Autoimmune diseases. Autoimmune diseases are generally thought of as relatively rare, but they are among the leading causes of morbidity and mortality, at least in the Western World. Epidemiological studies showed that at least 5% of the general population may be affected. Thus, ten millions Americans may suffer from an autoimmune disease. Most autoimmune diseases are more frequent in young and middle-age women. Collectively, the incidence of autoimmune diseases is high, even though individually autoimmune diseases may be rare. While rheumatoid arthritis and type I insulin-dependent diabetes mellitus (IDDM) are frequent, other diseases, such as myasthenia, autoimmune hemolytic anemia or scleroderma, are relatively uncommon. Most autoimmune diseases, e.g. thyroiditis, lupus erythematosus and scleroderma, affect women far more often than men. Although most diseases occur at any age, some, such as IDDM, occur more often in childhood and others, such as myasthenia and rheumatoid arthritis, typically develop after 30-40 years of age.

Organ-specific and systemic autoimmune diseases. Autoimmune diseases are differentiated into organ-specific and systemic diseases. Organ-specific diseases are primarily characterized by a homogeneous autoantibody response against a strictly defined target as evidenced by autoantibodies against the acetylcholine receptor in the motor plate of muscles in myasthenia, the rhesus antigen of red blood cells in autoimmune hemolytic anemia, myelin in neuron sheaths in multiple sclerosis, dermal antigens in pemphigus, or β cells of pancreatic Langerhans islets in IDDM. In contrast to organ-specific diseases, systemic autoimmune diseases are characterized by widely heterogeneous autoantibody responses against ubiquitous targets including DNA, nucleoproteins, and histones. Lupus erythematosus, rheumatoid arthritis and scleroderma are typical examples of systemic autoimmune diseases.

Contributing factors. Even though autoimmunity is still a mystery, there is compelling evidence that multifactorial, including genetic, microbial and environmental influences contribute to the development of autoimmune diseases. In addition to family studies, twin studies showed that autoimmune diseases are more frequent in homozygotic than heterozygotic twins even though differences in disease concordance suggest other factors are also contributing. Molecular mimicry probably accounts for the impact of viral and bacterial infections in autoimmunity. When a foreign protein penetrates the body, the immune system mounts a specific antibody response and when it closely resembles a protein of the body, autoantibodies are formed that can be pathogenic. For instance, molecular mimicry is the causative mechanism of cardiac changes in rheumatic fever due to cross-reactivity between streptococcal and cardiac myosin. There is experimental and epidemiological evidence that chemicals including vinyl chloride, silica, trichloroethylene and hexachlorobenzene can induce or accelerate autoimmune diseases. The Spanish toxic oil syndrome caused by adulterated rapeseed oil and the eosinophilia-fasciitis syndrome induced by contaminated L-tryptophan are thought to have at least an autoimmune component. They affected thousands and killed hundreds of persons. Many isolated case reports of drug-induced autoimmune reactions can be found in the medical literature. However, the majority of well-documented case reports of autoimmune reactions induced by medicinal products incriminated a relatively small number of products. The clinical presentation is more or less variable with respect to the spontane-ous disease, and the underlying mechanisms are not known.

Nonclinical prediction of the potential for inducing autoimmunity. No standardized and validated animal models or assays are available to predict the potential of new molecular entities to exacerbate or accelerate autoimmune diseases, or induce autoimmune reactions in treated or exposed human beings. Animal models of experimental autoimmune diseases have long been used in the context of biomedical research. Some models proved useful to gain more insight in the pathophysiology of these diseases and to investigate the therapeutic potential of candidate new drugs. Their possible value for the detection of autoimmunogenic drugs and chemicals is not known. The detection of autoantibodies in conventional toxicity studies is usually negative even when known human autoimmunogens are being tested. So far, attempts to reproduce organ-specific autoimmune reactions induced by drugs in laboratory animals have been unsuccessful. The popliteal lymph node assay (PLNA) was first developed in the early 1980s and since then many studies have been devoted to this assay and refinements of the standard protocol. Although much remains to be done to delineate the optimal technique and the most adequate endpoints to be measured, the PLNA is so far the most promising nonclinical tool to predict systemic autoimmunity induced by drugs and chemicals.

MCQs