One might wonder why these self-reactive lymphocytes have not been deleted or inactivated by the usual mechanisms of self-tolerance. One reason is that lower-affinity self-reactive B and T cells are not removed efficiently and are present in the naive lymphocyte repertoire as ignorant lymphocytes (see Section 15-4). Pathogens may provide substantially higher local doses of the eliciting antigen in an immunogenic form, whereas normally it would be relatively unavailable to lymphocytes. Some examples of autoimmune syndromes thought to involve molecular mimicry are the rheumatic fever that sometimes follows streptococcal infection, and the reactive arthritis that can occur after enteric infection.
Once self-reactive lymphocytes have been activated by such a mechanism, their effector functions can destroy tissues. Autoimmunity of this type is sometimes transient, and remits when the inciting pathogen is eliminated. This is the case in the autoimmune hemolytic anemia that follows mycoplasma infection. The anemia ensues when antibodies against the pathogen cross-react with an antigen on red blood cells, leading to hemolysis (see Section 15-13). The autoantibodies disappear when the patient recovers from the infection. Sometimes, however, the autoimmunity persists well beyond the initial infection. This is true in some cases of rheumatic fever (Fig. 15.44), which occasionally follows a sore throat, scarlet fever, or local skin infections (impetigo)
Streptococcal cell wall stimulates antibody response Some antibodies cross-react with heart valve tissue, causing rheumatic fever plasma cell heart antibodies in blood bacteria
Fig. 15.43 Virus infection can break tolerance to a transgenic viral protein expressed in pancreatic β cells. Mice made transgenic for the lymphocytic choriomeningitis virus (LCMV) nucleoprotein under the control of the rat insulin promoter express the nucleoprotein in their pancreatic β cells but do not respond to this protein and therefore do not develop an autoimmune diabetes. However, if the transgenic mice are infected with LCMV, a potent antiviral cytotoxic T‑cell response is elicited, and this kills the β cells, leading to diabetes. It is thought that infectious agents can sometimes elicit T‑cell responses that cross‑react with self peptides (a process known as molecular mimicry) and that this could cause autoimmune disease in a similar way.
Fig. 15.44 Antibodies against streptococcal cell-wall antigens cross-react with antigens on heart tissue. The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies (yellow) cross‑react with the heart valves, whereas others (blue) do not. An epitope in the heart (orange) is structurally similar, but not identical, to a bacterial epitope (red).
caused by Streptococcus pyogenes. The similarity of epitopes on streptococcal antigens to self epitopes leads to antibody-mediated, and possibly T-cellmediated, damage to a variety of tissues, including heart valves and the kidney. Although the tissue injury is typically transient, especially with antibiotic treatment, it can become chronic. Similarly, Lyme disease, an infection with the spirochete Borrelia burgdorferi, can be followed by late-developing autoimmunity (Lyme arthritis). In this case, the mechanism is not entirely clear, but it is likely to involve cross-reactivity of pathogen and host components, leading to autoimmunity.
15-27 Drugs and toxins can cause autoimmune syndromes.