Ideally, the effector functions of the immune system would be targeted only to foreign pathogens and never to self tissues. In practice, because foreign and self proteins are chemically similar, strict discrimination between self and nonself is impossible. Yet the immune system maintains tolerance to self. This is accomplished by layers of regulation, all of which use surrogate markers to distinguish self from nonself to properly direct the immune response. When these mechanisms break down, autoimmune disease can result. Minor breaches of single regulatory barriers probably occur every day but are quelled by the effects of other regulatory layers; thus, tolerance operates at the level of the overall immune system. For disease to occur, multiple layers of tolerance have to be overcome and the effect needs to be chronic. These layers begin with central tolerance in the bone marrow and thymus, and include peripheral mechanisms such as anergy, cytokine deviation, and regulatory T cells. Sometimes immune responses do not occur simply because the antigens are not available, as in immune sequestration.
Perhaps because of selective pressure to mount effective immune responses to pathogens, the dampening of immune responses to promote self-tolerance is limited and prone to failure. Genetic predisposition has an important role in determining which individuals will develop an autoimmune disease. Environmental forces also have a significant role, because even identical twins are not always both affected by the same autoimmune disease. Influences from the environment include infections, toxins, and chance events.
When self-tolerance is broken and autoimmune disease ensues, the effector mechanisms are quite similar to those employed in responses to pathogens. Although the details vary from disease to disease, both antibody and T cells can be involved. Much has been learned about immune responses made to tissue antigens by examining the response to nonself transplanted organs and tissues; lessons learned in the study of graft rejection apply to autoimmunity and vice versa. Transplantation has brought on syndromes of rejection that are in many ways similar to autoimmune disease, but the targets are either major or minor histocompatibility antigens. T cells are the main effectors in graft rejection and graft-versus-host disease, although antibodies can also contribute.
For each of the undesirable responses discussed here, the question is how to control the response without adversely affecting protective immunity to infection. The answer may lie in a more complete understanding of the regulation of the immune response, especially the suppressive mechanisms important in tolerance. The deliberate control of the immune response is examined further in Chapter 16.
Questions.
15.1 True or False: Inflammatory bowel disease—Crohn's disease and ulcerative colitis—is a disease in which the adaptive immune system causes tissue damage in response to self antigens.
15.2 Matching: Match the following monogenic autoimmune diseases with the associated defective gene.
15.3 Multiple Choice: Which of the following statements is incorrect?
A. The autoantibodies induced by procainamide, a drug widely used to treat abnormal heart rhythms, are similar to the autoantibodies that characterize systemic lupus erythematosus.
B. Inflammatory mediators released during the course of an infection can lead to activation of self‑reactive lymphocytes and thus cause an autoimmune response.
C. Crohn’s disease and Blau syndrome are both strongly associated with loss‑of‑function mutations in NOD2, among other causes.
D. ATG16L1 and IRGM are genes that contribute to autophagy under normal circumstances, and defects in these have been linked to Crohn’s disease.
15.4 Multiple Choice: Which of the following options correctly describe a transplantation scenario?
A. A syngeneic skin graft from a young mouse is rejected by an adult mouse.
B. An allogeneic skin graft from a male mouse is not rejected by a female mouse.
C. A syngeneic skin graft from a male mouse is rejected by a female mouse.
D. A skin autograft is rejected 3 weeks after transplantation.