Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. The reasons for the high prevalence in women are unknown, but circumstantial evidence links autoimmune diseases with preceding infections. Animal models of autoimmune diseases have shown that infections can induce autoimmune disease. For example, coxsackievirus B3 (CB3) infection of susceptible mice results in inflammation of the heart (myocarditis) that resembles myocarditis in humans. The same disease can be induced by injecting mice with heart proteins mixed with adjuvant(s), which indicates that an active infection is not necessary for the development of autoimmune disease. We have found that CB3 triggers autoimmune disease in susceptible mice by stimulating elevated levels of proinflammatory cytokines from mast cells during the innate immune response. Sex hormones may further amplify this hyperimmune response to infection in susceptible persons, which leads to an increased prevalence of autoimmune diseases in women.

********** Autoimmune diseases are the third most common category of disease in the United States after cancer and heart disease; they affect approximately 5%-8% of the population or 14-22 million persons (1). Autoimmune diseases can affect virtually every site in the body, including the endocrine system, connective tissue, gastrointestinal tract, heart, skin, and kidneys. At least 15 diseases are known to be the direct result of an autoimmune response, while circumstantial evidence implicates >80 conditions with autoimmunity (2). In several instances, such as rheumatoid arthritis, multiple sclerosis, and myocarditis, the autoimmune disease can be induced experimentally by administering self-antigen in the presence of adjuvant (collagen, myelin basic protein, and cardiac myosin, respectively) (3). An important unifying theme in autoimmune diseases is a high prevalence in women (Figure 1) (4,5). Conservative estimates indicate that 6.7 million or 78.8% of the persons with autoimmune diseases are women (4).

Soon after autoimmune diseases were first recognized more than a century ago, researchers began to associate them with viral and bacterial infections. Autoimmune diseases tend to cluster in families and in individuals (a person with one autoimmune disease is more likely to get another), which indicates that common mechanisms are involved in disease susceptibility. Studies of the prevalence of autoimmune disease in monozygotic twins show that genetic as well as environmental factors (such as infection) are necessary for the disease to develop (6). Genetic factors are important in the development of autoimmune disease, since such diseases develop in certain strains of mice (e.g., systemic lupus erythematosus or lupus in MRL mice) without any apparent infectious environmental trigger. However, a body of circumstantial evidence links diabetes, multiple sclerosis, myocarditis, and many other autoimmune diseases with preceding infections (Table) (7,8). More often, many different microorganisms have been associated with a single autoimmune disease, which indicates that more than one infectious agent can induce the same disease through similar mechanisms (Table) (9). Since infections generally occur well before the onset of symptoms of autoimmune disease, clinically linking a specific causative agent to a particular autoimmune disease is difficult (Figure 2). This difficulty raises the question of whether autoimmune diseases really can be attributed to infections.

[FIGURE 2 OMITTED]

Are Autoimmune Diseases Caused by Infections?

To address the question of whether autoimmune diseases can be induced by infections, first autoimmunity needs to be defined. Autoimmune disease occurs when a response against a self-antigen(s) involving T cells, B cells, or autoantibodies induces injury systemically or against a particular organ. Understanding of autoimmune diseases is hindered by the fact that some level of autoimmunity, in the form of naturally occurring autoantibodies and self-reactive T and B cells, is present in all normal persons (6). Thus, on a proportional basis, developing autoimmune disease is the relatively uncommon consequence of a common autoimmune response. Although an autoimmune response occurs in most persons, clinically relevant autoimmune disease develops only in susceptible persons (Figure 2).

[FIGURE 2 OMITTED]

Given those circumstances, how can infections induce autoimmune disease? A mechanism often called on to explain the association of infection with autoimmune disease is “molecular mimicry,” that is, antigens (or more properly epitopes) of the microorganism closely resemble self-antigens. The induction of an immune response to the microbial antigen thus results in cross-reaction with self-antigens and induction of autoimmunity (10). Although epitope-specific cross-reactivity between microbes and self-tissues has been shown in some animal models (11,12), molecular mimicry has not been clearly demonstrated to occur in human diseases (13). Another possibility is that microorganisms expose self-antigens to the immune system by directly damaging tissues during an active infection. This mechanism has been referred to as the “bystander effect” (14,15). However, whether pathogens mimic self-antigens, release sequestered self-antigens, or both, is difficult to determine.