Perhaps the clearest evidence of external causative agents in human autoimmunity comes from the effects of certain drugs, which elicit autoimmune reactions in a small proportion of patients. Procainamide, a drug used to treat heart arrhythmias, is notable for inducing autoantibodies similar to those in SLE, although these are rarely pathogenic. Several drugs are associated with the development of autoimmune hemolytic anemia, in which autoantibodies against surface components of red blood cells attack and destroy these cells (see Section 15-13). Toxins in the environment can also cause autoimmunity. When heavy metals, such as gold or mercury, are administered to susceptible strains of mice, a predictable autoimmune syndrome, including the production of autoantibodies, ensues. The extent to which heavy metals promote autoimmunity in humans is debatable, but the animal models show that environmental factors such as toxins could have roles in certain syndromes.
The mechanisms by which drugs and toxins cause autoimmunity are uncertain. For some drugs it is thought that they react chemically with self proteins and form derivatives that the immune system recognizes as foreign. The immune response to these haptenated self proteins can lead to inflammation, complement deposition, destruction of tissue, and finally immune responses to the original self proteins.
15-28 Random events may be required for the initiation of autoimmunity.
Although scientists and physicians would like to attribute the onset of ‘spontaneous’ diseases to some specific cause, this may not always be possible. There might not be one virus or bacterium, or even any understandable pattern of events that precedes the onset of autoimmune disease. The chance encounter in the peripheral lymphoid tissues of a few autoreactive B and T cells that can interact with each other, at just the moment when an infection is providing pro-inflammatory signals, may be all that is needed. This could be a rare event, but in a susceptible individual such events could be more frequent and/or more difficult to control.
Thus, the onset or incidence of autoimmunity can seem to be random. Genetic predisposition represents, in part, an increased chance of occurrence of this random event. This view, in turn, could explain why many autoimmune diseases appear in early adulthood or later, after enough time has elapsed to permit low-frequency events to occur. It may also explain why, after certain kinds of aggressive therapies, the disease eventually recurs after a long interval of remission.
Summary.
The specific causes of most autoimmune diseases are not known. Genetic risk factors, including particular alleles of MHC class II molecules and polymorphisms or mutations of other genes, have been identified, but many individuals with genetic variants that predispose to a particular autoimmune disease do not get the disease. Epidemiological studies of genetically identical populations of animals have highlighted the role of environmental factors in the initiation of autoimmunity, but although environmental factors have a strong influence on disease, they are not well understood. Some toxins and drugs are known to cause autoimmunity, but their role in the common autoimmune diseases is unclear. Similarly, some autoimmune syndromes can follow viral or bacterial infections. Pathogens can promote autoimmunity by causing nonspecific inflammation and tissue damage, and can sometimes elicit responses to self proteins if they express molecules resembling self, a phenomenon known as molecular mimicry. More research is needed to define specific contributions of environmental factors to autoimmune diseases. It may prove that for most diseases no single environmental trigger that induces disease will be found, but rather a combination of triggers, or even stochastic, or chance, events, will have important roles.
Responses to alloantigens and transplant rejection.