patients as an adverse effect. We investigated the ability of hydralazine to promote/stabilize the triplex DNA form of poly(dA).2poly(dT). Under conditions of low ionic strength, the polynucleotide melted as a double helix with a melting temperature (Tm) of 55.3 degrees C. Hydralazine destabilized this duplex form by reducing its Tm to 52.5 degrees C. Spermidine (2.5 microM), a natural polyamine, provoked the triplex form of poly(dA)-.2poly(dT) with two melting transitions, Tm1 of 42.8 degrees C corresponding to triplex-->duplex+single-stranded DNA and Tm2 of 65.4 degrees C, corresponding to duplex melting. Triplex DNA thus formed in the presence of spermidine was further stabilized by hydralazine (250 microM) with a Tm1 of 53.6 degrees C. A similar stabilization effect of hydralazine was found on triplex DNA formed in the presence of 5 mM Mg2+. CD spectra revealed conformational perturbations of DNA in the presence of spermidine and hydralazine. These results support the hypothesis that hydralazine is capable of stabilizing unusual forms of DNA. In contrast with the weak immunogenicity of DNA in its right-handed B-DNA conformation, these unusual forms are immunogenic and have the potential to elicit anti-DNA antibodies. To test this possibility, we analysed sera from a panel of 25 hydralazine-treated patients for anti-(triplex DNA) antibodies using an ELISA. Our results showed that 72% of sera from hydralazine-treated patients contained antibodies reacting toward the triplex DNA. In contrast, there was no significant binding of normal human sera to triplex DNA. Taken together our data indicate that hydralazine and related drugs might exert their action by interacting with DNA and stabilizing higher-order structures such as the triplex DNA.

Etiology, environmental relationships, epidemiology, and genetics of systemic lupus erythematosus.

The etiology of systemic lupus erythematosus (SLE) and the many lupuslike syndromes continues to challenge investigators. Focus is now on the role of heat-shock proteins, apoptosis, the possible role of diet factors, and in particular, the role of lipids. The role of various infections as either triggering mechanisms or in contributing to morbidity is receiving close attention. In particular, retroviruses are being carefully studied with all the molecular tools available. This area has real promise and carries with it the possibility of anti-infection treatments. Considerably more attention is being paid to the hormonal aspects of SLE and their modulation of the immune system. Environmental associations continue to intrigue investigators and clinicians, and both drugs and other environmental factors provide excellent investigational models. We continue to need good prevalence and incidence studies. Genetically, there is an increasing sophistication in the type of studies, and the ensuing data may well provide real insights into various subsets of SLE.