For a disease to be classified as autoimmune, the tissue damage must be shown to be caused by the adaptive immune response to self antigens. Autoinflammatory reactions directed against the commensal microbiota of the intestines, such as those seen in inflammatory bowel diseases (IBDs), are a special case in that the target antigens are not strictly ‘self,’ but are derived from the ‘extended self’ of the intestinal microbiota. IBD, nevertheless, shares immunopathogenic features with other autoimmune diseases. The most convincing proof that the immune response is causal in autoimmunity is the transfer of disease by transferring the active component of the immune response to an appropriate recipient. Autoimmune diseases are mediated by autoreactive lymphocytes and their soluble products, pro-inflammatory cytokines, and autoantibodies responsible for inflammation and tissue injury. A few autoimmune diseases are caused by antibodies that bind to cell-surface receptors, causing either excess activity or inhibition of receptor function. In some diseases, transplacental passage of IgG autoantibodies can cause disease in the fetus and neonate. T cells can be involved directly in inflammation or cellular destruction, and they are typically required to initiate and sustain an autoantibody response. Similarly, B cells are important antigen-presenting cells for sustaining autoantigen-specific T-cell responses and causing epitope spreading. In spite of our knowledge of the mechanisms of tissue damage and the therapeutic approaches that this information has engendered, it remains to be determined how autoimmune responses are induced.
The genetic and environmental basis of autoimmunity.
Given the complex mechanisms that exist to prevent autoimmunity, it is not surprising that autoimmune diseases are the result of multiple factors, both genetic and environmental. We first discuss the genetic basis of autoimmunity, attempting to understand how genetic defects perturb various tolerance mechanisms. Genetic defects alone are not, however, always sufficient to cause autoimmune disease. Environmental factors also play a part, although these factors are poorly understood. As we shall see, genetic and environmental factors together can overcome tolerance mechanisms and result in disease.
15-18 Autoimmune diseases have a strong genetic component.
It is increasingly clear that some individuals are genetically predisposed to autoimmunity. Perhaps the clearest demonstration of this is found in inbred mouse strains that are prone to various types of autoimmune diseases. Mice of the NOD strain are very likely to get diabetes, with female mice becoming diabetic faster than males (Fig. 15.31). For reasons that are still unclear, many autoimmune diseases are more common in females than in males (see Fig. 15.37 below), with some disorders (SLE and MS) showing a high degree of sexual dimorphism. Autoimmune diseases in humans also have a genetic component. Some autoimmune diseases, including type 1 diabetes, run in families, suggesting a role for genetic susceptibility. Most convincingly, if one identical (monozygotic) twin is affected, the other twin is quite likely to be affected as well, whereas concordance of disease is much less in nonidentical (dizygotic) twins.
Environmental influences are also clearly involved. For example, although most members of a colony of NOD mice develop diabetes, they do so at different ages. Moreover, disease onset often differs from one animal colony to the next, even though all the mice are genetically identical. Thus, environmental variables must be, in part, determining the rate of diabetes development in genetically susceptible individuals. Particularly striking is the importance of the intestinal microbiota in the development of IBD in mice that
Fig. 15.30 The enzyme peptidyl arginine deiminase converts the arginine residues of tissue proteins to citrulline.